Diabetic nephropathy is the most common cause of end-stage renal diseases . Currently, multifactorial intervention, including strict control of blood glucose, blood pressure (BP), dyslipidemia, and renin–angiotensin–aldosterone system (RAAS) blockade, are suggested to improve the patient outcome [2–4]. Among those interventions, long-term blood glucose control is essential to decrease the likelihood of vascular complications, including nephropathy in patients with type 2 diabetes [4–6]. Incretin-based therapies are one of the most promising arms enabling long-term glycemic control in type 2 diabetes treatment with a lower risk of hypoglycemia and weight gain . The dipeptidyl peptidase-4 (DPP-4) inhibitors represent a class of glucose-lowering agents potentiating the action of the incretin hormones [8,9]. The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are secreted from the intestinal endocrine cells in response to food ingestion to stimulate insulin secretion from pancreatic beta cells for lowering postprandial glucose level. Once secreted, the incretin hormones are rapidly degraded by DPP-4 and lose their biological activities. Pharmacological inhibition of DPP-4 results in the accumulation of the incretin hormones to enhance their actions. GLP-1 and GIP transduce their effects via their specific receptors, the GLP-1 receptor (GLP-1R)  and the GIP receptor. As those receptors for incretins are widely distributed in multiple organs , GLP-1 and GIP have been shown to exert extrapancreatic action beyond glycemic control [12–16]. In addition, DPP-4 cleaves multiple substrates other than GLP-1 or GIP [17–21]. Therefore, treatment of diabetes with DPP-4 inhibitors is likely to involve a variety of extrapancreatic effects, including organ protection. Such pleiotropic action of DPP-4 inhibitors might occur by both incretin-dependent and incretin-independent mechanisms.
INCRETIN IN KIDNEY PHYSIOLOGY
Although the localization of GLP-1R in the kidney remained controversial, some study revealed receptor expression in the glomeruli and proximal tubules at mRNA levels in the rodents . The expression of the receptor in the glomerular capillary wall and vascular structure in rodents was demonstrated by in-situ hybridization [23▪]. Autoradiographic analysis in humans showed that GLP-1Rs were found in the renal arteries but not in tubules and glomeruli . In contrast, an immunohistochemical analysis of the human kidney showed immunoreactive GLP-1Rs expressed predominantly in the proximal tubules . This controversy in the receptor mapping could be a matter of species difference and methodological issues. Moreover, recent commercially available antibodies against GLP-1Rs do not seem specific and sensitive, which suggests a careful interpretation of the results from immunological detection methods . GLP-1 infusion increases sodium excretion in the kidney and diuresis, accompanied by increased excretion of calcium, phosphate, and chloride in both rodents and humans [22,27,28]. GLP-1 infusion markedly decreases the proximal tubular sodium reabsorption in both human and rodents [22,27,29], which might constitute a mechanism for the increments in electrolyte excretion. GLP-1 and GLP-1 mimetics are known for their antihypertensive effects, possibly via reducing salt retention in rodent hypertension models [30,31]. In humans, GLP-1 and GLP-1 mimetics often lower BP in patients with type 2 diabetes . The antihypertensive action of GLP-1 might be caused by a combination of GLP-1-mediated natriuresis and diuresis, but is also considered to imply improved endothelial functions [32,33].
ACTION OF DIPEPTIDYL PEPTIDASE-4 INHIBITORS IN THE KIDNEY: INCRETIN-DEPENDENT EFFECTS
The main mode of action of a DPP-4 inhibitor is to increase the level of circulating incretin hormones, such as GLP-1. GLP-1, accumulated by DPP-4 inhibitors in a physiological range, stimulates insulin secretion from the pancreatic beta cells, constituting a glucose-lowering effect of DPP-4 inhibitors. Such glycemic control by DPP-4 inhibitors may reduce the risk for the further development of complications of type 2 diabetes, including kidney and cardiovascular diseases. DPP-4 inhibitors are known to have additional effects beyond glycemic control. As mentioned above, GLP-1Rs are distributed in the kidney to transduce GLP-1 action to the kidney. A recent study showed that GLP-1 plays an anti-inflammatory role by decreasing the receptor for advanced glycation end-products (RAGEs) and by reducing monocyte chemoattractant protein-1 (MCP-1) expression in the mesangial cells . GLP-1 is also shown to exert renoprotective role via inhibition of angiotensin II in glomerular endothelium . DPP-4 inhibitors might augment such action of GLP-1 in the kidney (Table 1).
