Journal of Investigative Medicine:
EB Symposium Manuscript
Cardinal Role of the Intrarenal Renin-Angiotensin System in the Pathogenesis of Diabetic Nephropathy
Kobori, Hiroyuki MD, PhD, FJSIM, FAHA, FASN, FJSH, FJSN, FACP*; Kamiyama, Masumi PhD*; Harrison-Bernard, Lisa M. PhD†; Navar, L. Gabriel PhD*
From the *Department of Physiology, and Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, and †Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA.
Received September 7, 2012, and in revised form October 21, 2012.
Accepted for publication October 22, 2012.
Reprints: Hiroyuki Kobori, MD, PhD, FJSIM, FAHA, FASN, FJSH, FJSN, FACP, Departments of Medicine and of Physiology, Director of the Molecular Core in Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, 1430 Tulane Ave, #SL39/M720, New Orleans, LA 70112. E-mail: firstname.lastname@example.org.
Drs Kobori and Kamiyama contributed equally to this work.
The authors’ laboratories are supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK072408); National Center for Research Resources (P20RR017659); National Heart, Lung, and Blood Institute (R01HL026371); and by the American Heart Association Grant-in-Aid (GRNT2250875 and GRNT3020018). Supported in part by a grant from the National Center for Research Resources (R13 RR023236).
Abstract: Diabetes mellitus is one of the most prevalent diseases and is associated with increased incidence of structural and functional derangements in the kidneys, eventually leading to end-stage renal disease in a significant fraction of afflicted individuals. The renoprotective effects of renin-angiotensin system (RAS) blockade have been established; however, the mechanistic pathways have not been fully elucidated. In this review article, the cardinal role of an activated RAS in the pathogenesis of diabetic nephropathy (DN) is discussed with a focus on 4 themes: (1) introduction to RAS cascade, (2) intrarenal RAS in diabetes, (3) clinical outcomes of RAS blockade in DN, and (4) potential of urinary angiotensinogen as an early biomarker of intrarenal RAS status in DN. This review article provides a mechanistic rational supporting the hypothesis that an activated intrarenal RAS contributes to the pathogenesis of DN and that urinary angiotensinogen levels provide an index of intrarenal RAS activity.
Diabetes affects 220 million people worldwide, including 24 million Americans, and is the sixth leading cause of death in the United States. It is associated with increased incidence of functional and structural alterations in the kidneys, eventually leading to end-stage renal failure in many patients. Diabetic nephropathy (DN) is the most common cause of end-stage renal failure in the United States, accounting for 45% of patients starting dialysis.1,2 Type 2 diabetes mellitus (T2D) is the most common type of diabetes accounting for 90% to 95% of all diagnosed cases of diabetes and affecting 8% of the US population.3,4 Obesity has been identified as the principal risk factor associated with the rising prevalence of T2D.5 The epidemic proportions of obesity and diabetes justify the enormous effort to identify novel pathways and mechanisms involved in their prevention and treatment. Diabetes is a chronic and debilitating disease that is characterized by progressive albuminuria, declining glomerular filtration rate (GFR), functional and structural deterioration of the kidney, and increased risk of cardiovascular disease.
