Many chronic diseases are now in pandemic proportions and increasingly a major cause of morbidity and mortality worldwide. Diabetes mellitus, especially type 2 diabetes, plays a starring role in this problem,1,2 with diabetic complications being a very important public health issue. A paradigmatic example of diabetic complications is diabetic nephropathy, the largest single cause of end-stage renal disease, and a medical catastrophe of worldwide dimensions.3
In recent years, our knowledge of the pathophysiological processes that lead to diabetic nephropathy has notably improved on a genetic and molecular level. Thus, the classic view of metabolic and hemodynamic alterations as the main causes of renal injury in diabetes has been transformed significantly, with clear evidence indicating that these traditional factors are only a partial aspect of a much more complex picture. One of the most important changes is related to the participation of immune-mediated inflammatory processes in the pathophysiology of diabetes mellitus and its complications.4,5
Although diabetic nephropathy is traditionally considered a nonimmune disease, accumulating evidence now indicates that immunologic and inflammatory mechanisms play a significant role in its development and progression.6,7 Therefore, diverse cells, including leukocytes, monocytes, and macrophages,8–10 as well as other molecules, such as chemokines (monocyte chemoattractant protein-1),11,12 adhesion molecules (intercellular adhesion molecule-1 (ICAM-1)),13,14 enzymes (cyclooxygenase-2, nitric oxide synthase),15–18 growth factors (vascular endothelial growth factor, growth hormone, IGF, TGF-β),19–22 and nuclear factors (NF-κB),23,24 are implicated in processes related to diabetic nephropathy. Less is known, however, about the role of inflammatory cytokines in diabetic renal injury.
The purpose of this review is to bring together current information concerning the role of inflammatory cytokines in the development and progression of diabetic nephropathy. Specific emphasis is placed on the mechanisms underlying the potential contribution of these molecules to renal injury. In addition, we examine data from genetic studies and discuss potential therapeutic strategies that target cytokines in the treatment of diabetic nephropathy.
INFLAMMATORY CYTOKINES IN DIABETES MELLITUS
Cytokines are a group of pharmacologically active, low molecular weight polypeptides that possess autocrine, paracrine, and juxtacrine effects with characteristic features (Table 1).25 These molecules cluster into several classes (i.e., interleukins, tumor necrosis factors, interferons, colony-stimulating factors, transforming growth factors and chemokines), which are relevant humoral mediators in a highly complex, coordinated network regulating inflammatory immune responses with the participation of different cytokine-associated signaling pathways (Figure 1). In addition, they exert important pleiotropic actions as cardinal effectors of injury.26 Cytokines are produced by a wide variety of cells in the body, playing an important role in many physiological responses that have a therapeutic potential.27
At the present time it is recognized that chronic low-grade inflammation and activation of the innate immune system are closely involved in the pathogenesis of diabetes mellitus.28–30 Increasing evidence suggests that individuals who progress to diabetes mellitus display features of inflammation years before the disease onset.31,32 Moreover, population-based studies suggest that inflammatory parameters, including inflammatory cytokines, are strong predictors of the development of diabetes.33–35 The main cytokines involved in the pathogenesis of diabetes are IL-1, TNF-α, and IL-6.36 In addition, studies in recent years have shown that inflammation, and more specifically inflammatory cytokines, are determinant in the development of microvascular diabetic complications, including neuropathy, retinopathy, and nephropathy.5,7,37–40
INFLAMMATORY CYTOKINES IN DIABETIC NEPHROPATHY
When considering the role of cytokines in pathophysiological processes underlying disease, it is necessary to take into account the fact that the activities of these molecules are very complex, as reflected by important features, including their pleiotropic actions—and thus a cytokine may trigger several different cellular responses depending on diverse factors, such as cell type, timing, and context. Cytokines share receptor subunits; act synergistically in many contexts, and, therefore, the association of two cytokines can markedly amplify their effects; cytokines stimulate the cells that produce them, or adjacent cells, or even can intervene through direct cell–cell interaction; and, finally, cytokines induce the expression of other cytokines and cytokine receptors (Table 1).41 In light of the data obtained from experimental and clinical studies, cytokines are often classified according their pro- or antiinflammatory activities.
In 1991, Hasegawa et al. reported that glomerular basement membranes from diabetic rats induced significantly greater amounts of TNF-α and IL-1 in cultured peritoneal macrophages than when these cells were incubated with basement membranes from nondiabetic rats.42 These new findings were the first to suggest that inflammatory cytokines may participate in the pathogenesis of diabetic nephropathy.42,43 Today, it is known that among inflammatory cytokines, IL-1, IL-6, IL-18 and TNF-α are relevant to the development of diabetic nephropathy, with diverse actions potentially involved in the development of complications (Table 2).
IL-1
In experimental models of diabetic nephropathy, renal expression of IL-1 increases,44,45 which is related to subsequent expression of chemotactic factors and adhesion molecules. IL-l enhances the synthesis of ICAM-1 and vascular cellular adhesion molecule-1 by glomerular endothelial cells, and induces de novo synthesis and expression of ICAM-1 by glomerular mesangial cells and renal tubular epithelia. In addition, this cytokine induce transient expression of E-selectin by endothelial cells.46,47
IL-1 is also involved in the development of abnormalities in intraglomerular hemodynamics related to prostaglandin synthesis by mesangial cells. Treatment of glomerular mesangial cells with recombinant human IL-1 induces prostaglandin E2 synthesis and the release of a phospholipase A2 activity.48 In addition, pretreatment of resting mesangial cells with this cytokine results in an amplified secretory prostaglandin E2 response to angiotensin II.49 Furthermore, in vitro studies demonstrate that IL-1 directly increases vascular endothelial cell permeability.50
Finally, IL-1 dysregulates the generation of hyaluronan by renal proximal tubular epithelial cells. Primary cultures of human proximal tubular epithelial cells stimulated with IL-1 leads to a significant increase in hyaluronan concentrations in the culture supernatant.51 Increased production of glomerular hyaluronan initiates glomerular hypercellularity in experimental model of diabetes.52
IL-6
In 1991, Sekizuka et al.53 reported that serum levels of IL-6 were significantly higher in patients with type 2 diabetic nephropathy than the levels observed in diabetic patients without nephropathy, which suggests that this cytokine may play a role in the pathogenesis of diabetic nephropathy. Early after that report, Suzuki et al.54 analyzed kidney biopsies in patients with diabetic nephropathy by high-resolution in situ hybridization. These authors observed that cells infiltrating the mesangium, interstitium, and tubules were positive for mRNA encoding IL-6. Furthermore, they found a relationship between the severity of diabetic glomerulopathy (mesangial expansion) and expression of IL-6 mRNA in glomerular cells (mesangial cells and podocytes), which indicated that IL-6 may affect the dynamics of extracellular matrix surrounding those cells. More recent studies in type 2 diabetic patients demonstrate a significant association between IL-6 and glomerular basement membrane thickening, a crucial lesion of diabetic nephropathy and a strong predictor of renal progression.55,56
