Up-Regulation of Renin-Angiotensin System in Diabetes and Hypertension: Implications on the Development of Diabetic Nephropathy (original) (raw)
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Role of the renin angiotensin system in diabetic nephropathy
World Journal of Diabetes, 2010
1 Ziyadeh FN. Renal tubular basement membrane and collagen type IV in diabetes mellitus. Kidney Int 1993; 43: 114-120 2 Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993; Breitbart RE, Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res 2000; 87: E1-E9 9 Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 2000; 275: 33238-33243 10 Zatz R, Dunn BR, Meyer TW, Anderson S, Rennke HG, Brenner BM. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest 1986; 77: 1925-1930 11 Shiota A, Yamamoto K, Ohishi M, Tatara Y, Ohnishi M, Maekawa Y, Iwamoto Y, Takeda M, Rakugi H. Loss of ACE2 accelerates time-dependent glomerular and tubulointerstitial damage in streptozotocin-induced diabetic mice. Hypertens Res 2010; 33: 298-307 12 Gilbert RE, Cox A, Wu LL, Allen TJ, Hulthen UL, Jerums G, Cooper ME. Expression of transforming growth factor-beta1 and type IV collagen in the renal tubulointerstitium in experimental diabetes: effects of ACE inhibition. Diabetes 1998; 47: 414-422 13 Wolf G, Mueller E, Stahl RA, Ziyadeh FN. Angiotensin IIinduced hypertrophy of cultured murine proximal tubular cells is mediated by endogenous transforming growth factorbeta. J Clin Invest 1993; 92: 1366-1372 14 Kalinyak JE, Sechi LA, Griffin CA, Don BR, Tavangar K, Kraemer FB, Hoffman AR, Schambelan M. The renin-angiotensin system in streptozotocin-induced diabetes mellitus in the rat. J Am Soc Nephrol 1993; 4: 1337-1345 15 Tesch GH. MCP-1/CCL2: a new diagnostic marker and therapeutic target for progressive renal injury in diabetic nephropathy. Am J Physiol Renal Physiol 2008; 294: F697-F701
BACKGROUND Diabetic nephropathy is part of the microvascular complication of diabetes mellitus alongside neuropathy and retinopathy. Many mechanisms have been presented as the pathophysiology of diabetic nephropathy but this could be attributed to the renin-angiotensin system. The alteration in prorenin and renin homeostasis has been reported in patients with diabetes mellitus, it's noticed to a reduction in conversion of prorenin to renin thereby leading to accumulation of prorenin binding to (pro)renin. AIM This article is targeted at explaining the contributory roles of the alteration in the prorenin and renin homeostasis in the pathogenesis of diabetic nephropathy and explaining why some of the drugs that act along renin-angiotensin pathways, especially angiotensin receptor blockers can be very helpful in the management of diabetic nephropathy. METHODS A careful literature search was made on some scientific databases such as PubMed, EMBase, Google Scholar, Research Gate, and...
Renin and angiotensinogen gene expression in experimental diabetes mellitus
Kidney International, 1992
Renin and angiotensinogen gene expression in experimental diabetes mellitus. The renin-angiotensin system may play a role in the initiation and progression of diabetic kidney disease. In this study, the local intrarenal renin-angiotensin system was examined in streptozotocintreated rats maintained moderately hyperglycemic by daily low-dose insulin injection. Four weeks after induction of diabetes, plasma renin activity was significantly lower in the diabetic compared to a nondiabetic control group (diabetes: 2.30 0.30 vs. control: 6.93 1.36 ng Al/ml/hr; P < 0.01). Renal tissue renin content (diabetes: 1.81 0.46 vs. control: 2.05 0.27 Lg Al/mg protein/hr; P < 0.05) and renal renin mRNA (diabetes: 2.32 0.16 vs. control: 1.89 0.12 pg/Lg RNA; P = NS) were not different between diabetic and control rats. Renal and liver angiotensinogen mRNA were lower in the diabetic group. Glomerular renin mRNA was not different between the diabetic and sham group. The dissociation between systemic renin activity (a decrease), and in renal renin content or mRNA in the diabetic rats (no change), suggests a post-translational alteration in renin processing and/or renin secretion.
AJP: Renal Physiology, 2011
Randomized clinical trials have clearly shown that inhibition of the renin-angiotensin system (RAS) will slow the rate of progression of diabetic nephropathy, but controversy remains about whether the observed beneficial effects result from more than control of blood pressure. Deletion of eNOS in a model of type II diabetes, db/db mice (eNOS−/− db/db), induces an accelerated nephropathy and provides an excellent model of human diabetic nephropathy. As is frequently seen in type II diabetes, blood pressure is moderately elevated in eNOS−/− db/db mice. To determine the role of elevated blood pressure per se vs. additional deleterious effects of the RAS in mediation of disease progression, 8-wk-old eNOS−/− db/db mice were randomly divided into three groups: vehicle, treatment with the angiotensin-converting enzyme inhibitor (ACEI) captopril, or treatment with “triple therapy” (hydralazine, resperine, hydrocholorothiazide), and the animals were euthanized after treatment for 12 wk. Bloo...
