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)

Substantial evidence suggests that the intrarenal renin-angiotensin system (RAS) plays a role in the pathogenesis of diabetic nephropathy. Although the glomerular RAS is activated in the streptozotocin (STZ)-diabetic rat, the status of the glomerular RAS in the Zucker diabetic fatty (ZDF) rat, which is a commonly used genetic model of diabetes, is not known. Angiotensinogen (AGT), angiotensin II (Ang II), angiotensin converting enzyme (ACE), and angiotensin converting enzyme 2 (ACE2) were measured in glomeruli isolated from 4-week-old STZ-diabetic rats and 32-week-old ZDF rats. Glomerular injury was evaluated by histopathologic methods. Both STZ-diabetic and ZDF rats exhibited marked hyperglycemia and renal hypertrophy, but only ZDF rats demonstrated proteinuria and glomerulosclerosis. Glomerular AGT and Ang II levels were increased significantly in STZ-diabetic compared with nondiabetic control rats, accompanied by a reduction in ACE2 activity. In contrast, glomerular AGT, Ang II, and ACE2 were similar in ZDF rats and lean controls. ACE levels were not affected by diabetes in either diabetic model. In conclusion, the glomerular RAS is activated in the STZ diabetic rat but not in the ZDF rat despite a similar degree of hyperglycemia. The mechanism of nephropathy in the ZDF rat may involve factors other than hyperglycemia and RAS activation, such as hypertension and hyperlipidemia.
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PMID:Glomerular renin angiotensin system in streptozotocin diabetic and Zucker diabetic fatty rats. 1835 68

The discovery of a (pro)renin receptor [(P)RR] and the introduction of renin inhibitors in the clinic have brought renin and prorenin back into the spotlight. The (P)RR binds both renin and its inactive precursor prorenin, and such binding triggers intracellular signalling that upregulates the expression of profibrotic genes, potentially leading to cardiac and renal fibrosis, growth and remodelling. Simultaneously, binding of renin to the (P)RR increases its angiotensin I-generating activity, whereas binding of prorenin allows the 'inactive' renin precursor to become fully enzymatically active. Therefore, the (pro)renin receptor system could be considered as having two functions, an angiotensin-independent function related to (P)RR-induced intracellular signalling and its downstream effects and an angiotensin-dependent function related to the increased catalytic activity of receptor-bound (pro)renin. A (P)RR blocker has already been described which blocks both functions, thus preventing diabetic nephropathy, cardiac fibrosis and ocular neovascularization. On-going experimental studies should now determine which of the two functions plays the more important role in pathological situations. The results of these studies are extremely important in view of the clinical use of renin inhibitors, since it is well known that their administration results in increased levels of both renin and prorenin. Although this rise can be interpreted as evidence of effective renin-angiotensin system blockade, it could also result in increased (P)RR activation.
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PMID:Prorenin and (pro)renin receptor: a review of available data from in vitro studies and experimental models in rodents. 1837 5

In diabetic nephropathy, glomerular mesangial cells exhibit aberrant anabolic activity that includes excessive production of extracellular matrix (ECM) proteins, leading to crowding of filtration surface areas and possible renal failure. In the present study, a murine mesangial cell line (MES-13 cells) was studied to determine the roles of the renin-angiotensin system (RAS) and the insulin-like growth factor (IGF) axis in the anabolic response to elevated glucose levels. Culture of MES-13 cells in medium containing supra-physiological glucose concentrations (>5.5 mmol/l) resulted in increased production of ECM proteins including laminin, fibronectin, and heparan sulfate proteoglycan with concurrent increases in IGF-binding protein (IGFBP)-2 production. These responses were blocked by the angiotensin receptor antagonists saralasin and losartan, while exogenous angiotensin II (Ang II) treatment directly stimulated increases in ECM and IGFBP-2. In all experiments, IGFBP-2 levels were correlated with anabolic activity implicating IGFBP-2 as a possible mediator in cellular responses to high glucose and Ang II. Such mediation appears to involve IGFBP-2 modulation of IGF-I signaling, since all responses to high glucose or Ang II were blocked by immuno-neutralization of IGF-I. These data suggest alterations in the IGF axis as key mechanisms underlying nephropathic responses of mesangial cells to Ang II and high glucose.
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PMID:Angiotensin II- and glucose-stimulated extracellular matrix production: mediation by the insulin-like growth factor (IGF) axis in a murine mesangial cell line. 1839 86