RENIN-ANGIOTENSIN SYSTEM CASCADE
The importance of the renin-angiotensin system (RAS) in the regulation of blood pressure (BP) and fluid and electrolyte homeostasis has been well recognized.6,7 As indicated in Figure 1, the balance between vasoconstrictor and vasodilator effects is determined by the actions of angiotensin II and angiotensin 1–7. The formation of angiotensin II is dependent on the substrate availability of angiotensinogen (AGT) and angiotensin I and the activities of renin, angiotensin-converting enzyme (ACE), ACE2, and ACE-independent enzymatic pathways including serine proteases such as chymase. Angiotensin 1–7 can be formed directly from angiotensin II hydrolyzed by ACE2 or indirectly from angiotensin I via an intermediate step of the formation of angiotensin 1–9 hydrolyzed by ACE2 and ACE in sequence. The actions of angiotensin II are determined by signaling via angiotensin II type 1 (AT1) and type 2 (AT2) receptors8 and the putative angiotensin 1–7 receptor, Mas.9,10
INTRARENAL RAS IN DIABETES
Emerging evidence has demonstrated the importance of local RAS11 in the brain,12 heart,13 adrenal glands,14 vasculature,15,16 and kidneys.6–8,17 In particular, the renal RAS is unique because all of the components necessary to generate intrarenal angiotensin II are present along the nephron in both interstitial and intratubular compartments (Fig. 2).7,10 Angiotensinogen has been localized primarily at the mRNA level,18 and immunoreactive AGT7 has been found in the proximal tubules. Detailed localization of the AGT in the proximal tubular segments was controversial; however, divergent localization of AGT mRNA and protein was reported recently.19,20 The proximal convoluted tubules and proximal straight tubules exhibit positive immunostaining for AGT (Fig. 3). Furthermore, weak expression of AGT protein was also observed in glomeruli and vasa recta, whereas the distal tubules and collecting ducts are negative.21–25 Angiotensinogen mRNA is found strongly in the proximal straight tubules. Recent evidence suggests that AGT is constitutively secreted in the proximal straight tubule as in the liver.26 Renin mRNA and renin-like activity have been demonstrated in cultured proximal tubular cells, and low concentrations of renin have been detected in proximal tubule fluid in rats27–30 Moreover, there is abundant expression of ACE mRNA31 and protein32,33 on brush border membranes of proximal tubules of human kidney. Finally, ACE is also present in proximal and distal tubular fluid but is greater in proximal tubule fluid.34 Angiotensin-converting enzyme 2 protein is found in proximal tubule cells, glomerular podocytes,35 and tunica media of renal arterioles.36 In addition, experimental studies have shown that intrarenal ACE-independent, serine-protease–dependent pathways have an increased role in the conversion of angiotensin I to angiotensin II in diabetic models, thus influencing renal hemodynamics.37
Data concerning intrarenal RAS states in diabetes are inconsistent.38–40 Although various studies support an association between RAS and DN, direct measurements have failed to establish that intrarenal angiotensin II is consistently elevated in diabetes.40 However, intrarenal AGT levels are elevated in patients with DN.41 In rodent diabetic models, renin content varies, and ACE expression has been shown to be increased or unchanged in glomeruli and vessels.39,42 In the T2D mouse kidney, proximal tubule ACE immunostaining is decreased, whereas ACE2 immunostaining is increased compared with control mice (Fig. 3).37 However, AT1 receptor protein levels were significantly elevated in renal cortex from streptozotocin-induced diabetic rats compared with control rats associated with down-regulation of AT2 receptors.39,42 The cortical collecting ducts of streptozotocin-induced diabetic kidneys displayed a striking increase in AT1 receptor immunostaining intensity relative to control kidneys (Fig. 3).39 Moreover, it was recently shown that prorenin expression is elevated in the cortical collecting ducts of type 1 diabetic (T1D) rats.43 Furthermore, studies in models of T2D show increased intrarenal angiotensin II levels and AGT mRNA levels, which are prevented by treatment with an angiotensin II receptor blocker (ARB).44 Finally, increases in renal cortical AGT (Fig. 3) and angiotensin II levels associated with increased reactive oxygen species (ROS) and renal injury have been observed in Zucker diabetic fatty obese rats compared with control lean rats.46,47
Recent studies have identified a major role for intrarenal ACE-independent formation of angiotensin II in T2D. Park et al.37 reported that afferent arteriole vasoconstriction in control kidneys that is produced by angiotensin I was significantly attenuated by ACE inhibition, but not by serine protease inhibition. In contrast, afferent arteriole vasoconstriction produced by the intrarenal conversion of angiotensin I to angiotensin II was significantly attenuated by serine protease inhibition, but not by ACE inhibition in diabetic kidneys.37 Therefore, there appears to be a switch from ACE-dependent to serine protease–dependent angiotensin II formation in the T2D kidney. It has been suggested that chymase may be responsible for serine protease–dependent angiotensin II formation in the diabetic kidney.48 It is plausible that pharmacological targeting of these serine protease–dependent pathways may provide further protection from diabetic renal vascular disease.