ACTION OF DIPEPTIDYL PEPTIDASE-4 INHIBITORS IN THE KIDNEY: INCRETIN-INDEPENDENT EFFECTS
Studies demonstrating organ protection by GLP-1 sometimes utilize supraphysiologic concentrations of GLP-1; therefore, the renoprotective effect of DPP-4 inhibitors might, in part, occur via GLP-1-independent mechanisms. In support of this, the renal effect of DPP-4 inhibitor was evidenced even in GLP-1Rs-ablated mice . Expression of DPP-4 has been demonstrated in various tissues and particularly high enzymatic activity was found in the rat kidney . Moreover, a whole-body autoradiographic analysis in rats on the distribution of the radiolabeled linagliptin, a DPP-4 inhibitor, demonstrated the highest accumulation of DPP-4 inhibitor in the kidney . Such an accumulation was not evident in DPP-4-deficient rat , indicating that the kidney might be a tissue where a significant interaction between DPP-4 and DPP-4 inhibitor takes place. DPP-4 modulates multiple substrates other than GLP-1, such as the brain natriuretic peptide (BNP) , substance P , neuropeptide Y (NPY) , stromal-derived factor 1α (SDF-1α) , and high-mobility group protein B1 (HMGB1)  (Table 1). These substrates are involved in vascular tone regulation, inflammation, cell migration, and cell differentiation. For example, SDF-1α is a chemokine-attracting stem cell and is upregulated in ischemic tissues [39▪]. DPP-4 inhibition increases SDF-1α to recruit regenerative stem cells to ischemic sites, resulting in facilitation of recovery from ischemia–reperfusion injury . On the other hand, DPP-4 has nonenzymatic actions such as binding to the adjacent membrane proteins, as well as extracellular matrix proteins, to exert adhesion molecule-like functions , suggesting DPP-4 inhibition might affect the extracellular matrix metabolism or remodeling. Both the incretin-dependent and incretin-independent action of DPP-4 inhibitors may participate in its pleiotropic function in kidney pathophysiology.
DIPEPTIDYL PEPTIDASE-4 INHIBITORS IN PROGRESSIVE KIDNEY DISEASES: PRECLINICAL STUDIES
Diabetic kidney disease model
Emerging studies have shown the renoprotective effects of GLP-1R-mediated signals in the diabetic kidney model [35,42,43]. In line with these observations, the pathway comprising GLP-1, DPP-4, and the GLP-1R provides interesting aspects of diabetic kidney disease. First, the expression level of DPP-4 is upregulated in the kidney and the other tissues of high-fat diet-fed rats . Similarly, upregulation of DPP-4 in the glomerular epithelial cells occurs during inflammation , which is often associated with the glomerulosclerosis in diabetic nephropathy. Another observation is the downregulation of GLP-1Rs in the glomeruli and tubules of diabetic rats, which is reversed by DPP-4 inhibition . These facts may give DPP-4 inhibitors additional potentials for the treatment of diabetic nephropathy.
The renal-protective actions of DPP-4 inhibitors have been explored in diabetic animal models. The effects of chronic low-dose sitagliptin administration were assessed for metabolic profile and aggravation of renal lesions in a rat type 2 diabetic nephropathy model. Zucker diabetic fatty (ZDF) rats and their control rats were treated for 6 weeks with vehicle or sitagliptin. Sitagliptin in diabetic rats promoted an amelioration of renal lesions including glomerular, tubulointerstitial, and vascular lesions. As sitagliptin decreased the serum glucose level, as well as glycated hemoglobin (HbA1c), and lipids, it remained undetermined whether the effects of sitagliptin were independent of the glycemic control . Recently, a study with similar experimental settings of low-dose sitagliptin administration for 6 weeks in ZDF rat demonstrated that sitagliptin prevented the tubulointerstitial and glomerular lesions . Although sitagliptin significantly reduced the level of glycemia and HbA1c, it also decreased interleukin (IL)-1β and tumor necrosis factor-α, BAX/Bcl-2 ratio, Bid protein levels, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells in the kidney . Therefore, in addition to the glucose-lowering effects, sitagliptin might exert protective effects against inflammation and proapoptotic state in the kidney of diabetic rats.
