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)

Activated mesangial cells are thought to play a pivotal role in the development of kidney fibrosis under chronic pathological conditions, including DN (diabetic nephropathy). Their prolonged survival may enhance the development of the disease since they express increased amounts of growth factors and extracellular matrix proteins. CTGF (connective tissue growth factor) is one of the growth factors produced by activated mesangial cells and is reported to play a key role in the pathogenesis of DN. Previous studies have shown that addition of exogenous CTGF to HMCs (human mesangial cells) rapidly activates ERK1/2 (extracellular-signal-regulated kinase 1/2) MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase) MAPK, but not the p38 MAPK, despite the activation of the upstream kinases, MKK3/6 (MAPK kinase 3/6). The aim of the present study was to investigate whether the lack of phosphorylated p38 MAPK by CTGF has an anti-apoptotic effect on activated HMCs. We show that in HMC CTGF induces the rapid transcriptional activation and synthesis of MKP-1 (MAPK phosphatase-1), a dual specificity phosphatase that dephosphorylates p38 MAPK. This in turn prevents the anti-apoptotic protein, Bcl-2, from being phosphorylated and losing its function, leading to the survival of the cells. Knockout of MKP-1 protein in mesangial cells treated with CTGF, using siRNA (small interfering RNA) or antisense oligonucleotides, allows p38 MAPK activation and induces mesangial cell death.
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PMID:Connective tissue growth factor (CTGF) promotes activated mesangial cell survival via up-regulation of mitogen-activated protein kinase phosphatase-1 (MKP-1). 1748 38

This study aimed to investigate the effect of the Rho-kinase inhibitor fasudil on the development of diabetic nephropathy and clarify a contribution of the Rho/Rho-kinase pathway to the pathogenesis of diabetic nephropathy. Diabetes was induced in male Sprague-Dawley rats with an intraperitoneal injection of streptozotocin. Animals were then divided into the following 4 groups; normal control rats, diabetic rats, diabetic rats administered fasudil orally and diabetic rats administered fluvastatin (3-hydroxy-methylglutaryl coenzyme A reductase inhibitor, statin) orally. After 1 month of treatment, neither fasudil nor statin had any influence on blood glucose or blood pressure in diabetic rats. While urinary excretion of albumin and 8-hydroxydeoxyguanosine (8-OHdG) was increased in diabetic rats, both of these increases were abolished by fasudil and statin. Rho activity was enhanced in the renal cortex of diabetic rats compared to normal controls, and this enhancement was abolished by statin treatment. Expression of transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) mRNA was up-regulated in the renal cortex of diabetic rats, and this was abolished by fasudil as well as statin. Expression of NOX4 mRNA (catalytic subunit of NAD(P)H oxidase) was up-regulated in the renal cortex of diabetic rats, an effect which was also abolished by fasudil as well as statin. The present study demonstrates that the Rho/Rho-kinase pathway is involved in up-regulation of TGF-beta, CTGF and NAD(P)H oxidase in diabetic kidney. We conclude that suppression of the Rho/Rho-kinase pathway could be a new strategy for the treatment of diabetic nephropathy.
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PMID:The Rho-kinase inhibitor, fasudil, attenuates diabetic nephropathy in streptozotocin-induced diabetic rats. 1751 84

Diabetic nephropathy (DN) remains a major complication in both type 1 and type 2 diabetes. Systemic administration of antitransforming growth factor-beta (TGF-beta) antibody has shown some promise in mouse models of DN. However, chronic blockade of the multifunctional TGB-beta could be problematic. Several downstream effects of TGF-beta are mediated by connective tissue growth factor (CTGF), which is up-regulated in several renal cells and secreted in the urine in the diabetic state. Using murine models of DN (type 1 and type 2) and a CTGF antisense oligonucleotide (ASO) of novel chimeric chemistry, we evaluated the specific role of this target in DN. In the type 1 model of DN, C57BL6 mice were made diabetic using streptozotocin injections and hyperglycemic animals were treated with CTGF ASOs (20 mg/kg/2 qw) for 4 months. ASO, but not mismatch control oligonucleotide, -treated animals showed significant reduction in target CTGF expression in the kidney with a concomitant decrease in proteinuria and albuminuria. Treatment with the CTGF ASO for 8 wk reduced serum creatinine and attenuated urinary albuminuria and proteinuria in diabetic db/db mice, a model of type 2 DN. The ASO also reduced expression of genes involved in matrix expansion such as fibronectin and collagen (I and IV) and an inhibitor of matrix degradation, PAI-1, in the renal cortex, contributing to significant reversal of mesangial expansion in both models of DN. Pathway analyses demonstrated that diabetes-induced phosphorylation of p38 MAPK and its downstream target CREB was also inhibited by the ASO. Our results strongly suggest that blocking CTGF using a chimeric ASO holds substantial promise for the treatment of DN.
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PMID:Specific down-regulation of connective tissue growth factor attenuates progression of nephropathy in mouse models of type 1 and type 2 diabetes. 1755 73