CLINICAL OUTCOMES FOR RAS BLOCKADE IN DN
Angiotensin II receptor blockers and ACE inhibitors retard the development and progression of renal dysfunction in human studies.49–52 Table 1 summarizes major clinical trials concerning the effects of RAS inhibition in the development and progression of renal dysfunction in both diabetic and nondiabetic renal disease. In BENEDIC (Bergamo Nergamo Nephrologic Diabetes Complications Trial),53 patients with diabetes with no history of microalbuminuria were randomized to trandolapril versus placebo over median of 3.6 years’ follow-up. Trandolapril resulted in a significant decrease in the development of microalbuminuria and limited the progression of renal dysfunction. This reduction was still significant even after adjusting for BP reduction by trandolapril. In the AASK (African American Study of Kidney Disease and Hypertension) trial,54 the reduction of microalbuminuria by ACE inhibitors was also shown in the nondiabetic renal population in which patients were randomized to ramipril versus amlodipine. The benefit of ARB therapy in patients with DN has been studied in 2 large trials. In the RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) trial55 and the IDN (Irbesartan Diabetic Nephropathy) trial,56 evaluating patients with T2D with nephropathy, the addition of ARB to standard therapy resulted in improvements in all causes of mortality, progression to end-stage renal disease, and doubling of serum creatinine. In the first direct comparison of ARB with an ACE inhibitor, the DETAIL (Diabetics Exposed to Telmisartan And Enalapril) trial57 evaluated patients with T2D randomized to either enalapril or telmisartan. Telmisartan was not inferior to enalapril in the primary end point of change in baseline estimated GFR. Recently, ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial)58 showed that ARBs and ACE inhibitors were equally effective in improving renal outcome (dialysis, doubling of serum creatinine, and death), and the number of events for the composite outcome was similar for telmisartan and ramipril. In the dual-therapy group, even though there was a significant reduction in proteinuria, there was an increase in adverse effects and worsening renal outcomes. The beneficial effect of ARB was also confirmed in a most recent megatrial.59,60 The ROADMAP (Randomized Olmesartan and Diabetes Microalbuminuria Prevention) trial is a randomized, double-blind, multicenter study conducted in Europe, including 4447 patients with diabetes and at least 1 additional cardiovascular risk factor, but no evidence of renal dysfunction. The participants were randomized to receive either olmesartan at 40 mg/d (n = 2232) or placebo (n = 2215), and all were allowed to take additional non-RAS antihypertensives to reach target BP (<130/80 mm Hg), until the predefined number of adjudicated microalbuminuria events occurred at a median follow-up of 3.2 years. The primary end point was time to onset of albuminuria. The results show that there was a cumulative incidence of microalbuminuria of 8.2% with olmesartan and 9.8% with placebo; the primary end point, time to onset of microalbuminuria, was delayed by 23% with olmesartan (hazard ratio, 0.77; P = 0.01), with the majority of this effect being BP independent. What is missing, however, is an actual marker to test for the efficacy of treatment. If indeed the major factor initiating the DN is an inappropriate increase in intrarenal RAS, then it would seem particularly worthwhile to have a direct means of evaluating the status of the intrarenal RAS in patients and the efficacy of treatment in reducing or arresting RAS activation in the kidneys.
URINARY AGT AS A NEW BIOMARKER OF INTRARENAL RAS STATUS IN DIABETES
Clinically, microalbuminuria is the most commonly used early marker of DN.61 Diabetic nephropathy is thought to be a unidirectional process from microalbuminuria to end-stage renal failure.62 However, recent studies demonstrate that a large proportion of DN patients revert to normoalbuminuria and that one third of them exhibit reduced renal function even in the microalbuminuria stage.63 It is claimed that urinary inflammatory markers are high in microalbuminuric T1D having diminished renal function, but not in microalbuminuric T1D patients with stable renal function. However, no single marker has been sufficient to represent the whole panel.64 Therefore, a more sensitive and more specific marker for activation of RAS in DN would be highly advantageous.