International Journal of Pharmacy Practice & Drug Research
To evaluate the effect of Angiotensin Converting Enzyme Inhibitors (ACEI) and Angiotensin Receptor Blockers (ARB) in glycemic control among the Diabetic Nephropathy patients. A cross sectional study was done among the type 2 diabetics presenting consecutively to a diabetes specialty hospital with Diabetic Nephropathy. 35 patients were studied over a period of five months Patients were subjected to the clinical and laboratory investigations. The patient had average age of 57.1 years and the average duration of diabetes mellitus was 9.35 years and patients are grouped into two as ACEI and ARB. Both the groups are also treated for glycemic control with Gliclazide-Metformin combination (48.57%) and Glimepride-Metformin combination (28.57%) & others (22.86%). We found that at initial visit, average Blood Glucose (F) was 132mg/dl & 134mg/dl and Average Blood Glucose (PP) was 211mg/dl & 226mg/dl in ACEI & ARB groups respectively. The Initial average HbA1c values are 8.33 % & 8.71 % in ACEI & ARB groups respectively. On subsequent visits it is found to be reduced to 127mg/dl & 115mg/dl of Blood Glucose (F) and 208mg/dl & 189mg/dl of Blood Glucose (PP) in both groups respectively and HbA1c is also found to be reduced to 8.17 and 7.08 in both groups respectively. Thus we conclude that among the two groups ARB group has significant effect on glycemic control compared to ACEI group.
The Renin-Angiotensin System in the Pathophysiology of Type 2 Diabetes
Obesity Facts, 2012
Increased activation of the renin-angiotensin system (RAS) has been related to cardiovascular disease and type 2 diabetes mellitus. Most randomized clinical trials have demonstrated that RAS blockade reduces the incidence of type 2 diabetes, which has been explained by improved insulin secretion and insulin sensitivity. In this review, an overview of the mechanisms that may underlie the association between the RAS and type 2 diabetes will be provided, with focus on skeletal muscle and adipose tissue function. This will include discussion of several human studies performed in our laboratory to investigate the metabolic and hemodynamic effects of the RAS, combining in vivo measurements of whole-body and tissue metabolism with molecular and immunohistochemical approaches. Available data suggest that the detrimental effects of the RAS on insulin secretion are mediated by a reduction in pancreatic blood flow and induction of islet fibrosis, oxidative stress as well as inflammation, where...
Pakistan journal of pharmaceutical sciences, 2014
Diabetes mellitus is a multifactorial disorder of hyperglycemia caused by a combination of biochemical, molecular and genetic factors, which leads to the dysfunction of various organs including kidneys. Diabetic nephropathy (DN) is one of the microvascular complications of diabetes that results due to poor glycemic control. Several molecular and biochemical pathways have been implicated in the pathogenesis of DN. Of these, the Renin Angiotensin Aldosterone System (RAAS) is considered as a key pathway. RAAS involves various subsystems which contribute to the development of DN. Mutations in several genes of the RAAS pathway have been associated with the development of DN. These genes or their products present them as therapeutic targets for potent drugs to control or prevent DN, and development of new drugs for targeting the RAAS. Drugs in use for DN are mainly the Angiotensin Converting Enzyme (ACE) inhibitors, Angiotensin Receptors Blockers (ARB) and renin inhibitors which play impo...
Hyperglycemia and Renin-dependent hypertension synergize to model diabetic nephropathy
Journal of the American Society of Nephrology : JASN, 2012
Rodent models exhibit only the earliest features of human diabetic nephropathy, which limits our ability to investigate new therapies. Hypertension is a prerequisite for advanced diabetic nephropathy in humans, so its rarity in typical rodent models may partly explain their resistance to nephropathy. Here, we used the Cyp1a1mRen2 rat, in which the murine renin-2 gene is incorporated under the Cytochrome P4501a1 promoter. In this transgenic strain, administration of low-dose dietary indole-3-carbinol induces moderate hypertension. In the absence of hypertension, streptozotocin-induced diabetes resulted in a 14-fold increase in albuminuria but only mild changes in histology and gene expression despite 28 weeks of marked hyperglycemia. In the presence of induced hypertension, hyperglycemia resulted in a 500-fold increase in albuminuria, marked glomerulosclerosis and tubulointerstitial fibrosis, and induction of many of the same pathways that are upregulated in the tubulointerstitium in...
Pakistan journal of pharmaceutical sciences
Diabetes mellitus is a multifactorial disorder of hyperglycemia caused by a combination of biochemical, molecular and genetic factors, which leads to the dysfunction of various organs including kidneys. Diabetic nephropathy (DN) is one of the microvascular complications of diabetes that results due to poor glycemic control. Several molecular and biochemical pathways have been implicated in the pathogenesis of DN. Of these, the Renin Angiotensin Aldosterone System (RAAS) is considered as a key pathway. RAAS involves various subsystems which contribute to the development of DN. Mutations in several genes of the RAAS pathway have been associated with the development of DN. These genes or their products present them as therapeutic targets for potent drugs to control or prevent DN, and development of new drugs for targeting the RAAS. Drugs in use for DN are mainly the Angiotensin Converting Enzyme (ACE) inhibitors, Angiotensin Receptors Blockers (ARB) and renin inhibitors which play impo...