Recent studies by our group also show a significant overexpression of IL-6 in the diabetic rat kidneys, with an increase in the levels of mRNA encoding IL-6 in the renal cortex being directly associated with an elevation in its urinary excretion.45 Importantly, wet kidney weight, an accurate index of renal hypertrophy and one of the earliest renal changes during diabetes,57 is increased in diabetic rats and associated with renal mRNA expression of IL-6 and urinary excretion of this cytokine.45 Moreover, a direct correlation was observed between urinary levels and renal expression of IL-6 with urinary albumin excretion.45 These results support previous findings on the development of renal injury mediated by IL-6, which has been related to alterations in endothelial permeability, induction of mesangial cell proliferation, and increased fibronectin expression.54,58–60
IL-18
IL-18 is a potent inflammatory cytokine that induces IFN-γ,61 which in turn induces functional chemokine receptor expression in human mesangial cells.62 In addition, IL-18 leads to production of other inflammatory cytokines (including IL-1 and TNF-α), upregulation of ICAM-1, as well as apoptosis of endothelial cells.63–65 IL-18 is constitutively expressed in renal tubular epithelia,66 and recent studies demonstrate that infiltrating monocytes, macrophages, and T cells, along with proximal tubular cells, are potential sources of this cytokine.67,68
Serum and urinary levels of IL-18 have been reported increased in patients with diabetic nephropathy, with an independent relationship between these parameters and urinary albumin excretion.69–71 In addition, urinary excretion of β-2 microglobulin, a marker of tubulointerstitial injury, is also positively associated with serum IL-18.70 Moreover, in a longitudinal study, serum and urinary concentrations of this cytokine were directly correlated with albumin excretion rate, as well as with changes in albuminuria during the follow-up period.70
TNF-α
TNF-α is a pleiotropic inflammatory cytokine that is mainly produced by monocytes, macrophages, and T cells. In addition, and similar to other inflammatory cytokines, the expression and synthesis of TNF-α is not limited to hematopoietic cells. Thus, intrinsic renal cells, including mesangial, glomerular, endothelial, dendritic, and renal tubular cells are able to produce this cytokine.72–76 Furthermore, recent studies show that TNF-α can be stored within cells in a proactive form, and the TNF-α–converting enzyme can rapidly increase levels of the active cytokine.77
Reported actions of TNF-α on renal cells include the activation of second messenger systems, transcription factors, synthesis of cytokines, growth factors, receptors, cell adhesion molecules, enzymes involved in the synthesis of other inflammatory mediators, acute phase proteins, and MHC proteins.78 This variety of biologic activities results in diverse effects with a significant role in the development of renal damage in diabetes.
TNF-α is cytotoxic to renal cells and able to induce direct renal injury.79 In addition, other relevant TNF-α effects have been reported, such as induction of apoptosis and necrotic cell death,80,81 alterations of intraglomerular blood flow and GFR as a result of the hemodynamic imbalance between vasoconstrictive and vasodilatory mediators,82 as well as alterations of endothelial permeability. TNF-α alters the distribution of adhesion receptors involved in cell–cell adhesion (i.e., vascular endothelial-cadherin-catenin complexes) and prevents the formation of F-actin stress fibers. This results in restructuring of the intercellular junction leading to loss of endothelial permeability.83 On the other hand, TNF-α directly induces reactive oxygen species (ROS) in diverse cells, including mesangial cells.84 Recent experimental studies using isolated rat glomeruli demonstrate this cytokine activates NADPH oxidase through protein kinase C/phosphatidylinositol-3 kinase and mitogen-activated protein kinase pathways.85 Therefore, TNF-α, independent of hemodynamic factors, prompts the local generation of ROS, resulting in alterations of the barrier function of the glomerular capillary wall and leading to enhanced albumin permeability.86
Experimental studies have consistently reported that mRNA encoding TNF-α and protein levels increase in glomerular and proximal tubule cells from diabetic rats.45,73,74,87–89 These investigations demonstrated a significant role of TNF-α in the development of renal hypertrophy and hyperfunction, two main alterations during the initial stage of diabetic nephropathy.88,89 TNF-α has a stimulatory effect on sodium-dependent solute uptake in cultured mouse proximal tubular cells,90 and in those studies diabetic rats exhibited enhanced urinary TNF-α excretion, sodium retention, and renal hypertrophy, which were prevented by administration of the anti–TNF-α agent TNFR:Fc, a soluble TNF-α receptor fusion protein.89,90 In addition to these data on renal hypertrophy and hyperfunction, mRNA levels and urinary TNF-α concentrations in the renal cortex directly and independently correlate with urinary albumin excretion.45,87 More importantly, studies that used the microdialysis technique demonstrate a significant increase in levels of TNF-α in renal interstitial fluid and urine (without evidence of cellular infiltrates in cortex or medulla), which precedes the development of albuminuria, suggesting a direct correlation between urine and renal interstitial fluid concentrations of TNF-α and urinary albumin excretion. Furthermore, shortly after the rise in albuminuria, urinary TNF-α concentration increases significantly, indicating a stimulatory effect for albuminuria on the production of renal TNF-α.91
Finally, important data about the potential implications of TNF-α in diabetic nephropathy also derive from clinical investigations. Studies by our group and others found that diabetic patients with nephropathy have higher serum and urinary concentrations of TNF-α than nondiabetic subjects or diabetic patients without renal involvement. These studies suggest a direct and independent association between the levels of this cytokine and clinical markers of glomerular and tubulointerstitial damage, with a significant rise in serum and urinary TNF-α as diabetic nephropathy progresses.69,92,93
GENETICS OF DIABETIC NEPHROPATHY AND INFLAMMATORY CYTOKINES
Only a modest number of individuals with diabetes will develop overt kidney disease (approximately one third to one half).94 The rates of development and progression of diabetic nephropathy reveal important interindividual variation, even when corrected for potential confounding influences. In addition, there is consistent familial aggregation of kidney disease (albuminuria, creatinine clearance, and end-stage renal disease) with renal histological changes.94–96 Today, there is mounting evidence for the role of genetic factors in diabetic nephropathy.94,97–99
Hypertension, poor glycemic control, and albuminuria, the main known risk factors for diabetic nephropathy, do not explain all of the interindividual variability for the rates of developing nephropathy. Many studies have examined the variability of candidate genes in diverse pathogenic pathways for this complication, including the renin-angiotensin, nitric oxide, and bradykinin systems. There has been no consistent or replicated evidence for the contribution of a set of candidate genes or surrogate markers for diabetic nephropathy risk.94 It is important to note that diverse factors, including small sample size, incomplete genetic dissection of the polymorphisms in the candidate gene, and extensive genetic and phenotypic heterogeneity, may contribute to explain the failure to identify risk genes.
Although >99% of human genes are shared across same the population, variations in sequence may have great predictive relevance. Single nucleotide polymorphisms (SNPs) are sequence variations that occur when a single nucleotide in the genome is altered. SNPs, which make up approximately 90% of all human genetic variation, occur in every 100 to 300 bases along the 3 billion–base human genome. Approximately 300,000 SNPs are thought to have functional significance because they occur in coding regions, splice junctions, and promoter regions. Some of these SNPs have a major impact on the susceptibility to disease or on human response to disease or to a drug.