Diabetic nephropathy (DN), the leading cause of end-stage renal failure, is clinically manifested by albuminuria and a progressive decline in glomerular filtration rate. The factors and mechanisms that contribute to progression of DN are still undefined. To address the contribution of B(2)-kinin receptors (B2KR) to the development of DN, we studied B2KR knockout mice (B2KR(-/-)) and their wild-type littermates (B2KR(+/+)). Diabetes was induced by daily injections of streptozotocin (50 mg/kg body wt) for 3-5 days. A total of 48 mice divided into 4 groups were used: group 1, wild-type control (B2KR(+/+) C); group 2, wild-type diabetic (B2KR(+/+) D); group 3, B2KR knockout control (B2KR(-/-) C); and group 4, B2KR knockout diabetic (B2KR(-/-) D). Glucose levels and albumin excretion rate (AER) were measured at predetermined intervals. Half of the mice were killed at 3 mo, and the remaining half, at 6 mo. Plasma glucose levels were markedly elevated in both B2KR(+/+) D and B2KR(-/-) D groups of mice compared with their controls. Diabetic B2KR(-/-) mice displayed reduced AER as well as reduced glomerular and tubular injury compared with diabetic B2KR(+/+) mice. The renoprotection conferred by deletion of B2KR was associated with increased renal expression of B(1)-kinin and angiotensin II AT(2) receptors and decreased expression of connective tissue growth factor. At a cellular level, our findings demonstrate that bradykinin downregulates the expression of AT(2) receptors in mesangial cells. These findings provide the first evidence that targeted deletion of B2KR protects against the development of DN.
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PMID:Targeted deletion of B2-kinin receptors protects against the development of diabetic nephropathy. 1759 25

Connective tissue growth factor (CTGF/CCN2) is thought to play a role in normal wound repair and bone remodeling, but also promotes fibrosis in several disease processes including diabetic nephropathy, sclerodoma and pancreatitis. A contribution to desmoplasia associated with pancreatic cancer progression has also been proposed. CTGF is induced by TGFbeta in diverse cell types, but TGFbeta receptor mediated signaling is impaired in pancreatic cancers and cell lines, usually due to DPC4/Smad4 mutations which arise during the later stages of intraepithelial neoplastic progression. Therefore, in order to define signaling pathways that mediate basal and TGFbeta-induced CTGF expression in normal and transformed cells, we compared CTGF gene regulation in pancreatic cancer cells and fibroblasts by measuring the effects of small molecule inhibitors and dominant negative mutants of signaling proteins on CTGF promoter reporter activity, message, and protein expression. We determined that the previously identified TEF-1 cis element is essential for CTGF promoter reporter activity in pancreatic cancer cell lines. Whereas p38 mediated CTGF induction by TGFbeta in fibroblasts, MEK/ERK signaling mediated TGFbeta-induced CTGF expression in pancreatic cancer cells and was also responsible for basal CTGF expression in pancreatic cancer cell lines with defective Smad signaling. Since activating Ras mutations occur in the earliest stages of pancreatic cancer, CTGF may be induced independent of Smad4 in pancreatic cancer cells.
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PMID:Expression of connective tissue growth factor in pancreatic cancer cell lines. 1778 99