Diabetic nephropathy is the single most common cause of end-stage renal disease (ESRD) and accounts for significant morbidity and mortality. While the incidence of ESRD increased dramatically in the 1980s and 1990s, the U.S. Renal Data System (USRDS) 2005 Annual Data Report shows that 338 out of every million Americans had kidney failure in 2003, down slightly from 340 per million in 2002. This report shows that the numbers of people developing ESRD have stabilized despite the persistent increase in the number of people diagnosed with type 2 diabetes mellitus (T2DM). These data attest to both the efficacy of the currently available therapeutic regimens for the treatment of ESRD as well as better overall patient care. Unfortunately, these encouraging statistics do not apply to all patients. According to the USRDS report, the most marked ESRD decrease was seen in young Caucasian men (<40 years of age), while in other patient groups, particularly African Americans, ESRD has not changed much at all. These observations suggest that more in-depth studies, addressing specific issues, such as race, are needed to understand the disease process fully in order to create novel therapeutic strategies to eradicate the disease completely in all patient populations. The most commonly used therapeutic treatments for diabetic nephropathy are angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (Ang II) receptor blockers (ARBs), implicating the importance of the renin-angiotensin-aldosterone system (RAAS) in the pathophysiology of diabetic nephropathy. The RAAS is not the only vasoactive hormonal system that is involved in the disease process. Over the past decade, studies have suggested that other vasoactive hormones, including endothelin, urotensin II, and the kallikrein-kinin system (KKS), are instrumental in mediating structural and functional alterations in the renal vasculature and parenchyma, leading to the development and progression of diabetic nephropathy. This review will summarize our current understanding of the contribution of vasoactive hormones in the pathophysiology of diabetic nephropathy with specific emphasis on the RAAS, especially the more recently identified components of this hormonal pathway.
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PMID:Vasoactive hormones and the diabetic kidney. 1845 58

The Incipient to Overt: Angiotensin II Blocker, Telmisartan, Investigation on Type 2 Diabetic Nephropathy (INNOVATION) study previously showed that treatment with telmisartan, an angiotensin II receptor blocker, effectively reduced the transition from incipient to overt nephropathy in Japanese type 2 diabetic patients. However, that large study included both normotensive and hypertensive patients. In the present post hoc analysis, we aimed to assess whether or not telmisartan elicits beneficial effects on the progression of microalbuminuria in normotensive patients. We randomized 163 microalbuminuric (urinary albumin-to-creatinine ratio: UACR of 100 to 300 mg/g creatinine) normotensive type 2 diabetic patients to treatment with telmisartan (40 or 80 mg once daily) or placebo over 52 weeks. The patients treated with either dose of telmisartan showed lower transition rates from microalbuminuria to overt nephropathy compared to the placebo group. In addition, more patients on telmisartan reverted to normoalbuminuria (UACR<30 mg/g creatinine): 15.5% of the 40 mg group, 19.6% of the 80 mg group, and 1.9% of the placebo group. In normotensive patients treated with telmisartan, changes in UACR were not significantly correlated with changes in blood pressure. Side effects did not differ among the groups. The present study demonstrates that telmisartan prevents the progression of microalbuminuria (in some cases induces remission of albuminuria) in normotensive Japanese patients with type 2 diabetes. Telmisartan is shown to be safe and well tolerated in these patients.
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PMID:Microalbuminuria reduction with telmisartan in normotensive and hypertensive Japanese patients with type 2 diabetes: a post-hoc analysis of The Incipient to Overt: Angiotensin II Blocker, Telmisartan, Investigation on Type 2 Diabetic Nephropathy (INNOVATION) study. 1863 77