The effects of linagliptin on the diabetic animal kidney were initially investigated in streptozotocin (STZ)-induced diabetes in endothelial nitric oxide synthase knockout mice . Linagliptin, alone or in combination with angiotensin receptor blocker (ARB) telmisartan, was administered for 12 weeks and showed no effect on glycemic control in diabetic rats. However, when combined with telmisartan, linagliptin significantly reduced albuminuria, whereas monotherapy with either telmisartan or linagliptin failed. Histologically, linagliptin, alone and in combination with telmisartan, significantly reduced the glomerular sclerosis and immunoreactivity of malondialdehyde, a biomarker of oxidative stress, indicating an antioxidative role of linagliptin. This study may show a benefit of linagliptin on top of an ARB in the treatment of diabetic kidney diseases. Kanasaki et al.[50▪▪] recently demonstrated a new aspect of linagliptin concerning renal protection in diabetic animals. In the study, linagliptin was administered to mice with established diabetes by STZ introduction. By 24 weeks after the onset of diabetes, the mice exhibited kidney fibrosis and massive upregulation of DPP-4 expression in the kidney. Linagliptin administration at 20 weeks in this model significantly reduced the enzyme activity and protein level of DPP-4, and ameliorated kidney fibrosis without altering the blood glucose levels. Interestingly, such induction of DPP-4 in the kidney was associated with suppressed levels of microRNA 29s. Linagliptin restored microRNA 29s expression to reduce DPP-4 levels. Such microRNA 29s induction by linagliptin also contributed to the inhibition of endothelial-to-mesenchymal transition induced by TGF-β2. The study indicates a novel pleiotropic action of linagliptin to reverse the fibrotic kidney damage in diabetes [50▪▪].
The potential benefit of attenuating upregulated DPP-4 activity in the diabetic kidney was also shown in an animal study employing vildagliptin. In a rat model of STZ-induced type 1 diabetes, treatment with vildagliptin for 24 weeks resulted in the amelioration of glomerular lesions and interstitial expansion in the kidney . It also decreased proteinuria, albuminuria, and improved creatinine clearance. Vildagliptin markedly downregulated DPP-4 activity and increased GLP-1 levels, which probably prevented oxidative DNA damage and renal cell apoptosis by activating GLP-1Rs and modulating cyclic adenosine monophosphate (cAMP) . In addition, another vildagliptin analog, PKF275-055, demonstrated a renoprotective effect in STZ-induced type 1 diabetes model rats [51▪]. At 8 weeks after the onset of diabetes and the start of vildagliptin, the vildagliptin arm showed decreased urinary albumin excretion and ameliorated glomerular morphology in diabetic rats. Moreover, vildagliptin downregulated macrophage infiltration and the activity of nuclear factor-κB, indicating renoprotection by vildagliptin through anti-inflammatory action in the early stage of diabetic nephropathy [51▪].
Other progressive kidney disease model
As mentioned above, DPP-4 is widely expressed in the kidney and has been known to be involved in inflammation and ischemia–reperfusion injury in the lungs and heart. Given these facts, growing numbers of studies have tested the effects of DPP-4 inhibitors in various kidney disease models.
Administration of sitagliptin for 8 weeks to rats with 5/6 nephrectomy attenuated renal dysfunction [52▪]. Histologically, glomerulosclerosis and tubulointerstitial injury were significantly decreased and apoptosis in kidney cells reduced by sitagliptin. Mechanistically, sitagliptin downregulates DPP-4 activity and increases the renal expansion of GLP-1Rs. Moreover, sitagliptin extinguishes subtotal nephrectomy-activated phosphatidylinositol 3-kinase–FoxO3a pathways to reduce the subsequent expansion of inflammation and apoptosis in the kidney.
