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)

Diabetes and hyperhomocysteinemia (HHcy) are two independent risk factors for glomeruloslerosis and renal insufficiency. Although PPARgamma agonists such as ciglitazone (CZ) are known to modulate diabetic nephropathy, the role of CZ in diabetes-associated HHcy and renopathy is incompletely defined. We tested the hypothesis that induction of PPARgamma by CZ decreases tissue Hcy level; this provides a protective role against diabetic nephropathy. C57BL/6J mice were administered alloxan to create diabetes. Mice were grouped to 0, 1, 10, 12, and 16 wk of treatment; only 12- and 16-wk animals received CZ in drinking water after a 10-wk alloxan treatment. In diabetes, PPARgamma cDNA, mRNA, and protein expression were repressed, whereas an increase in plasma and glomerular Hcy levels was observed. CZ normalized PPARgamma mRNA and protein expression and glomerular level of Hcy, whereas plasma level of Hcy remained unchanged. GFR was dramatically increased at 1-wk diabetic induction, followed by hypofiltration at 10 wk, and was normalized by CZ treatment. This result corroborated with glomerular and preglomerular arteriole histology. A steady-state increase of RVR in diabetic mice became normal with CZ treatment. CZ ameliorated decrease bioavailability of NO in the diabetic animal. Glomerular MMP-2 and MMP-9 activities as well as TIMP-1 expression were increased robustly in diabetic mice and normalized with CZ treatment. Interestingly, TIMP-4 expression was opposite to that of TIMP-1 in diabetic and CZ-treated groups. These results suggested that diabetic nephropathy exacerbated glomerular tissue level of Hcy, and this caused further deterioration of glomerulus. CZ, however, protected diabetic nephropathy in part by activating PPARgamma and clearing glomerular tissue Hcy.
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PMID:Ciglitazone, a PPARgamma agonist, ameliorates diabetic nephropathy in part through homocysteine clearance. 1878 Jul 70

Glomerulosclerosis, defined as phenotype transition of mesangial cell and deposition of extracellular matrix, remains a chronic disease with excessive morbidity and mortality. The molecular mechanism underlying the suppression of mesangial cell activation is not fully understood. Since activation of peroxisome proliferators-activated receptor gamma (PPARgamma) has been proposed to decrease the effects of transforming growth factor-beta (TGF-beta) on glomerulosclerosis, we examined here whether and how telmisartan, an angiotensin II type 1 receptor blocker with PPARgamma-modulating activity, inhibited TGF-beta-induced glomerulosclerosis in rat glomerular mesangial cells. Protein levels of PPARgamma were detected by Western blot. Activation of PPARgamma response element (PPRE) was analyzed by luciferase assays. Deposition of extracellular matrix was tested by confocal laser scanning. The results showed that telmisartan, but not valsartan, another angiotensin II type 1 receptor blocker, up-regulated PPARgamma protein levels in a dose-dependent manner (P<0.05). Activation of PPRE, represented by luciferase activity, was also increased with higher concentration of telmisartan in a dose-dependent manner (P<0.05). Furthermore, telmisartan inhibited TGF-beta-induced alpha-smooth muscle actin expression and collagen IV secretion in mesangial cells. GW9662, an inhibitor of PPAR-gamma, blocked the inhibitory effects of telmisartan on TGF-beta-induced glomerulosclerosis in mesangial cells. Our study indicates a benefit of telmisartan as a PPARgamma agonist against TGF-beta-induced mesangial cells activation in renal glomerulus. It may provide possibility that telmisartan works as a potential agent against diabetic nephropathy and hypertensive renal disease.
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PMID:Telmisartan but not valsartan inhibits TGF-beta-mediated accumulation of extracellular matrix via activation of PPARgamma. 1884 35

DN (diabetic nephropathy) is a chronic disease characterized by proteinuria, glomerular hypertrophy, decreased glomerular filtration and renal fibrosis with loss of renal function. DN is the leading cause of ESRD (end-stage renal disease), accounting for millions of deaths worldwide. TZDs (thiazolidinediones) are synthetic ligands of PPARgamma (peroxisome-proliferator-activated receptor gamma), which is involved in many important physiological processes, including adipose differentiation, lipid and glucose metabolism, energy homoeostasis, cell proliferation, inflammation, reproduction and renoprotection. A large body of research over the past decade has revealed that, in addition to their insulin-sensitizing effects, TZDs play an important role in delaying and preventing the progression of chronic kidney disease in Type 2 diabetes. Although PPARgamma activation by TZDs is in general considered beneficial for the amelioration of diabetic renal complications in Type 2 diabetes, the underlying mechanism(s) remains only partially characterized. In this review, we summarize and discuss recent findings regarding the renoprotective effects of PPARgamma in Type 2 diabetes and the potential underlying mechanisms.
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PMID:Role of PPARgamma in renoprotection in Type 2 diabetes: molecular mechanisms and therapeutic potential. 1903 81