An insertion (I)/deletion (D) polymorphism of the angiotensin-converting-enzyme (ACE) gene influences the circulating and renal activity of the renin-angiotensin-aldosterone system. This Practice Point commentary discusses a 2008 paper by Parving et al. that analyzed the interaction between losartan and the I/D polymorphism in patients in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. The investigators found that patients with type 2 diabetes and proteinuria who have the D allele have an unfavorable renal prognosis, which is improved by losartan treatment (vs placebo) when given together with conventional antihypertensive treatment. No significant improvement in outcomes was observed in losartan-treated patients with the II genotype. Previous observational studies had suggested a decreased beneficial effect of ACE inhibitors in patients with type 1 diabetic nephropathy who have the DD genotype. Prospective studies in this area are needed before I/D genotype characterization can be used to guide the choice of therapy in patients with diabetes and proteinuria.
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PMID:ACE gene polymorphism and the prognosis and treatment of overt diabetic nephropathy. 880 48

Tubular damage is a major feature in the development of diabetic nephropathy. This study investigates the effects of the thiazolidindione rosiglitazone on angiotensin II and advanced glycation end product-induced tubular activation in human proximal tubular epithelial cells IN VITRO. Angiotensin II and advanced glycation end products, both induced a dose-dependent sustained activation of the redox-sensitive transcription factor, Nuclear Factor KAPPA B (NF-kappaB). Nuclear translocation of NF-kappaB was evident already after one hour and persistent for more than four days. Co-incubation of proximal tubular epithelial cells with rosiglitazone significantly reduced angiotensin II and advanced glycation end product-mediated generation of reactive oxygen species, angiotensin II-dependent advanced glycation end product formation, NF-kappaB activation, and NF-kappaB-dependent pro inflammatory gene expression. Most importantly, rosiglitazone effects on NFkappaB activation were maximal at later time points, indicating that rosiglitazone treatment confers long lasting renoprotective effects.
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PMID:Rosiglitazone reduces angiotensin II and advanced glycation end product-dependent sustained nuclear factor-kappaB activation in cultured human proximal tubular epithelial cells. 1871 92

Angiotensin II (ANGII) plays a central role in the enhanced sodium reabsorption in early type 1 diabetes in man and in streptozotocin-induced (STZ) diabetic rats. This study investigates the effect of untreated STZ-diabetes leading to diabetic nephropathy in combination with ANGII treatment, on the abundance and localization of the renal Na(+),K(+)-ATPase (NKA), a major contributor of renal sodium handling. After 7 weeks of STZ-diabetes (i.v. 65 mg kg(-1)) a subgroup of control (C) and diabetic (D7) Wistar rats were treated with ANGII (s.c. minipump 33 microg kg(-1) h(-1) for 24 h; CA and D7A). We measured renal function and mRNA expression, protein level, Serin23 phosphorylation, subcellular distribution, and enzyme activity of NKA alpha-1 subunit in the kidney cortex. Diabetes increased serum creatinine and urea nitrogen levels (C versus D7), as did ANGII (C versus CA, D7 versus D7A). Both diabetes (C versus D7) and ANGII increased NKA alpha-1 protein level and enzyme activity (C versus CA, D7 versus D7A). Furthermore, the combination led to an additive increase (D7 versus D7A, CA versus D7A). NKA alpha-1 Ser23 phosphorylation was higher both in D7 and ANGII-treated rats in the non-cytoskeletal fraction, while no signal was detected in the cytoskeletal fraction. Control kidneys showed NKA alpha-1 immunopositivity on the basolateral membrane of proximal tubular cells, while both D7 and ANGII broadened NKA immunopositivity towards the cytoplasm. Our study demonstrates that diabetes mellitus (DM) increases the mRNA expression, protein level, Ser23 phosphorylation and enzyme activity of renal NKA, which is further elevated by ANGII. Despite an increase in total NKA quantity in diabetic nephropathy, the redistribution to the cystosol suggests the Na(+) pump is no longer functional. ANGII also caused translocation from the basolateral membrane, thus in diabetic states where ANGII level is acutely elevated, the loss of NKA will be exacerbated. This provides another mechanism by which ANGII blockade is likely to be protective.
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PMID:Na+,K+-ATPase is modulated by angiotensin II in diabetic rat kidney--another reason for diabetic nephropathy? 1901 Nov 29