Similarly, gemigliptin was tested in a mouse unilateral ureteral obstruction (UUO) model [53▪]. Gemigliptin significantly reduced albuminuria, urinary excretion of 8-isoprostane, and renal fibrosis by UUO. In obstructed kidneys, DPP-4 activity was significantly increased and gemigliptin reduced it. UUO significantly increased the levels of phosphorylated Smad2/3, TGF-β1, Toll-like receptor 4, high-mobility group box-1, NADPH oxidase 4, and NF-κB, and gemigliptin markedly suppressed them, indicating targeted therapy inhibiting DPP-4 may constitute a new approach in the management of progressive renal disease.
The possible renoprotective effects of sitagliptin against dyslipidemia-related kidney injury were investigated in apolipoprotein E knockout (apoE-/-) mice [54▪]. ApoE-/- mice with a high-fat diet were administered sitagliptin for 16 weeks. ApoE-/- mice with a high-fat diet showed increased albuminuria and urinary 8-hydroxy-2-deoxyguanosine excretions, and lipid disposition and glomerular mesangial matrix in the kidney. Sitagliptin ameliorated these dyslipidemia-related derangements. Such effects of sitagliptin are likely to occur via reduction in Akt levels, a restoration of AMP-activated kinase activity, and inhibition of TGF-β1, fibronectin, and mitogen activated protein kinase (MAPK) pathways.
A DPP-4 inhibitor MK0626 was tested in another metabolic kidney injury model . A Western diet comprising high fructose and high fat in mice for 16 weeks induced obese, hypertension, and proteinuria. Those mice receiving the Western diet also exhibited elevated plasma DPP-4 activity and uric acid level as well as increased DPP-4 activity and MCP-1 and IL-12 levels in the kidney, indicating a correlation with macrophage-driven inflammation and glomerular and tubulointerstitial injury. MK0626 abrogated the elevation of DPP-4 activity either in plasma or in the kidney, and ameliorated proteinuria, glomerular and tubular injury via a reduction of serum uric acid level and renal oxidative stress without alteration of BP and systemic insulin sensitivity. This study offers a novel advantageous aspect of DPP-4 inhibition in obesity-related kidney diseases.
DIPEPTIDYL PEPTIDASE-4 INHIBITORS IN PROGRESSIVE KIDNEY DISEASES: CLINICAL STUDIES
An initial report demonstrating the favorable effect of DPP-4 inhibitors in human diabetic kidney disease was an uncontrolled observational study with sitagliptin . Thirty-six patients with type 2 diabetes whose HbA1c were higher than 6.5%, despite receiving lifestyle education and medical treatment for at least 6 months, were enrolled in 6 months sitagliptin treatment (50 mg/day). Sitagliptin treatment significantly reduced urinary albumin excretion in all groups of normoalbuminuria, microalbuminuria, and macroalbuminuria at baseline. Sitagliptin treatment also reduced blood glucose level, SBP and DBP, level of highly sensitive C-reactive protein and soluble vascular cell adhesion molecule 1, suggesting that the effect of sitagliptin on albuminuria was likely dependent on reduction in blood glucose, BP reduction, and inflammation, as well as yet undetermined factors caused by DPP-4 inhibition. Recently, another study investigating the effect of sitagliptin on urinary albumin excretion was performed . It is open-labeled, prospective, randomized study comparing sitagliptin and other oral glucose-lowering agents. A total of 85 patients with type 2 diabetes whose HbA1c were lower than 8.4% were randomized to a group taking sitagliptin (50 mg/day) or a group taking other oral antidiabetic agents, and observed for 6 months. Although both of the treatments significantly reduced HbA1c and fasting plasma glucose level, only sitagliptin significantly lowered urine albumin excretion, indicating that the effects of sitagliptin might be independent of the glucose-lowering effect. Moreover, even normoalbuminuric patients showed a reduction in the urinary albumin excretion, suggesting sitagliptin prevents the development of microalbuminuria in diabetic patients.