Our previous findings demonstrated that emodin could improve the renal function in rats with diabetic nephropathy, but little is known about its molecular mechanisms. In this study, we investigated the effects of emodin on high glucose (HG)-induced cell proliferation and fibronectin (FN) protein expression in rat mesangial cells, and explored the possible mechanism. Cell proliferation and cell cycle were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assay, respectively. The protein levels of FN, p-p38MAPK, t-p38MAPK, p-CREB, PPARgamma, and CTGF in rat mesangial cells were detected by Western blot. Our results demonstrated that emodin significantly suppressed HG-induced cell proliferation and arrested cell cycle progress. Protein expression of FN, phospho-p38MAPK, phospho-CREB and CTGF was markedly reduced, and PPARgamma protein level was significantly increased after emodin treatment. In conclusion, emodin suppressed HG-induced cell proliferation and FN expression in rat mesangial cells through inhibiting the p38MAPK pathway involved CREB, PPAPgamma and CTGF, suggesting a potential role of emodin in the treatment of diabetic nephropathy.
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PMID:Emodin suppresses cell proliferation and fibronectin expression via p38MAPK pathway in rat mesangial cells cultured under high glucose. 1952 36

Diabetic nephropathy is a leading cause of morbidity and mortality in hyperglycemic patients. Angiotensin converting enzyme inhibitors and angiotensin-II AT(1) receptor blockers are currently employed to treat patients with diabetic nephropathy; but these agents are considered to be inadequate to control the symptoms of diabetic nephropathy. Recent studies suggest that PPAR ligands are promising agents to prevent the progression of diabetic nephropathy. In the present review, we discussed the novel role of PPARalpha and PPARgamma agonists in the management of diabetic nephropathy.
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PMID:Emerging role of PPAR ligands in the management of diabetic nephropathy. 1964 56

Increased glomerular permeability to proteins is a characteristic feature of diabetic nephropathy (DN). The slit diaphragm is the major restriction site to protein filtration, and the loss of nephrin, a key component of the slit diaphragm, has been demonstrated in both human and experimental DN. Both systemic and glomerular hypertension are believed to be important in the pathogenesis of DN. Human immortalized podocytes were subjected to repeated stretch-relaxation cycles by mechanical deformation with the use of a stress unit (10% elongation, 60 cycles/min) in the presence or absence of candesartan (1 microM), PD-123319 (1 microM), and rosiglitazone (0.1 microM). Nephrin mRNA and protein expression were assessed using quantitative real-time PCR, immunoblotting, and immunofluorescence, and the protein expression of AT(1) receptor and angiotensin II secretion were evaluated. Exposure to stretch induced a significant approximately 50% decrease in both nephrin mRNA and protein expression. This effect was mediated by an angiotensin II-AT(1) mechanism. Indeed, podocyte stretching induced both angiotensin II secretion and AT(1) receptor overexpression, podocyte exposure to angiotensin II reduced nephrin protein expression, and both the AT-1 receptor antagonist candesartan and a specific anti-angiotensin II antibody completely abolished stretch-induced nephrin downregulation. Similar to candesartan, the peroxisome proliferator-activated receptor (PPAR)-gamma agonist, rosiglitazone, also inhibited stretch-induced nephrin downregulation, suggesting interference with stretch-induced activation of the angiotensin II-AT(1) receptor system. Accordingly, rosiglitazone did not alter stretch-induced angiotensin II secretion, but it prevented AT(1) upregulation in response to stretch. These results suggest a role for hemodynamic stress in loss of nephrin expression and allude to a role of PPAR-gamma agonists in the prevention of this loss.
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PMID:Stretch reduces nephrin expression via an angiotensin II-AT(1)-dependent mechanism in human podocytes: effect of rosiglitazone. 1990 46

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor that has a central role in the regulation of insulin sensitivity and adipocyte differentiation. Expression of PPARgamma has been reported in the kidney, including medullary collecting ducts, glomeruli and tubular cells. Thiazolidinediones (TZDs) are synthetic PPARgamma agonists and are used widely in patients with type 2 diabetes. It has been gradually discovered that TZDs have various other actions, such as vascular protective, anti-inflammatory, anti-fibrotic and anti-proliferative actions, over and above their effects on glucose and lipid metabolism. In this review, we will focus on current knowledge and insights on the role of PPARgamma agonists in kidney diseases, especially in diabetic nephropathy, non-diabetic kidney diseases and dialysis therapy.
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PMID:[The role of PPARgamma agonists in kidney diseases]. 2015 3