Cytokine genes influence nuclear transcription and cell function with several allelic polymorphisms having demonstrable effects in human disease.100 Because inflammatory cytokines significantly modulate the pathogenesis of diabetic nephropathy, their genetic variability may affect the susceptibility to renal progression (Figure 2).101
Genes encoding IL-1 and IL-1 receptor antagonist (IL-1Ra), a naturally occurring antiinflammatory agent, map to the long arm of chromosome 2. The IL-1β gene has two base exchange (C→T) polymorphic sites at promoter −511 and exon 5+3953, whereas IL-1Ra gene (IL-1RN) contains a variable number of 86 bp tandem repeat sequence in intron 2. There is a significant association between carriage of IL-1β allele 2 (−511 C/T polymorphism) and IL-1RN allele 2 (2 copies of the repeat sequence) with diabetic nephropathy.102–104
Concerning IL-6, the gene encoding this cytokine is located at chromosome 7p21, whereas the gene encoding the IL-6 receptor (IL-6R) maps to chromosome 1q21, with diverse polymorphic regions at both genes. A C/G polymorphism at position −634 in the promoter region of the IL-6 gene is a potential genetic susceptibility factor for the progression of diabetic nephropathy. In that study, Kitamura et al.105 found a significant positive association of the IL-6 −634 G/G homozygote with macroalbuminuria in type 2 diabetic patients from Japan. More recently, Wang et al.106 identified a previously unreported amino acid change (V385I) that is associated with type 2 diabetes and diabetic nephropathy. This variant has been not previously seen in whites, Pima Indians, or Koreans.106–108
Finally, the TNF-α gene located on chromosome 6p is highly polymorphic. Most of the variants are SNPs, but there are also various dinucleotide repeats (GA). Polymorphism of the TNF-α gene at the −308 position is significantly related to an increased risk of kidney failure in patients with type 2 diabetes.101
The rationale for studying cytokine gene polymorphisms in diabetic nephropathy is based on diverse aspects: It gives us a better understanding of the origin and pathogenesis of this complication; it improves our knowledge of interindividual variation in the development and progression of diabetic nephropathy; in a clinical setting, it may permit the identification those patients at high risk for susceptibility, severity, or poor clinical outcome; it helps us understand the interindividual responses to therapeutic strategies; and, it may identify new targets for drug development and, therefore, novel interventions to prevent or delay diabetic nephropathy. However, the cytokine network is highly complex, with multiple interactive signals of gene activation and suppression. Thus, the association of individual polymorphisms in cytokine genes may be noninformative, whereas specific combinations of cytokine genotypes may be much more relevant.109
THERAPEUTIC IMPLICATIONS OF INFLAMMATORY CYTOKINES
Despite the benefits derived from the current therapeutics for diabetic nephropathy, mainly strict control of glucose and BP as well as blockade of the renin-angiotensin system, these strategies still provide imperfect protection against renal progression.110 This imperfection points to the need for newer therapeutic agents that have potential to affect primary mechanisms contributing to the pathogenesis of diabetic nephropathy.111 Nephropathy occurs as a result of an interaction between metabolic and hemodynamic factors, which activate diverse pathways that lead to renal damage. Growing evidence highlights the importance of inflammatory mechanisms in the development and progression of diabetic nephropathy. Therefore, investigation into antiinflammatory strategies may offer new approaches of further effect. In fact, blockade of the renin-angiotensin-aldosterone system, the current principal strategy in the treatment of diabetic nephropathy, provides pleiotropic, antiinflammatory actions potentially relevant in the therapeutic approach to this complication.112–115 Other new therapies against inflammatory molecules and pathways germane to diabetic nephropathy therapies may be on the horizon.116,117
In a recent study, Utimura et al.118 demonstrated that mycophenolate mofetil, an immunosuppressive antiinflammatory drug, largely prevented the development of albuminuria and glomerular injury in experimental diabetic nephropathy. The beneficial effect of mycophenolate mofetil was not related to any effect on glomerular hemodynamics or improvement of metabolic control, and, therefore, the authors conclude that benefit probably resulted directly from its immunosuppressive and antiinflammatory properties.
Inhibition of inflammatory cytokines as therapy for diabetic nephropathy, also derive from studies on the modulation of TNF-α. Moriwaki et al.119 recently reported the effect of the chimeric anti–TNF-α antibody, infliximab, on diabetic nephropathy. In that study, diabetic rats treated with infliximab showed a reduction of albuminuria as well as decreased urinary excretion of TNF-α. Previous studies with pentoxifylline (PTF) also suggest that inhibition of TNF-α may be therapeutic in the treatment of diabetic nephropathy.120,121
PTF is a methylxanthine-derived phosphodiesterase inhibitor that possesses significant antiinflammatory properties. The drug inhibits transcription of the TNF-α gene and reduces levels of mRNA encoding TNF-α.120,121 In addition, PTF shows a significant effect in modulating IFN-γ, IL-1β, and IL-6.122–124 In different models of renal disease where TNF-α plays a central role, such as lupus nephritis and crescentic glomerulonephritis, PTF prevents or attenuates renal injury.125,126 Regarding diabetic nephropathy, recent experimental studies show that administration of PTF prevents an increase in renal expression, synthesis, and excretion of TNF-α during diabetes, which was directly and significantly associated with a reduction in renal sodium retention, renal hypertrophy, and urinary albumin excretion.45,89 In addition to these experimental results, clinical trials have demonstrated that PTF significantly reduces clinical markers of glomerular and tubulointerstitial injury in diabetic subjects.127–130 Electrophoretic analysis of urinary protein after PTF administration show this drug is able to reduce the urinary excretion of both high molecular (Ig G, ceruloplasmin, transferring, and albumin) and low molecular weight proteins (α1-antitrypsin, α1-acid glycoprotein, collagenase inhibitor, α1-microglobulin, trypsin inhibitor, lysozyme, and β2-microglobulin).130
This antiproteinuric effect of PTF has been recently analyzed in comparison with angiotensin-converting enzyme inhibition in type 2 diabetic patients, and the results of these studies indicate that PTF is equivalent in efficacy and safety to captopril.131,132 Finally, addition of PTF to blockers of the renin-angiotensin system, both angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers, provides an additive and significant reduction of urinary albumin excretion.133,134 This beneficial effect on albuminuria is independent from BP and glycemic control. However, it is significant and directly related to a reduction in urinary excretion of TNF-α.134
CONCLUSIONS
Providing diabetic patients protection from the development and progression of renal injury remains a challenge for nephrologists. Because of the pathogenic complexity of diabetic nephropathy, new therapeutic interventions targeting primary mechanisms contributing to renal damage are critical for the future treatment of this complication. Inflammatory cytokines exert an important diversity of actions implicated in diabetic nephropathy, from development to the initial stages of diabetes to progression and to late stages of renal failure. The recognition of these molecules as significant pathogenic factors in this complication will provide new therapeutic targets. The development of new techniques for examining changes in the expression of pathogenic genes involved in inflammatory pathways as well as better ability to assess interindividual genetic variability will undoubtedly uncover important information regarding the pathogenic mechanisms of diabetic nephropathy. Likewise, this effort will also facilitate the identification of high-risk patients and perhaps lead to novel and unexpected therapies. From a therapeutic perspective, limited experience is available regarding the inhibition of inflammatory cytokines in diabetic nephropathy. To date, studies have focused on the effect of PTF on urinary albumin excretion, showing a beneficial antiproteinuric effect of this drug. However, further clinical trials are necessary to examine the potential renoprotective efficacy of PTF and other antiinflammatory cytokines in establishing remission or even regression of diabetic nephropathy.