A large, randomized, placebo-controlled trial testing the effect of saxagliptin on cardiovascular outcomes in high-risk type 2 diabetes patients for a median of 2.1 years [Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction (SAVOR-TIMI 53) trial] demonstrated that patients treated with saxagliptin were significantly more likely to have an improved albumin-to-creatinine ratio (10.7% in the saxagliptin group and 8.7% in the placebo group) than patients receiving placebo, and less likely to have a worsening ratio (13.3% in the saxagliptin group and 15.9% in the placebo group) at the end of the treatment period. Mean HbA1c level was significantly lower in the saxagliptin group than in the placebo group (7.6 vs. 7.9% at 1 year, 7.5 vs. 7.8% at 2 years, and 7.7 vs. 7.9% at the end of the treatment period); therefore, it is not clear whether the effect of sitagliptin was dependent or independent of improved glycemic control [58▪▪].
The ability of linagliptin to reduce urinary albumin on top of the standard treatment in patients with type 2 diabetes was analyzed by pooling data from four similarly designed, randomized, double-blind, placebo-controlled, phase III trials [59▪▪]. The study involved 217 individuals with type 2 diabetes and prevalent albuminuria under treatment with RAAS inhibitors. The participants were randomized to either linagliptin 5 mg/day or placebo. Linagliptin significantly reduced urinary albumin excretion (32% reduction in urinary albumin-to-creatinine ratio; UACR) at 24 weeks, whereas placebo showed only a 6% reduction in UACR. Interestingly, the degree of UACR reduction did not correlate with the level of change in HbA1c and SBP, indicating that the amendment in urinary albumin excretion by linagliptin is independent of glycemic and BP controls.
Recently, a small, nonrandomized, cross-over study with sitagliptin and alogliptin administration on top of ARB treatment in type 2 diabetic patients with incipient nephropathy was carried out . Four weeks of alogliptin treatment (25 mg/day), after 4 weeks of sitagliptin (50 mg/day) administration, significantly reduced the urinary level of albumin, whereas BP, serum lipids, estimated glomerular filtration rate, and HbA1c were not changed. Interestingly, a reduction in the urinary oxidative marker 8-hydroxy-2′-deoxyguanosine, and an increase in urinary cAMP level and serum SDF-1α level were observed at 4 weeks after switch from sitagliptin to alogliptin, indicating that stronger inhibition of DPP-4 activity on top of treatment with ARB might offer additional protection against early diabetic nephropathy via antioxidative stress pathway.
It has been increasingly accepted that GLP-1Rs activation and DPP-4 inhibition play a role in the amelioration of kidney disease such as diabetic nephropathy by a process that appears to be independent of glucose lowering. Although not fully elucidated, possible mechanisms underlying such protective properties include systemic effects such as the facilitation of natriuresis and reduction of BP, and also local effects of a reduction of oxidative stress, inflammation, and improvement of endothelial function in the kidney. DPP-4 inhibitors may also have a GLP-1-independent mode of protective action such as the restoration of other DPP-4 substrates which have proven renal effects. The favorable outcomes from animal experiments encourage clinical validation of the renal benefits of DPP-4 inhibitors; however, so far conclusive evidence to translate the results from animal model to humans is scarce. In addition, there might be an issue of whether DPP-4 inhibitors are effective as an add-on or alternative to the recommended standard therapy such as RAAS inhibition, either in diabetic or nondiabetic kidney diseases. Long-term, large, randomized controlled studies are needed to elucidate the impact of DPP-4 inhibitors on progressive kidney diseases.
Financial support and sponsorship
Y.M., Y.F., and M.H. received JSPS Grants-in-Aid for Scientific Research.
Conflicts of interest
M.H. has received research grants from Astellas, Astrazeneca, Bristol Myers, Boehringer Ingelheim, Daiichi-Sankyo, Eli lilly, Kowa, Kyowahakko-Kirin, Mitsubishi-Tanabe, MSD, Novartis, Novo Nordisk, Ono, Sanwa Kagaku, Sanofi, and Takeda.
