Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The incidence of chronic kidney disease, such as diabetic nephropathy, is increasing throughout the world. Many biologically active peptides play important roles in the kidney. The classical example is the renin-angiotensin system (RAS). Angiotensin II plays critical roles in the progression of chronic kidney disease through its vasoconstrictor action, stimulatory action on cell proliferation, and reactive oxygen-generating activity. A renin inhibitor, aliskiren, has recently been shown to be a clinically effective drug to reduce proteinuria in patients with diabetic nephropathy. (Pro)renin receptor, a specific receptor for renin and prorenin, was newly identified as a member of the RAS. When bound to prorenin, (pro)renin receptor activates the angiotensin I-generating activity of prorenin in the absence of cleavage of the prosegment, and directly stimulates the pathway of mitogen-activated protein kinase independently from the RAS. The kidney peptides that antagonize the intrarenal RAS may have renoprotective actions. Adrenomedullins, potent vasodilator peptides, have been shown to have renoprotective actions. On the other hand, urotensin II, a potent vasoconstrictor peptide, may promote the renal dysfunction in chronic kidney disease together with the renal RAS. Thus, in addition to the renin inhibitor and (pro)renin receptor, adrenomedullins and urotensin II may be novel targets to develop therapeutic strategies against chronic kidney disease.
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PMID:The renin-angiotensin system, adrenomedullins and urotensin II in the kidney: possible renoprotection via the kidney peptide systems. 1947 9

1. (Pro)renin receptor (PRR) binding to renin or prorenin mediates angiotensin (Ang) II-dependent and -independent effects. Expression of the PRR is increased in kidneys of diabetic rats, but its role in diabetic nephropathy is unknown. In the present study, we investigated the contribution of the PRR to the development of diabetic nephropathy through enhancement of renal production of tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta. 2. Normoglycaemic control and streptozotocin-diabetic Sprague-Dawley rats were used in the study. The urine albumin : creatinine ratio (UACR), renal interstitial fluid (RIF) levels of AngII, TNF-alpha and IL-1beta and renal expression of TNF-alpha and IL-1beta were evaluated in control, untreated diabetic and diabetic rats treated with either a PRR blocker (PRRB; 0.2 mg/kg per day NH3-RILLKKMPSV-COOH), the AT(1) receptor antagonist valsartan (2 mg/kg per day) or combined therapy, administered directly into the renal cortical interstitium for 14 days via osmotic minipumps. 3. Compared with values in normoglycaemic control rats, UACR and RIF AngII, TNF-alpha and IL-1beta were significantly higher in untreated diabetic rats. Treatment of diabetic rats with the PRRB or valsartan alone and in combination significantly reduced UACR and RIF TNF-alpha and IL-1beta levels. Renal expression of TNF-alpha and IL-1beta was higher in untreated diabetic rats than in control rats, but was reduced significantly following treatment with PRRB or valsartan alone and in combination. Renal PRR expression was increased in untreated and PRRB-treated diabetic rats and reduced in rats receiving valsartan alone or combination therapy. The PRRB had no effect on RIF AngII levels, whereas valsartan alone and in combination with the PRRB significantly increased AngII levels. 4. In conclusion, the PRR is involved in the development and progression of kidney disease in diabetes by enhancing renal production of the inflammatory cytokines TNF-alpha and IL-1beta, independent of renal AngII effects.
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PMID:(Pro)renin receptor contributes to diabetic nephropathy by enhancing renal inflammation. 1993 Apr 21

Activation of prorenin/renin receptor [(P)RR] mediates non-enzymatic pathway for the physiological function of prorenin/renin. It also plays a role in the pathogenesis of diabetic nephropathy. However, the mechanisms of regulating (P)RR expression are only partially understood. In the present study, we examine the change of (P)RR under hyperglycemic conditions in the kidneys of streptozotocin (STZ)-induced diabetic (DM) rats and cultured rat renal glomerular mesangial cells (MCs). The (P)RR mRNA level was significantly lower in the kidney of (DM) rats than that of untreated control animals, meanwhile the plasma and renal angiotensin II (Ang II) levels and Ang II type 2 receptor (AT(2)R) mRNA level, but not Ang II type 1 receptor (AT(1)R) mRNA level were increased in (DM) rats. In cultured MCs, Ang II reduced the (P)RR expression and this inhibitory effect was blocked by the AT(2)R antagonist, PD123319, but not the AT(1)R antagonist, losartan. The AT(2)R agonist CGP42112A produced a similar effect as Ang II. Exposure to high glucose (30mM) resulted in a decrease in the (P)RR expression. PD123319, but not losartan, reversed high glucose induced (P)RR expression reduction. The present results indicate that activation of AT(2)R, but not AT(1)R, is most likely responsible for the reduced (P)RR expression in response to Ang II and high glucose in glomerular MCs and the renal tissue of STZ-treated rats.
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PMID:Angiotensin II type 2 receptor mediated angiotensin II and high glucose induced decrease in renal prorenin/renin receptor expression. 1987 25