DISCLOSURES
None.
;)
Figure 1: Intracellular cytokine-associated signaling pathways. JAK, Janus kinase; Tyk, Tirosine kinase; STAT, signal transducer and activator of transcription; MYD88, myeloid differentiation factor-88; IRAK, IL receptor–associated kinase; TRAF, TNF receptor–associated factor; TAK, TGF-β–associated kinase; NIK, NF-κB–inducing kinase; IKK, inhibitor of NF-κB kinase; TRADD, TNF receptor–associated death domain; RIP, receptor interacting protein; MEKK, mitogen-activated protein kinase/Erk kinase kinase; JNK, c-Jun N-terminal kinase.
Figure 2: Schematic representation of inflammatory cytokine gene polymorphims implicated in diabetic nephropathy. Green boxes represent exons. Chromosome location of the gene is indicated in parenthesis. IL-1RN, IL-1 receptor antagonist gene; VNTR, variable number of tandem repeat.
Table 1: Characteristic features of cytokines
Table 2: Potential role of inflammatory cytokines in diabetic nephropathy
The authors have been supported by Fundacio[Combining Acute Accent]n Canaria de Investigacio[Combining Acute Accent]n y Salud (FUNCIS), Sociedad Espan[Combining Tilde]ola de Nefrologi[Combining Acute Accent]a (SEN) and Asociacio[Combining Acute Accent]n Cienti[Combining Acute Accent]fica para la Investigacio[Combining Acute Accent]n Nefrolo[Combining Acute Accent]gica (ACINEF).
Published online ahead of print. Publication date available at www.jasn.org.
REFERENCES
1. Beaglehole R, Yach D: Globalisation and the prevention and control of non-communicable disease: The neglected chronic disease of adults. Lancet 362 : 1763 –1764, 2003
2. Yach D, Hawkes C, Gould C, Hofman K: The global burden of chronic diseases: Overcoming impediments to prevention and control. JAMA 291 : 2616 –2622, 2004
3. Ritz E, Rychlik I, Locatelli F, Halimi S: End-stage renal failure in type 2 diabetes: A medical catastrophe of worldwide dimensions. Am J Kidney Dis 34 : 795 –808, 1999
4. Williams MD, Nadler JL: Inflammatory mechanisms of diabetic complications. Curr Diab Rep 7 : 242 –248, 2007
5. Navarro JF, Mora C: Role of inflammation in diabetic complications. Nephrol Dial Transplant 20 : 2601 –2604, 2005
6. Tuttle KR: Linking metabolism and immunology: Diabetic nephropathy is an inflammatory disease. J Am Soc Nephrol 16 : 1537 –1538, 2005
7. Mora C, Navarro JF: Inflammation and diabetic nephropathy. Curr Diabetes Rep 6 : 463 –468, 2006
8. Galkina E, Ley K: Leukocyte recruitment and vascular injury in diabetic nephropathy. J Am Soc Nephrol 17 : 368 –377, 2006
9. Shikata K, Makino H: Role of macrophages in the pathogenesis of diabetic nephropathy. Contrib Nephrol 1 : 46 –54, 2001
10. Chow F, Ozols E, Nikolic-Paterson DJ, Atkins R, Tesch G: Macrophages in mouse type 2 diabetic nephropathy: Correlation with diabetic state and progressive renal injury. Kidney Int 65 : 116 –128, 2004
11. Ihm CG: Monocyte chemotactic peptide-1 in diabetic nephropathy. Kidney Int Suppl 60 : S20 –S22, 1997
12. Chow F, Nikolic-Paterson DJ, Ozols E, Atkins R, Rollin BJ, Tesch G: Monocyte chemoattractant protein-1 promotes the development of diabetic renal injury in streptozotocin-treated mice. Kidney Int 69 : 73 –80, 2006
13. Okada S, Shikata K, Matsuda M, Ogawa D, Usui H, Kido Y, Nagase R, Wada J, Shikata Y, Makino H: Intercellular adhesion molecule-1 deficient mice are resistant against renal injury after induction of diabetes. Diabetes 52 : 2586 –2593, 2003
14. Chow FY, Nikolic-Paterson DJ, Ozols E, Atkins R, Tesch G: Intercellular adhesion molecule-1 deficiency is protective against nephropathy in type 2 diabetic db/db mice. J Am Soc Nephrol 16 : 1711 –1722, 2005
15. Cheng H, Wang C, Moeckel G, Zhang M, Mckanna J, Harris R: Cyclooxygenase-2 inhibitor blocks expression of mediators of renal injury in a model of diabetes and hypertension. Kidney Int 62 : 929 –939, 2002
16. Komers R, Lindsley J, Oyama TT, Anderson S: Cyclo-oxygenase-2 inhibition attenuates the progression of nephropathy in uninephrectomized diabetic rats. Clin Exp Pharmacol Physiol 34 : 36 –41, 2007
17. Levine DZ: Hyperfiltration, nitric oxide, and diabetic nephropathy. Curr Hypertens Rep 8 : 153 –157, 2006
18. Quaggin SE, Coffman TM: Toward a mouse model of diabetic nephropathy: Is endothelial nitric oxide synthase the missing link? J Am Soc Nephrol 18 : 364 –366, 2007
19. Nakagawa T: Uncoupling of the VEGF-endothelial nitric oxide axis in diabetic nephropathy: an explanation for the paradoxical effects of VEGF in renal disease. Am J Physiol Renal Physiol 292 : F1665 –F1672, 2007
20. Flyvbjerg A, Khatir DS, Jensen LJ, Dagnaes-Hansen F, Gronbaek H, Rasch R: The involvement of growth hormone (GH), insulin-like growth factors (IGFs) and vascular endothelial growth factor (VEGF) in diabetic kidney disease. Curr Pharm Des 10 : 3385 –3394, 2004
21. Pantsulaia T: Role of TGF-beta in pathogenesis of diabetic nephropathy. Georgian Med News 131 : 13 –18, 2006
22. Schena FP, Gesualdo L: Pathogenetic mechanisms of diabetic nephropathy. J Am Soc Nephrol 16 [Suppl 1]: S30 –S33, 2005
23. Mezzano S, Aros C, Droguet A, Burgos ME, Ardiles L, Flores C, Schneider H, Ruiz-Ortega M, Egido J: NF-kappaB activation and overexpression of regulated genes in human diabetic nephropathy. Nephrol Dial Transplant 19 : 2505 –2512, 2004
24. Schmid H, Boucherot A, Yasuda Y, Henger A, Brunner B, Eichinger F, Nitsche A, Kiss E, Bleich M, Grone HJ, Nelson PJ, Schlondorff D, Cohen CD, Kretzler M; European cDNA Bank (ERCB) Consortium: Modular activation of nuclear factor-kappaB transcriptional programs in human diabetic nephropathy. Diabetes 2006 55 : 2993 –3003, 2006