The present study investigated the combined effect of low doses of fenofibrate (PPAR-alpha agonist) and rosiglitazone (PPAR-gamma agonist) in diabetes-induced experimental nephropathy. Rats were administered streptozotocin (55 mg/kg i.p., once) to induce experimental diabetes mellitus. The development of diabetic nephropathy was assessed biochemically and histologically. In addition, the lipid profile and renal oxidative stress were assessed. The single administration of streptozotocin produced diabetes, which induced the renal oxidative stress, altered the lipid profile, and subsequently produced nephropathy in 8 weeks by elevating serum creatinine, blood urea nitrogen, proteinuria, and inducing glomerular damage. Treatment with low dose fenofibrate (30 mg/kg/day p.o.) normalizes the altered lipid profile in diabetic rats, whereas the low dose rosiglitazone (1mg/kg/day p.o.) treatment has no effect on lipid alteration in diabetic rats. Treatment with low dose rosiglitazone partially reduced the elevated glucose level in diabetic rats, whereas fenofibrate treatment has no effect on it. The low dose combination of fenofibrate and rosiglitazone was more effective in attenuating the diabetes-induced nephropathy and renal oxidative stress as compared to treatment with either drug alone or lisinopril (1mg/kg/day p.o., employed as a standard agent). It may be concluded that diabetes-induced oxidative stress and lipid alterations may be responsible for the induction of nephropathy in diabetic rats. The concurrent administration of fenofibrate and rosiglitazone at low doses may have prevented the development of diabetes-induced nephropathy by reducing the lipid alteration, decreasing the renal oxidative stress and certainly providing the direct nephroprotective action.
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PMID:The low dose combination of fenofibrate and rosiglitazone halts the progression of diabetes-induced experimental nephropathy. 2034 78

Dysfunction of macro- and microvessels is a major cause of morbidity and mortality in patients with cardio-renovascular diseases such as atherosclerosis, hypertension, and diabetes. Renal failure and impairment of renal function due to vasoconstriction of the glomerular arteriole in diabetic nephropathy leads to renal volume retention and increase in plasma homocysteine level. Homocysteine, which is a nonprotein amino acid, at elevated levels is an independent cardio-renovascular risk factor. Homocysteine induces oxidative injury of vascular endothelial cells, involved in matrix remodeling through modulation of the matrix metalloproteinase (MMP)/tissue inhibitor of metalloproteinase (TIMP) axis, and increased formation and accumulation of extracellular matrix protein, such as collagen. In heart this leads to increased endothelial-myocyte uncoupling resulting in diastolic dysfunction and hypertension. In the kidney, increased matrix accumulation in the glomerulus causes glomerulosclerosis resulting in hypofiltration, increased renal volume retention, and hypertension. PPARgamma agonist reduces tissue homocysteine levels and is reported to ameliorate homocysteine-induced deleterious vascular effects in diabetes. This review, in light of current information, focuses on the beneficial effects of PPARgamma agonist in homocysteine-associated hypertension and vascular remodeling in diabetes.
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PMID:Homocysteine and Hypertension in Diabetes: Does PPARgamma Have a Regulatory Role? 2061 90

1. Volume expansion is observed in animal and human models of diabetic nephropathy, which is in a large part a result of disordered renal tubular cell sodium and water transport. 2. Sodium transport in the proximal tubule is increased in diabetes mellitus as a result of enhanced activity of the sodium-hydrogen exchanger-3 (NHE3), the key transporter for transcellular reabsorption of sodium. Transactivation of the epidermal growth factor receptor (EGFR) by factors inherent in the milieu of diabetes mellitus increases serum glucocorticoid regulated kinase-1 (Sgk1), a key regulator of NHE3. 3. Enhanced sodium and water reabsorption, occurring as a consequence of endogenous or pharmacological stimulation of the peroxisome proliferator-activated receptor gamma is Sgk1 mediated. 4. EGFR inhibitors, which are currently used clinically to treat malignancies, might have potential in attenuating the cellular mechanisms responsible for thiazolidinedione (TZD)-mediated sodium and water transport in diabetes. 5. In the present review, the authors focus on the importance of the EGFR in sodium and water uptake in the proximal tubule in the environment of pathophysiological and pharmacological influences.
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PMID:Renal epidermal growth factor receptor: its role in sodium and water homeostasis in diabetic nephropathy. 2115 63


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