Aliskiren, the first orally effective direct renin inhibitor, is an effective antihypertensive agent with distinctive properties including placebo-like tolerability, pharmacologic effects that persist after drug discontinuation, and a unique mechanism of action. When combined with agents that inhibit the renin-angiotensin-aldosterone system (RAAS), such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or beta-blockers, additional blood pressure reduction reflects more complete RAAS blockade. Concern that marked elevation in plasma renin concentration following aliskiren administration might lead to RAAS-induced paradoxical blood pressure increases appears unfounded, based upon analyses of patients participating in clinical trials. Studies in animals and humans indicate that aliskiren accumulates in renal tissue, blocks the intrarenal RAAS, and interferes with deleterious cellular effects of angiotensin II by mechanisms that may include enzymatic blockade of renin and prorenin at the site of the (pro)renin receptor. In patients with diabetic nephropathy, adding aliskiren to losartan resulted in an additional 20% reduction in urinary protein excretion. In patients with heart failure, aliskiren reduced brain natriuretic peptide levels when added to other RAAS inhibitors, suggesting an additional hemodynamic effect. The ASPIRE HIGHER clinical trials program is assessing whether the promising pharmacologic properties of aliskiren translate into long-term clinical benefits.
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PMID:Direct renin inhibition: an update. 1989 58

Inhibition of the renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in preventing and treating diabetic nephropathy. However, despite documented beneficial effects of RAAS inhibitors in diabetic patients with nephropathy, reversal of the progressive course of this disorder or at least long-term stabilization of renal function are often difficult to achieve, and many patients still progress to end-stage renal disease. Incomplete inhibition of the RAAS has been postulated as one of the reasons for unsatisfactory therapeutic responses to RAAS inhibition in some patients. Inhibition of renin, a rate-limiting step in the RAAS activation cascade, is the logical approach to overcome at least some of the above-mentioned problems associated with the treatment with traditional RAAS inhibitors. This article focuses on experimental and clinical studies evaluating the two principal approaches to renin inhibition: direct renin inhibition with competitive inhibitors (eg, aliskiren) and inhibition of the (pro)renin receptor.
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PMID:What is the role of renin inhibition in the treatment of diabetic kidney disease? 1995 90

The discovery of a (pro)renin receptor ((P)RR) and the introduction of renin inhibitors in the clinic has brought prorenin, the inactive proenzyme form of renin, back into the spotlight. The (P)RR binds both renin and its inactive precursor prorenin, and their binding triggers intracellular signaling that up-regulates the expression of profibrotic genes. Furthermore, binding of prorenin unmasks its active site and endows prorenin with angiotensin I-generating activity. Many studies have attempted to establish a link between (P)RR and hypertension, (P)RR and tissue fibrosis associated with hypertension and with diabetic nephropathy. Models of transgenic rats overexpressing (P)RR develop high blood pressure and have glomerulosclerosis, suggesting a link between increased (P)RR and these pathologies, but no definite proof of any role of (P)RR in other models of cardiovascular or renal diseases could be established because of the absence of any specific (P)RR antagonist and of tissue-specific (P)RR null mice. Nevertheless, a study in a large cohort of Japanese men has shown a correlation between a polymorphism in the (P)RR gene and increased ambulatory blood pressure. Finally, a mutation in the (P)RR gene is responsible for mental retardation and epilepsy, indicating that (P)RR is essential during brain development.
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PMID:Potential role of the (pro)renin receptor in cardiovascular and kidney diseases. 2038 69

(Pro)renin receptor ((P)RR), a specific receptor for renin and prorenin, is a 350 amino-acid protein with a single transmembrane domain and may play important pathophysiological roles in diabetic nephropathy. The aim of the present study is to clarify the expression of (P)RR in the kidney with end-stage renal disease due to diabetic nephropathy. The kidney tissues were obtained at autopsy from patients with and without Type 2 diabetes mellitus (n=5 without diabetes mellitus; and n=8 with diabetes mellitus). Immunocytochemistry showed that (P)RR was mainly expressed in the tubular cells and collecting duct cells of the kidney without diabetic nephropathy. Cells in glomeruli were very weakly and sporadically immunostained for (P)RR. Vascular smooth muscle cells and endothelial cells were very weakly or were not immunostained for (P)RR. Adipocytes in the adipose tissue around the kidney were positively immunostained for (P)RR. Immunostaining pattern of (P)RR in the kidney with diabetic nephropathy was similar to that without diabetic nephropathy. However, most notably, (P)RR immunostaining in the tubular cells and collecting duct cells was clearly and frequently more strongly observed in the kidney with diabetic nephropathy up to the end-stage renal disease. The present study has raised the possibility that (P)RR expressed in the diabetic kidney may play a pathophysiological role in angiotensin I generation and renal fibrosis found in end-stage renal disease.
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PMID:Expression of (pro)renin receptor in human kidneys with end-stage kidney disease due to diabetic nephropathy. 2038 87