Angiotensinogen is the only known substrate for renin, which is the rate-limiting enzyme of the RAS. Because the level of AGT is close to the Michaelis-Menten constant for renin, not only renin levels but also AGT levels can control the activity of the RAS, and up-regulation of AGT levels may lead to elevated angiotensin peptide levels.65,66 Recent studies on experimental animal models and transgenic mice have documented the involvement of AGT in the activation of the RAS.67–75 Genetic manipulations that lead to overexpression of the AGT gene have consistently been shown to cause hypertension.76,77 In human genetic studies, a linkage has been established between the AGT gene and hypertension.78–81 Enhanced intrarenal AGT mRNA and/or protein levels have also been observed in multiple experimental models of hypertension and diabetes including angiotensin II–dependent hypertensive rats,25,82–86 Dahl salt–sensitive hypertensive rats,87,88 and spontaneously hypertensive rats,89 as well as in kidney diseases including DN,44,46,47,90–92 immunoglobulin A nephropathy,93,94 and radiation nephropathy.95 In addition, models of T1D and T2D and patients with metabolic syndrome also exhibit increases in intrarenal AGT and urinary AGT excretion.44–47,96,97 Thus, AGT plays an important role in the development and progression of hypertension and kidney diseases and may be particularly useful as a predictor of developing kidney disease.7,17
In rodents, urinary excretion rates of AGT provide a specific index of the intrarenal RAS status and are correlated with kidney angiotensin II levels in angiotensin II–dependent hypertensive rats (Fig. 2).25,83–86 Because of its potential importance, a direct quantitative method to measure urinary AGT using human AGT enzyme-linked immunosorbent assay was recently developed.98 Using this system, urinary excretion rates of AGT have been used as an index of intrarenal RAS status in patients with chronic kidney disease99–102 and in patients with hypertension.103,104 Recently, 2 clinical studies showed the potential of urinary AGT levels as a novel biomarker of intrarenal RAS status in diabetes mellitus.105,106
To demonstrate that the administration of an ARB interferes with the vicious cycle of high glucose–ROS–AGT–angiotensin II–AT1 receptor–ROS by suppressing ROS and inflammation, 13 hypertensive DN patients who received ARBs were recruited and evaluated before and at 16 weeks after treatment.105 Urinary AGT, albumin, 8-hydroxydeoxyguanosine, 8-epi-prostaglandin F2α, monocyte chemoattractant protein 1 (MCP-1), interleukin 6, and interleukin 10 were assessed. Angiotensin II receptor blocker treatment reduced the BP and urinary levels of AGT, albumin, 8-hydroxydeoxyguanosine, 8-epi-prostaglandin F2α, MCP-1, and interleukin 6, while increasing urinary interleukin 10 levels. The reduction of urinary AGT correlated with the reduction of BP and urinary levels of albumin, 8-hydroxydeoxyguanosine, 8-epi-prostaglandin F2α, MCP-1, and interleukin 6 and the increased urinary interleukin 10 levels. These results suggest that the mechanisms by which ARBs exert their renoprotective effect may involve the suppression of intrarenal AGT levels in association with reduced anti-inflammatory and antioxidant effects in patients with T2D (Fig. 4).105
To determine if urinary AGT levels can be dissociated from urinary albumin or protein excretion rates in T1D juveniles, early-phase studies were performed in control and diabetic juveniles.106 Of the 55 juveniles recruited, 34 were patients with T1D, and 21 were sex- and age-matched control subjects. Because the primary focus of the study was comparison between characteristics of normoalbuminuric patients with T1D and those of control subjects, 6 microalbuminuric patients with T1D (urinary albumin-creatinine ratio >30 mg/g) were excluded. Consequently, 49 urine and plasma samples were analyzed. None of them received treatment with RAS blockade. Neither urinary albumin-creatinine ratios nor urinary protein-creatinine ratios were significantly increased in these patients with T1D compared with control subjects, suggesting that these patients were in their premicroalbuminuric phase of DN. However, urinary AGT-creatinine ratios were significantly increased in these patients compared with control subjects (12.1 ± 3.2 vs 4.2 ± 0.7 μg/g, P = 0.0454). Importantly, the AGT increase was not observed in plasma (26.3 ± 1.3 vs 29.5 ± 3.3 μg/mL, P = 0.3148) (Fig. 5). These data indicate that urinary AGT levels are increased in T1D subjects and that increased urinary AGT levels precede the increased urinary albumin levels, suggesting a possibility that urinary AGT levels serve as a very sensitive early marker of intrarenal RAS activation and may be one of the earliest predictors of DN in patients with diabetes.106
The complicated and pleiotropic actions of an activated RAS in pathogenesis of DN continue to receive recognition from emerging and ongoing studies. Clearly, the use of ARBs and ACE inhibitors has become common practice in treating patients with diabetes. Because RAS activation plays such a central role in the development and progression of DN, there has been extensive interest in the potential hope for reduction in morbidity and mortality by using agents that block 1 or more steps in the RAS. Accordingly, the assessment of urinary AGT as an early biomarker of the status of the intrarenal RAS may be of substantial importance. It may be particularly helpful in serving as a means to determine efficacy of the treatment to reduce intrarenal angiotensin II levels.
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diabetic nephropathy; renin-angiotensin system; angiotensinogen; kidney
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