25. Coppack SW: Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc 60 : 349 –356, 2001
26. AldhahiW, Hamdy O: Adipokines, inflammation, and the endothelium in diabetes. Curr Diab Rep 3 : 293 –298, 2003
27. Balwilk FR, Burke F: The cytokine network. Immunol Today 10 : 299 –304, 1989
28. Pickup J, Crook M: Is type II diabetes mellitus a disease of the innate immune system? Diabetologia 41 : 1241 –1248, 1998
29. Crook M: Type 2 diabetes mellitus: A disease of the innate immune system? An update. Diabet Med 21 : 203 –207, 2004
30. Pickup JC: Inflammation and activated innate immune system in the pathogenesis of type 2 diabetes. Diabetes Care 27 : 813 –823, 2004
31. Bloomgarden ZT: Inflammation and insulin resistance. Diabetes Care 26 : 1922 –1926, 2003
32. Dandona P, Aljada A, Bandyopadhyay A: Inflammation: The link between insulin resistance, obesity and diabetes. Trends Immunol 25 : 4 –7, 2004
33. Schmidt MI, Duncan BB, Sharrett AR, Lindberg G, Savage P, Offenbacher S, Azambuja M, Tracy R, Heiss G: Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities Study): A cohort study. Lancet 353 : 1649 –1652, 1999
34. Pradhan AD, Manson JE, Rifai N, Buring J, Ridker P: C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286 : 327 –334, 2001
35. Spranger J, Kroke A, Mo[Combining Diaeresis]hlig M, Hoffmann K, Bergmann M, Ristow M, Boeing H, Pfeiffer A: Inflammatory cytokines and the risk to develop type 2 diabetes: Results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC) Potsdam study. Diabetes 52 : 812 –817, 2003
36. Alexandraki K, Piperi C, Kalofoutis C, Singh J, Alaveras A, Kalofoutis A: The inflammatory process in type 2 diabetes. The role of cytokines. Ann N Y Acad Sci 1084 : 89 –117, 2006
37. Skundric DS, Lisak RP: Role of neuropoietic cytokines in development and progression of diabetic polyneuropathy: From glucose metabolism to neurodegeneration. Exp Diabesity Res 4 : 303 –312, 2003
38. Jeffcoate WJ, Game F, Cavanagh PR: The role of proinflammatory cytokines in the cause of neuropathic osteoarthropathy (acute Charcot foot) in diabetes. Lancet 336 : 2058 –2061, 2005
39. Mocan MC, Kadayifcilar S, Eldem B: Elevated intravitreal interleukin-6 levels in patients with proliferative diabetic retinopathy. Can J Ophthalmol 41 : 747 –752, 2006
40. Determinations of vitreous interleukin-1 (IL-1) and tumor necrosis factor (TNF) levels in proliferative diabetic retinopathy. Eye 20 : 1366 –1369, 2006
41. Vilcek J: The cytokines: An overview. In: The Cytokine Handbook, 4th Ed., edited by Thomson AW, Lotze MT, Academic Press, London, 2003 , pp 3 –18
42. Hasegawa G, Nakano K, Sawada M, Uno K, Shibayama Y, Ienaga K, Kondo M: Possible role of tumor necrosis factor and interleukin-1 in the development of diabetic nephropathy. Kidney Int 40 : 1007 –1012, 1991
43. Hasegawa G, Nakano K, Kondo M: Role of TNF and IL-1 in the development of diabetic nephropathy. Nefrologia 15 : 1 –4, 1995
44. Sassy-Prigent C, Heudes D, Jouquey S, Auberval D, Belair MF, Michel O, Hamon G, Bariety J, Bruneval P: Early glomerular macrophage recruitment in streptozotocin-induced diabetic rats. Diabetes 49 : 466 –475, 2000
45. Navarro JF, Milena FJ, Mora C, Leon C, Garci[Combining Acute Accent]a J: Renal pro-inflammatory cytokine gene expression in diabetic nephropathy: Effect of angiotensin-converting enzyme inhibition and pentoxifylline administration. Am J Nephrol 26 : 562 –570, 2006
46. Brady HR: Leukocyte adhesion molecules and kidney diseases. Kidney Int 45 : 1285 –1300, 1994
47. Park CW, Kim JH, Lee JH, Kim YS, Ahn HJ, Shin YS, Kim SY, Choi EJ, Chang YS, Bang BK: High glucose-induced intercellular adhesion molecule-1 (ICAM-1) expression through an osmotic effect in rat mesangial cells is PKC-NFkapa B-dependent. Diabetologia 43 : 1544 –1553, 2000
48. Pfeilschifter J, Pignat W, Vosbeck K, Ma[Combining Diaeresis]rki F: Interleukin 1 and tumor necrosis factor synergistically stimulate prostaglandin synthesis and phospholipase A2 release from rat renal mesangial cells. Biochem Biophys Res Commun 159 : 385 –394, 1989
49. Pfeilschifter J, Muhl H: Interleukin-1 and tumor necrosis factor potentiate angiotensin II- and calcium ionophore-stimulated prostaglandin E2 synthesis in rat renal mesangial cells. Biochem Biophys Res Commun 169 : 585 –595, 1990
50. Royall JA, Berkow RL, Beckman JS, Cunningham MK, Matalon S, Freeman BA: Tumor necrosis factor and interleukin 1 increase vascular endothelial permeability. Am J Physiol 257 : L339 –L410, 1989
51. Jones S, Jones S, Phillips AO: Regulation of renal proximal tubular epithelial cell hyaluronan generation: implications for diabetic nephropathy. Kidney Int 59 : 1739 –1749, 2001
52. Mahadevan P, Larkins RG, Fraser JR, Fosang AJ, Dunlop ME: Increased hyaluronan production in the glomeruli from diabetic rats: Link between glucose induced prostaglandin production and reduced sulphated proteoglycans. Diabetologia 38 : 298 –305, 1995
53. Sekizuka K, Tomino Y, Sei C, Kurusu A, Tashiro K, Yamaguchi Y, Kodera S, Hishiki T, Shirato I, Koide H: Detection of serum IL-6 in patients with diabetic nephropathy. Nephron 68 : 284 –285, 1994
54. Suzuki D, Miyazaki M, Naka R, Koji T, Yagame M, Endoh M, Sakai H: In situ hybridization of interleukin 6 in diabetic nephropathy. Diabetes 44 : 1233 –1238, 1995
55. Nosadini R, Velussi M, Brocco E, Bruseghin M, Abaterusso C, Saller A, Dalla Vestra M, Carraro A, Bortoloso E, Sambataro M, Barzon I, Frigato F, Muollo B, Chiesura-Corona M, Pacini G, Baggio B, Piarulli F, Sfriso A, Fioretto P: Course of renal function in type 2 diabetic patients with abnormalities of albumin excretion rate. Diabetes 49 : 476 –484, 2000