The renin-angiotensin system (RAS) plays a critical role in the development of diabetic nephropathy, and blockade of the RAS is currently used for treatment of diabetic nephropathy. One major problem for the current RAS inhibitors is the compensatory renin increase, which reduces the efficacy of RAS inhibition. We have shown that vitamin D exerts renoprotective actions by transcriptionally suppressing renin. Here we demonstrated that combination therapy with an AT1 receptor blocker and a vitamin D analog markedly ameliorated renal injury in the streptozotocin (STZ)-induced diabetes model due to the blockade of the compensatory renin rise by the vitamin D analog, leading to more effective RAS inhibition. STZ-treated diabetic DBA/2J mice developed progressive albuminuria and glomerulosclerosis within 13 weeks, accompanied by increased intrarenal production of angiotensin (Ang) II, fibronection, TGF-beta, and MCP-1 and decreased expression of slit diaphragm proteins. Treatment of the diabetic mice with losartan or paricalcitol (19-nor-1,25-dihydroxyvitamin D(2), an activated vitamin D analog) alone moderately ameliorated kidney injury; however, combined treatment with losartan and paricalcitol completely prevented albuminuria, restored glomerular filtration barrier structure, and markedly reduced glomerulosclerosis. The combined treatment suppressed the induction of fibronection, TGF-beta, and MCP-1 and reversed the decline of slit diaphragm proteins nephrin, Neph-1, ZO-1, and alpha-actinin-4. These were accompanied by blockade of intrarenal renin and Ang II accumulation induced by hyperglycemia and losartan. These data demonstrate that inhibition of the RAS with combination of vitamin D analogs and RAS inhibitors effectively prevents renal injury in diabetic nephropathy.
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PMID:Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: blockade of compensatory renin increase. 1883 78

Angiotensin converting enzyme (ACE) generates angiotensin II from angiotensin I, which plays a critical role in the pathophysiology of diabetic nephropathy. However, ACE2 generates angiotensin 1-7, which may protect the kidney by attenuating the effects of angiotensin II, since deletion of the Ace2 gene leads to glomerulosclerosis in mice, and pharmacologic inhibition of ACE2 exacerbates experimental diabetic nephropathy. We measured ACE2 and ACE expression in renal biopsies of patients with kidney disease due to type 2 diabetes to determine if the expression pattern is specific to diabetic nephropathy. ACE2 and ACE mRNA levels were measured by real-time PCR in laser microdissected renal biopsies from 13 diabetic and 8 control patients. ACE2 mRNA was significantly reduced by more than half in both the glomeruli and proximal tubules of the diabetic patients compared to controls, but ACE mRNA was increased in both compartments. There was a significant parallel decrease in ACE2 protein expression, determined by immunohistochemistry, in proximal tubules, a pattern not found in 12 patients with focal glomerulosclerosis or 10 patients with chronic allograft nephropathy. Our results suggest that the kidney disease of patients with type 2 diabetes is associated with a reduction in ACE2 gene and protein expression and this may contribute to the progression of renal injury.
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PMID:Decreased glomerular and tubular expression of ACE2 in patients with type 2 diabetes and kidney disease. 1940 93


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