Inhibition of (pro)renin Receptor Contributes to Renoprotective Effects of Angiotensin II Type 1 Receptor Blockade in 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...
(Pro)renin receptor: another member of the system controlled by angiotensin II?
Journal of the Renin-Angiotensin-Aldosterone System, 2012
The prorenin receptor [(P)RR] is upregulated in the diabetic kidney and has been implicated in the high glucose (HG)induced overproduction of profibrotic molecules by mesangial cells (MCs), which is mediated by ERK1/2 phosphorylation. The regulation of (P)RR gene transcription and the mechanisms by which HG increases (P)RR gene expression are not fully understood. Because intracellular levels of angiotensin II (AngII) are increased in MCs stimulated with HG, we used this in vitro system to evaluate the possible role of AngII in (P)RR gene expression and function by comparing the effects of AT1 receptor blockers (losartan or candesartan) and (P)RR mRNA silencing (siRNA) in human MCs (HMCs) stimulated with HG. HG induced an increase in (P)RR and fibronectin expression and in ERK1/2 phosphorylation. These effects were completely reversed by (P)RR siRNA and losartan but not by candesartan (an angiotensin receptor blocker that, in contrast to losartan, blocks AT1 receptor internalization). These results suggest that (P)RR gene activity may be controlled by intracellular AngII and that HG-induced ERK1/2 phosphorylation and fibronectin overproduction are primarily induced by (P)RR activation. This relationship between AngII and (P)RR may constitute an additional pathway of MC dysfunction in response to HG stimulation.
highlight that both DM and hypertension exacerbate each other in terms of subsequent complications (Cooper & Johnston, 2000) increasing the burden of social dysfunction and high risk of premature death. DM is a chronic metabolic disorder characterized by hyperglycemia and insufficiency of secretion or action of endogenous insulin. Nowadays, diabetes afflicts around 6.6% of the global adult population, or approximately 285 million individuals, and this is projected to increase by more than 50% to a 7.8% worldwide prevalence in 20 years. Considering that DM is an important health problem and it has been recognized as a major risk factor for the development of complications in target organs, including retinopathy, neuropathy, nephropathy and cardiovascular disease, the comprehension of the mechanisms involved in the association among diabetes is the subject of many research groups (International Diabetes Federation, 2009).
International Journal of Nephrology
Objective. The nephron (pro)renin receptor may play a pathophysiological role in renal disorders in hypertension or diabetes. The aim of this study was to determine the relationship of (pro)renin receptors and transdifferentiation between the renin-negative and renin-positive SMCs in the afferent arteriole by estimating the distribution of (pro)renin receptors in renin-positive and renin-negative SMCs of the afferent arteriole of kidneys in normal and streptozotocin- (STZ-) induced diabetic rats. Therefore in diabetes the renin granulation of afferent arterioles is different as in normal, the diabetes model for finding the differences to normal in distribution of (pro)renin receptors of afferent arterioles was used. Method. To estimate the number of (pro)renin receptors in arteriolar SMCs a special protocol of immunohistochemistry to stereology was followed. Results. Our results showed that on the surface of renin-positive SMCs the number of (pro)renin receptors was upregulated, whi...
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...
Renin-angiotensin system activation and interstitial inflammation in human diabetic nephropathy
Kidney international. Supplement, 2003
The molecular mechanisms of renal injury in diabetic nephropathy (DN) are not completely understood, although inflammatory cells play a key role. The renin-angiotensin system (RAS) is involved in kidney damage; however, few studies have examined the localization of RAS components in human DN. Our aim was to investigate in renal biopsies the expression of RAS and their correlation with proinflammatory parameters and renal injury. The biopsies from 10 patients with type 2 diabetes mellitus and overt nephropathy were studied for the expression of RAS components by immunohistochemistry (IH). In addition, by Southwestern histochemistry we studied the in situ detection of the activated nuclear factor kappa B (NFkappaB), and by IH and/or in situ hybridization (ISH), the expression of monocyte chemoattractant protein-1 (MCP-1) and regulated upon activation, normal T cell expressed and secreted (RANTES), whose genes are regulated by NFkappaB. Angiotensin-converting enzyme (ACE) immunostainin...
Blockade of the renin–angiotensin system for the primary prevention of diabetic nephropathy
Diabetes management, 2012
The prevention of chronic kidney disease is a primary goal for diabetes management. Lowering blood pressure can reduce the incidence of microalbuminuria in Type 1 or Type 2 diabetes, especially in patients with hypertension. Blockade of the renin-angiotensin system (RAS) is an effective strategy to reduce blood pressure in diabetic patients, but no more so than other antihypertensive strategies. RAS blockers have a more favorable side-effects profile compared to other antihypertensive agents, meaning that generally patients are more likely to take them. Any 'independent' effect of RAS blockade for the primary prevention of diabetic nephropathy, beyond blood-pressure control, remains to be clearly established. New combination strategies using renin inhibitors or aldosterone antagonists, to achieve a more complete RAS blockade, have the potential to improve renal outcomes in patients with diabetes. Summary There is clear evidence for the pathogenic role of the renin-angiotensin system (RAS) in the progression of diabetic kidney. Treatment with either an a ngiotensin-converting enzyme inhibitor or angiotensin receptor blocker have been shown to reduce proteinuria and preserve renal function in patients with diabetes and chronic kidney disease. While such data provide a strong rationale for early and sustained blockade of the RAS for the primary prevention of kidney disease, clinical trial evidence to support this goal is limited and inconsistent. By contrast, data from observational and clinical trials clearly demonstrate the primacy of blood-pressure control in the development of diabetic kidney disease, especially in hypertensive patients. Whether RAS blockade offers additional benefits for primary prevention, over-and-above blood-pressure control, remains contentious. At best, any 'independent effects' on primary prevention are modest, and certainly not the panacea envisaged by many practitioners. However, the better tolerability, efficacy and side-effects profile of RAS blockers, and other actions on retinopathy and cardiovascular disease, means that most patients with diabetes currently receive RAS blockers as first line antihypertensive agents. The future development of more effective 'escape-proof' regimens currently offers the best way forward to realize the hope that RAS blockade will ultimately prevent diabetic kidney disease in the clinic as effectively as it does in animal models.