56. Dalla Vestra M, Mussap M, Gallina P, Brueghin M, Cernigoi AM, Saller A, Plebani M, Fioretto P: Acute-phase markers of inflammation and glomerular structure in patients with type 2 diabetes. J Am Soc Nephrol 16 [Suppl 1]: S78 –S82, 2005
57. Thomson SC, Deng A, Bao D, Satriano J, Blantz RC, Vallon V: Ornithine decarboxylase, kidney size, and the tubular hypothesis of glomerular hyperfiltration in experimental diabetes. J Clin Invest 107 : 217 –224, 2001
58. Hirano T, Akira S, Taga T, Kishimoto T: Biological and clinical aspects of interleukin 6. Immunol Today 11 : 443 –449, 1990
59. Ruef C, Budde K, Lacy J, Northemann W, Baumann M, Sterzel RB, Coleman DL: Interleukin 6 is an autocrine growth factor for mesangial cells. Kidney Int 38 : 249 –257, 1990
60. Coleman DL, Ruef C: Interleukin-6: an autocrine regulator of mesangial cell growth. Kidney Int 41 : 604 –606, 1992
61. Okamura H, Tsutsui H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, Torigoe K, Okura T, Nukada Y, Hattori K, Akita K, Namba M, Tanabe F, Konishi K, Fukuda S, Kurimoto M: Cloning a new cytokine that induces IFN-production by T cells. Nature 378 : 88 –91, 1995
62. Schwartz M, Wahl M, Resch K, Radeke HH: IFNgamma induces functional chemokine receptor expression in human mesangial cells. Clin Exp Immunol 128 : 285 –294, 2002
63. Dai SM, Matsuno H, Nakamura H, Nishioka K, Yudoh K: Interleukin-18 enhances monocyte tumor necrosis factor alpha and interleukin-1 beta production induced by directo contact with T lymphocytes: implications in rheumatoid arthritis. Arthritis Rheum 50 : 432 –443, 2004
64. Marino E, Cardier JE: Differential effects of IL-18 on endothelial cell apoptosis mediated by TNF-alpha and Fas (CD59). Cytokine 22 : 142 –148, 2003
65. Stuyt RJ, Netea MG, Geijtenbeek TB, Kullberg BJ, Dinarello CA, van der Meer JW: Selective regulation of intercellular adhesion molecule-1 expression by interleukin-18 and interleukin-12 on human monocytes. Immunology 110 : 329 –334, 2003
66. Fantuzzi G, Reed DA, Dinarello CA: IL-12-induced IFN-gamma is dependent of caspase-1 processing of the IL-18 precursor. J Clin Invest 104 : 761 –767, 1999
67. Melnikov VY, Ecder T, Fantuzzi G, Siegmund B, Lucia MS, Dinarello CA, Schrier RW, Edelstein CL: Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. J Clin Invest 107 : 1145 –1152, 2001
68. Melnikov VY, Faubel S, Siegmund B, Lucia MS, Ljubanovic D, Edelstein CL: Neutrophil-independent mechanisms of caspase-1 and IL-18 mediated ischemic acute tubular necrosis in mice. J Clin Invest 110 : 1083 –1091, 2002
69. Moriwaki Y, Yamamoto T, Shibutani Y, Aoki E, Tsutsumi Z, Takahashi S, Okamura H, Koga M, Fukuchi M, Hada T: Elevated levels of interleukin-18 and tumor necrosis factor-alpha in serum of patients with type 2 diabetes mellitus: relationship with diabetic nephropathy. Metabolism 52 : 605 –608, 2003
70. Nakamura A, Shikata K, Hiramatsu M, Nakatou T, Kitamura T, Wada J, Itoshima T, Makino H: Serum interleukin-18 levels are associated with nephropathy and atherosclerosis in Japanese patients with type 2 diabetes. Diabetes Care 28 : 2890 –2895, 2005
71. Wong CK, Ho AWY, Tong PCY, Yeung CY, Kong APS, Lun SWM, Chan JCN, Lam CWK: Aberrant activation profile of cytokines and mitogen-activated protein kinases in type 2 diabetic patients with nephropathy.
72. Jevnikar AM, Brennan DC, Singer GG, Heng JE, Maslinski W, Wuthrich RP, Glimcher LH, Kelley VE: Stimulated kidney tubular epithelial cells express membrane associated and secreted TNF alpha. Kidney Int 40 : 203 –211, 1991
73. Nakamura T, Fukui M, Ebihara I, Osada S, Nagaoka I, Tomino Y, Koide H: mRNA expression of growth factors in glomeruli from diabetic rats. Diabetes 42 : 450 –456, 1993
74. Sugimoto H, Shikata K, Wada J, Horiuchi S, Makino H: Advanced glycation end products-cytokine-nitric oxide sequence pathway in the development of diabetic nephropathy: Aminoguanidine ameliorates the overexpression of tumour necrosis factor-alpha and inducible oxide synthase in diabetic rat glomerli. Diabetologia 42 : 878 –886, 1999
75. Dong X, Swaminathan S, Bachman LA, Croatt AJ, Nath KA, Griffin MD: Resident dendritic cells are the predominant TNF-secreting cell in early renal ischemia-reperfusion injury. Kidney Int 71 : 619 –628, 2007
76. Zhang B, Ramesh G, Norbury CC, Reeves WB: Cisplatin-induced nephrotoxicity is mediated by tumor necrosis factor-alpha produced by renal parenchymal cells. Kidney Int 72 : 37 –44, 2007
77. Wang X, Feuerstein GZ, Xu L, Wang H, Schumacher WA, Ogletree ML, Taub R, Duan JJ, Decicco CP, Liu RQ: Inhibition of tumor necrosis factor-alpha-converting enzyme by a selective antagonist protects brain from focal ischemic injury in rats. Mol Pharamcol 65 : 890 –896, 2004
78. Ortiz A, Bustos C, Alonso J, Alcazar R, Lopez-Armada MJ, Plaza JJ, Gonza[Combining Acute Accent]lez E, Egido J: Involvement of tumor necrosis factor-alpha in the pathogenesis of experimental, and human glomerulonephritis. Adv Nephrol Necker Hosp 24 : 53 –77, 1995
79. Bertani T, Abbate M, Zoja C, Coma D, Perico N, Ghezzi P, Remuzzi G: Tumor necrosis factor induces glomerular damage in rabbit. Am J Pathol 134 : 419 –430, 1989
80. Laster SM, Wood JG, Gooding LR: Tumor necrosis factor can induce both apoptotic and necrotic forms of cell lysis. J Immunol 141 : 2629 –2634, 1988
81. Boyle JJ, Weissberg PL, Bennett MR: Tumor necrosis factor-alpha promotes macrophage-induced vascular smooth muscle cell apoptosis by direct and autocrine mechanisms. Arterioscler Thromb Vasc Biol 23 : 1553 –1558, 2003
82. Baud L, Perez J, Friedlander G, Ardaillou R: Tumor necrosis factor stimulates prostaglandin production and cyclic AMP levels in rat cultured mesangial cells. FEBS Lett 239 : 50 –54, 1998