The (pro)renin receptor [(P)RR] specifically binds renin and prorenin and mediates their intracellular effects. It acts as co-factor for renin and prorenin by increasing their enzymatic activity on the cell-surface and it activates the mitogen activated protein kinases ERK1/2 (extracellular signal regulated kinase) cascade leading to cell proliferation and to upregulation of profibrotic genes expression. Studies in genetically modified animals over-expressing ubiquitously (P)RR or specifically in smooth-muscle cells suggest a direct role for (P)RR cardiovascular and renal pathologies. A putative (P)RR blocker consisting in part of the prosegment of prorenin gave spectacular results in the prevention of diabetic nephropathy and cardiac fibrosis but its mechanism of action and its specificity for (P)RR remain controversial. Unexpectedly, the total ablation of (P)RR gene is impossible in contrast to the other components of the renin angiotensin system (RAS) and studies in zebra fish and in embryonic stem cells indicate that (P)RR is necessary to cell survival and proliferation. Furthermore, a mutation of (P)RR is associated with mental retardation and epilepsy, pointing to an essential role of (P)RR in brain development. If the role of (P)RR in cardiovascular and renal diseases can be confirmed in (P)RR knockout animals, the benefit of a (P)RR blocker in order to optimize the tissue RAS blockade should really be addressed but not without a good understanding of all its functions and not only those related to the RAS.
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PMID:Twenty years of the (pro)renin receptor. 2040 87

We present a critical review on emerging concepts on the role of (pro)renin receptor, (P)RR, in diabetic and hypertensive nephropathy. Discovery of nonproteolytic activation of prorenin by the receptor led to nontoxic peptidic prorenin receptor blocker. The receptor blocker permitted long-term in vivo studies on the role of (P)RR in diabetic and hypertensive end-organ damage. Chronic infusion of receptor blocker prevented streptozotocin diabetic nephropathy and attenuated hypertensive cardiomyopathy and nephropathy. In support of these results, transgenic rats overexpressing the receptor nonselectively developed renal glomerulopathy with aging without elevating blood glucose or blood pressures. It indicated that the receptor overexpression alone is sufficient for end-organ damage, and diabetes mellitus and hypertension induce the end-organ damage by increasing (P)RR expression. We propose that (P)RR is a pivotal link between pathogenesis of diabetes mellitus and end-organ damage. (P)RR seems to activate this mechanism largely by activating receptor signals rather than by local angiotensin II. We realized that (P)RR blocker is a competitive inhibitor against prorenin, and its efficiency depends on ambient concentration of prorenin and renin. Optimization of the condition will be necessary to maximize the inhibitory and therapeutic effects.
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PMID:Renin/prorenin receptor, (P)RR, in end-organ damage: current issues in 2007. 2040 4

Previous studies have demonstrated that prorenin plays a significant role in the development and progression of nephropathy in streptozotocin-induced diabetic animals, a model for type 1 diabetes, through a (pro)renin receptor-dependent mechanism. However, whether this novel mechanism also contributes to the mechanism of diabetic nephropathy in type 2 diabetes has remained undetermined. In 16-week-old db/db mice, a model for type 2 diabetes, we found a significant degree of glomerulosclerosis, enhanced immunostaining for the active site of renin (representing non-proteolytically activated prorenin), and an increased immunoreactivity to activated extracellular-signal-related protein kinase 1/2 in the kidneys. These changes were blocked by the chronic subcutaneous administration (1 mg/kg/day) of a decoy peptide with the "handle region" structure, which competitively inhibits prorenin binding to a "handle region"-specific binding protein, such as the (pro)renin receptor. The kidneys of db/db mice also contained increased angiotensin (Ang) I and II levels, eliciting significant microalbuminuria. Treatment with the "handle region" peptide significantly decreased the renal content of Ang I and II and inhibited the development of microalbuminuria. Thus prorenin also contributes to the development of nephropathy in type II diabetes, probably through a (pro)renin receptor-dependent mechanism.
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PMID:Involvement of receptor-bound prorenin in development of nephropathy in diabetic db/db mice. 2040 15


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