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The first description of the role of DPP-4 and microRNA in the regulation of fibrosis in diabetic kidney. DPP-4 inhibitor linagliptin ameliorated kidney fibrosis in diabetic mice without altering the blood glucose levels associated with a suppression of DPP-4 activity and protein expression, and the restoration of microRNA 29s. Such microRNA 29s induction mediates the inhibition of TGF-β2-induced endothelial-to-mesenchymal transition linked to kidney fibrosis.
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DPP-4 inhibitor, PKF275-055, increased the serum-active GLP-1 concentration and the production of urinary cyclic AMP in diabetic rats. PKF275-055 decreased urinary albumin excretion and ameliorated the histological change of diabetic nephropathy without an impact on glucose control. Macrophage infiltration was inhibited, and inflammatory molecules and NF-kB activity were downregulated in the kidney, indicating a renoprotective effect of DPP-4 inhibitors through anti-inflammatory action in the early stage of diabetic nephropathy.
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DPP-4 inhibitor attenuated renal dysfunction and structural damage in rat remnant kidney. Reduction of apoptosis, inflammation, and an increase of antioxidant, as well as the activation of FoxO3a signaling, are suggested as the renoprotective mechanisms, indicating an application of DPP-4 inhibitors to the treatment of CKD.
53▪. Min HS, Kim JE, Lee MH, et al. Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction. Lab Invest 2014; 94:598–607.
Gemigliptin significantly decreased albuminuria, urinary excretion of 8-isoprostane, and renal fibrosis in a mouse unilateral ureteral obstruction model. Gemigliptin also substantially decreased the synthesis of several proinflammatory and profibrotic molecules, the infiltration of macrophages, and the levels of phosphorylated Smad2/3, TGFβ1, Toll-like receptor 4, high-mobility group box-1, NADPH oxidase 4, and NF-κB. This study indicates that inhibiting DPP-4 may be a useful new approach in the management of progressive renal disease, independent of GLP-1.
54▪. Li J, Guan M, Li C, et al. The dipeptidyl peptidase-4 inhibitor sitagliptin protects against dyslipidemia-related kidney injury in apolipoprotein E knockout mice. Int J Mol Sci 2014; 15:11416–11434.
The first report to show sitagliptin reverses the renal dysfunction and structural damage induced by dyslipidemia in apoE-/- mice. The renoprotective mechanism of sitagliptin may be because of a reduction in Akt levels, restoration of AMPK activity, and inhibition of TGF-β1, fibronectin, and p38/ERK MAPK signaling pathways.
55. Nistala R, Habibi J, Lastra G, et al. Prevention of obesity-induced renal injury in male mice by DPP4 inhibition. Endocrinology 2014; 155:2266–2276.
56. Hattori S. Sitagliptin reduces albuminuria in patients with type 2 diabetes. Endocr J 2011; 58:69–73.
57. Mori H, Okada Y, Arao T, Tanaka Y. Sitagliptin improves albuminuria in patients with type 2 diabetes mellitus. J Diabetes Investig 2014; 5:313–319.
58▪▪. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013; 369:1317–1326.
The results of a large, randomized, placebo-controlled trial SAVOR-TIMI 53 to test the effect of saxagliptin on the urinary albumin excretion in type 2 diabetic patients, demonstrating a reduction in the urinary albumin-to-creatinine ratio by saxagliptin.
59▪▪. Groop PH, Cooper ME, Perkovic V, et al. Linagliptin lowers albuminuria on top of recommended standard treatment in patients with type 2 diabetes and renal dysfunction. Diabetes Care 2013; 36:3460–3468.
A pooled analysis of 4 completed studies identified 217 individuals with type 2 diabetes and prevalent albuminuria while receiving stable doses of RAAS inhibitors. Participants were randomized to either linagliptin 5 mg/day or placebo. Addition of linagliptin to RAAS inhibitors led to a significant reduction in albuminuria in patients with type 2 diabetes and renal dysfunction. This observation was independent of the changes in glucose level or SBP.
60. Fujita H, Taniai H, Murayama H, et al. DPP-4 inhibition with alogliptin on top of angiotensin II type 1 receptor blockade ameliorates albuminuria via up-regulation of SDF-1α in type 2 diabetic patients with incipient nephropathy. Endocr J 2014; 61:159–166.