83. Wojciak-Stothard B, Entwistle A, Garg R, and Ridley AJ: Regulation of TNF-alpha-induced reorganization of the actin cytoskeleton and cell-cell junctions by Rho, Rac, and Cdc42 in human endothelial cells. J Cell Physiol 176 : 150 –165, 1998
84. Raedke HH, Meier B, Topley N, Fluge J, Habermehl GG, Resch K: Interleukin 1-alpha and tumor necrosis factor-alpha induce oxygen radical production in mesangial cells. Kidney Int 37 : 767 –775, 1990
85. Koike N, Takamura T, Kaneko S: Induction of reactive oxygen species from isolated rat glomeruli by protein kinase C activation and TNF-α stimulation, and effects of a phosphodiesterase inhibitor. Life Sci 80 : 1721 –1728, 2007
86. MaCarthy E, Sharma R, Sharma M, Li JZ, Ge XL, Dileepan KN, Savin VJ: TNF-alpha increases albumin permeability of isolated rat glomeruli through the generation of superoxide. J Am Soc Nephrol 9 : 433 –438, 1998
87. Navarro J, Milena F, Mora C, Leon C, Claverie F, Flores C, Garcia J: Tumor necrosis factor-alpha gene expression in diabetic nephropathy: Relatioship with urinary albumin excretion and effect of angiotensin-converting enzyme inhibition. Kidney Int Suppl 99 : S98 –S102, 2005
88. Dipetrillo K, Coutermarsh B, Gesek FA: Urinary tumor necrosis factor contributes to sodium retention and renal hypertrophy during diabetes. Am J Physiol Renal Physiol 284 : F113 –F121, 2003
89. DiPetrillo K, Gesek FA: Pentoxifylline ameliorates renal tumor necrosis factor expression, sodium retention, and renal hypertrophy in diabetic rats. Am J Nephrol 24 : 352 –359, 2004
90. Schreiner GF, Kohan DE: Regulation of renal transport processes and hemodynamics by macrophages and lymphocytes. Am J Physiol 258 : F761 –F767, 1990
91. Kalantarinia K, Awas AS, Siragy HM: Urinary and renal interstitial concentrations of TNF-alpha increase prior to the rise in albuminuria in diabetic rats. Kidney Int 64 : 1208 –1213, 2003
92. Navarro JF, Mora C, Maci[Combining Acute Accent]a M, Garci[Combining Acute Accent]a J: Inflammatory parameters are independently associated with urinary albumin excretion in type 2 diabetes mellitus. Am J Kidney Dis 42 : 53 –61, 2003
93. Navarro JF, Mora C, Muros M, Garci[Combining Acute Accent]a J: Urinary tumor necrosis factor-alpha is independently associated with clinical markers of renal injury in diabetic patients. Nephrol Dial Transplant 21 : 3428 –3434, 2006
94. Rich SS: Genetics of diabetes and its complications. J Am Soc Nephrol 17 : 353 –360, 2006
95. Fioretto P, Steffes MW, Barboso J, Rich SS, Miller ME, Mauer M: Is diabetic nephropathy inherited? Studies of glomerular structure in type 1 diabetic sibling pairs. Diabetes 48 : 865 –869, 1999
96. Langefeld CD, Beck SR, Bowden DW, Rich SS, Wagenknecht LE, Freedman BI: Heritability of GFR and albuminuria in Caucasians with type 2 diabetes mellitus. Am J Kidney Dis 5 : 796 –800, 2004
97. Seaquist ER, Goetz FC, Rich SS, Barbosa J: Familial clustering of diabetic kidney disease: Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 320 : 1161 –1165, 1989
98. Bowden DW: Genetics of diabetes complications. Curr DiabRep 2 : 191 –200, 2002
99. Placha G, Canani LH, Warram JH, Krolewski AS: Evidence for different susceptibility genes for proteinuria and ESRD in type 2 diabetes. Adv Chronic Kidney Dis 12 : 155 –169, 2005
100. Hollegaard MV, Bidwell JL: Cytokine gene polymorphism in human disease: on-line databases, Supplement 3. Genes Immun 7 : 269 –276, 2006
101. Lee SH, Lee TW, Ihm CG, Kim MJ, Woo JT, Chung JH: Genetics of diabetic nephropathy in type 2 DM: Candidate gene analysis for the pathogenic role of inflammation. Nephrology (Carlton) 10 [Suppl]: S32 –S36, 2005
102. Blakemore AI, Cox A, Gonzalez AM, Maskil JK, Hughes ME, Wilson RM, Ward JD, Duff GW: Interleukin-1 receptor antagonist allele (IL1RN*2) associated with nephropathy in diabetes mellitus. Hum Genet 97 : 369 –374, 1996
103. Loughrey BV, Maxwell AP, Fogarty DG, Middleton D, Harron JC, Patterson CC, Darke C, Savage DA: An interleukin 1B allele, which correlates with a high secretor phenotype, is associated with diabetic nephropathy. Cytokine 10 : 984 –988, 1998
104. Lee SH, Ihm CG, Sohn SD, Lee TW, Kim MJ, Koh G, Oh SJ, Woo JT, Kim SW, Kim JW, Kim YS, Lee BC, Kim SD, Cho BS, Lee HJ, Chung JH: Polymorphisms in interleukin-1 beta and interleukin-1 receptor antagonist genes are associated with kidney failure in Korean patients with type 2 diabetes mellitus. Am J Nephrol 24 : 410 –414, 2004
105. Kitamura A, Hasegawa G, Obayaxhi H, Kamiuchi K, Ishii M, Yano M, Tanaka T, Yamaguchi M, Shigeta H, Ogata M, Nakamura M, Yoshikawa T: Interleukin-6 polymorhpism (-634 C/G) in the promoter region and the progression of diabetic nephropathy in type 2 diabetes. Diabetic Med 19 : 1000 –1005, 2002
106. Wang H, Zhang Z, Chu W, Hale T, Cooper JJ, Elbein SC: Molecular screening and association analyses of the interleukin-6 receptor gene variants with type 2 diabetes, diabetic nephropathy, and insulin sensitivity. J Clin Endocrinol Metab 90 : 1123 –1129, 2005
107. Wolford JK, Colligan PB, Gruber JD, Bogardus C: Variants in the interleukin 6 receptor gene are associated with obesity in Pima Indians. Mol Gent Metab 80 : 338 –343, 2003
108. Kim LH, Lee HS, Kim YJ, Jung JH, Kim JY, Park BL, Shin HD: Identification of novel SNPs in the interleukin 6 receptor gene (IL6R). Human Mutat 21 : 450 –451, 2003
109. Rao M, Wong C, Kanetsky P, Girndt M, Stenvinkel P, Reilly M, Raj DSC: Cytokine gene polymorphism and progression of renal and cardiovascular diseases. Kidney Int 72 : 549 –556, 2007
110. Hostetter TH: Prevention of end-stage renal disease due to type 2 diabetes. N Engl J Med 345 : 910 –912, 2001
111. Williams ME, Tuttle K: The next generation of diabetic nephropathy therapies: An update. Adv Chronic Kidney Dis 12 : 212 –222, 2005
112. Dagenais NJ, Jamali F: Protective effects of angiotensin II interruption: Evidence for anti-inflammatory actions. Pharmacotherapy 25 : 1213 –1229, 2005
113. Dandona P, Dhindsa S, Ghanim H, Chaudhuri A: Angiotensin II and inflammation: The effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade. J Human Hypertens 21 : 20 –27, 2007
114. Han SY, Kim CH, Kim HS, Jee YH, Song HK, Lee HK, Han KH, Kim HK, Kang YS, Han YS, Kim YS, Cha DR: Spironolactone prevents diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. J Am Soc Nephrol 17 : 1362 –1372, 2006
115. Takebayashi K, Matsumoto S, Aso Y, Inukai T: Aldosterone blockade attenuates urinary chemoattractant protein-1 and oxidative stress in patients with type 2 diabetes complicated by diabetic nephropathy. J Clin Endocrinol Metab 91 : 2214 –2217, 2006
116. Fukami K, Cooper ME, Forbes JM: Agents in development for the treatment of diabetic nephropathy. Expert Opin Investig Drugs 14 : 279 –294, 2005
117. Bruno S, Cattaneo D, Perico N, Remuzzi G: Emerging drugs for diabetic nephropathy. Expert Opin Investig Drugs 14 : 747 –771, 2005
118. Utimura R, Fujihara CK, Mattar AL, Costa-Malheiros DMA, Noronha IL, Zatz R: Mycophenolate mophetil prevents the development of glomerular injury in experimental diabetes. Kidney Int 63 : 209 –216, 2003
119. Moriwaki Y, Inokuchi T, Yamamoto A, Ka T, Tsutsumi Z, Takahashi S, Yamamoto T: Effect of TNF-alpha inhibition on urinary albumin excretion in experimental diabetic rats. Acta Diabetol 44 : 215 –218, 2007
120. Han J, Thompson P, Beutler D: Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signalling pathway. J Exp Med 172 : 393 –394, 1990
121. Doherty GM, Jensen JC, Alexander HR, Buresh CM, Norton JA: Pentoxifylline suppression of tumor necrosis factor gene transcription. Surgery 110 : 192 –198, 1991
122. Voisin L, Breuille D, Ruot B, Ralliere C, Rambourdin F, Dalle M, Obled C: Cytokine modulation by PX differently affects specific acute phase proteins during sepsis in rats. Am J Physiol Regul Integr Comp Physiol 275 : 1412 –1419, 1998
123. Tissi L, Puliti M, Barluzzi R, Orefici G, Von Hunolstein C, Bistoni F: Role of tumor necrosis factor alpha, interleukin-1beta, and interleukin-6 in a mouse model of group B streptococcal arthritis. Infect Immun 67 : 4545 –4550, 1999
124. Cooper A, Mikhail A, Lethbridge LW, Kemeny DM, Macdougall IC: Pentoxifylline improves hemoglobin levels in patients with erythropoietin-resistant anemia in renal failure. J Am Soc Nephrol 15 : 1877 –1882, 2004
125. Segal R, Dayan M, Zinger H, Mozes E: Suppression of experimental systemic lupus erythematosus (SLE) in mice via TNF inhibition by an anti-TNFalpha monoclonal antibody and by pentoxifillyne. Lupus 10 : 23 –31, 2001
126. Chen YM, Ng YY, Lin SL, Chiang WC, Lan HY, Tsai TJ: Pentoxifylline suppresses renal tumour necrosis factor-alpha and ameliorates experimental crescentic glomerulonephritis in rats. Nephrol Dial Transplant 19 : 1106 –1115, 2004
127. Guerrero-Romero F, Rodri[Combining Acute Accent]guez-Mora[Combining Acute Accent]n M, Paniagua-Sierra J, Garci[Combining Acute Accent]a-Bulnes G, Salas-Rami[Combining Acute Accent]rez M, Amato D: Pentoxifylline reduces proteinuria in insulin-dependent and non-dependent diabetic patients. Clin Nephrol 43 : 116 –121, 1995
128. Navarro JF, Mora C, Rivero A, Gallego E, Chahin J, Maci[Combining Acute Accent]a M, Mendez ML, Garci[Combining Acute Accent]a J: Urinary protein excretion and serum tumor necrosis factor in diabetic patients with advanced renal failure: Effects of pentoxifylline administration. Am J Kidney Dis 33 : 458 –463, 1999
129. Navarro J, Mora C, Muros M, Maci[Combining Acute Accent]a M, Garci[Combining Acute Accent]a J: Effects of pentoxifylline administration on urinary N-acetyl-beta-glucosaminidase excretion in type 2 diabetic patients: A short-term, prospective, randomised study. Am J Kidney Dis 42 : 264 –270, 2003
130. Rodri[Combining Acute Accent]guez-Moran M, Gonzalez-Gonzalez G, Bermu[Combining Acute Accent]dez-Barba MV, Medina de la Garza CE, Tamez-Perez HE, Marti[Combining Acute Accent]nez-Marti[Combining Acute Accent]nez FJ, Guerrero-Romero F: Effects of pentoxifylline on the urinary protein excretion profile of type 2 diabetic patients with microproteinuria: A double-blind, placebo-controlled randomized trial. Clin Nephrol 66 : 3 –10, 2006
131. Aminorroaya A, Janghorbani M, Rezvanian H, Aminian T, Gharavi M, Amini M: Comparison of the effect of pentoxifylline and captopril on proteinuria in patients with type 2 diabetes mellitus. Nephron Clin Pract 99 : 73 –77, 2005
132. Rodri[Combining Acute Accent]guez-Moran M, Guerrero-Romero F: Pentoxifylline is as effective as captopril in the reduction of microalbuminuria in non-hypertensive type 2 diabetic patients. A randomized, equivalent trial. Clin Nephrol 64 : 91 –97, 2005
133. Harmankaya O, Seber S, Yilmaz M: Combination of pentoxifylline with angiotensin converting enzyme inhibitors produces an additional reduction in microalbuminuria in hypertensive type 2 diabetic patients. Ren Fail 25 : 465 –470, 2003
134. Navarro JF, Mora C, Muros M, Garci[Combining Acute Accent]a J: Additive antiproteinuric effect of pentoxifylline in patients with type 2 diabetes under angiotensin II receptor blockade: A short-term, randomised, controlled trial. J Am Soc Nephrol 16 : 2119 –2126, 2005