1,25-Dihydroxyvitamin D3 negatively regulates the renin-angiotensin system (RAS), which plays a critical role in the development of diabetic nephropathy. We tested if mice lacking the vitamin D receptor (VDR) are more susceptible to hyperglycemia-induced renal injury. Diabetic VDR knockout mice developed more severe albuminuria and glomerulosclerosis due to increased glomerular basement membrane thickening and podocyte effacement. More fibronectin (FN) and less nephrin were expressed in the VDR knockout mice compared to diabetic wild-type mice. In receptor knockout mice, increased renin, angiotensinogen, transforming growth factor-beta (TGF-beta), and connective tissue growth factor accompanied the more severe renal injury. 1,25-Dihydroxyvitmain D3 inhibited high glucose (HG)-induced FN production in cultured mesangial cells and increased nephrin expression in cultured podocytes. 1,25-Dihydroxyvitmain D3 also suppressed HG-induced activation of the RAS and TGF-beta in mesangial and juxtaglomerular cells. Our study suggests that receptor-mediated vitamin D actions are renoprotective in diabetic nephropathy.
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PMID:Renoprotective role of the vitamin D receptor in diabetic nephropathy. 1816 10

Patients with glycogen storage disease type Ia (GSD-Ia) develop renal disease of unknown etiology despite intensive dietary therapies. This renal disease shares many clinical and pathological similarities to diabetic nephropathy. We studied the expression of angiotensinogen, angiotensin type 1 receptor, transforming growth factor-beta1, and connective tissue growth factor in mice with GSD-Ia and found them to be elevated compared to controls. While increased renal expression of angiotensinogen was evident in 2-week-old mice with GSD-Ia, the renal expression of transforming growth factor-beta and connective tissue growth factor did not increase for another week; consistent with upregulation of these factors by angiotensin II. The expression of fibronectin and collagens I, III, and IV was also elevated in the kidneys of mice with GSD-Ia, compared to controls. Renal fibrosis was characterized by a marked increase in the synthesis and deposition of extracellular matrix proteins in the renal cortex and histological abnormalities including tubular basement membrane thickening, tubular atrophy, tubular dilation, and multifocal interstitial fibrosis. Our results suggest that activation of the angiotensin system has an important role in the pathophysiology of renal disease in patients with GSD-Ia.
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PMID:Angiotensin mediates renal fibrosis in the nephropathy of glycogen storage disease type Ia. 1807 99

Marked upregulation of the secreted extracellular matrix-associated protein connective tissue growth factor (CTGF) in the glomerulus coincides with the onset of diabetic nephropathy. Recent studies, including the one by Yokoi et al., shed light on the role of CTGF in glomerular injury.
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PMID:Unraveling the role of connective tissue growth factor in diabetic nephropathy. 1807 96

Induced in high glucose-1 (IHG-1) is an evolutionarily conserved gene transcript upregulated by high extracellular glucose concentrations, but its function is unknown. Here, it is reported that the abundance of IHG-1 mRNA is nearly 10-fold higher in microdissected, tubule-rich renal biopsies from patients with diabetic nephropathy compared with control subjects. In the diabetic nephropathy specimens, in situ hybridization localized IHG-1 to tubular epithelial cells along with TGF-beta1 and activated Smad3, suggesting a possible role in the development of tubulointerstitial fibrosis. Supporting this possibility, IHG-1 mRNA and protein expression also increased with unilateral ureteral obstruction. In the HK-2 proximal tubule cell line, overexpression of IHG-1 increased TGF-beta1-stimulated expression of connective tissue growth factor and fibronectin. IHG-1 was found to amplify TGF-beta1-mediated transcriptional activity by increasing and prolonging phosphorylation of Smad3. Conversely, inhibition of endogenous IHG-1 with small interference RNA suppressed transcriptional responses to TGF-beta1. In summary, IHG-1, which increases in diabetic nephropathy, may enhance the actions of TGF-beta1 and contribute to the development of tubulointerstitial fibrosis.
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PMID:IHG-1 amplifies TGF-beta1 signaling and is increased in renal fibrosis. 1850 67

We previously showed that the 12/15-lipoxygenase (12/15-LO) pathway of arachidonate acid metabolism is involved in multiple events related to diabetic nephropathy (DN), including glomerular hypertrophy and extracellular matrix deposition (Kang SW, Adler SG, Nast CC, LaPage J, Gu JL, Nadler JL, Natarajan R. Kidney Int 59: 1354-1362, 2001; Kang SW, Natarajan R, Shahed A, Nast CC, LaPage J, Mundel P, Kashtan C, Adler SG. J Am Soc Nephrol 14: 3178-3187, 2003; Kim YS, Lanting L, Adler SG, Natarajan R. Kindney Int 64: 1702-1714, 2003; Reddy MA, Adler SG, Kim YS, Lanting L, Rossi JJ, Kang SW, Nadler JL, Shahed A, Natarajan R. Am J Physiol Renal Physiol 283: F985-F994, 2002). In this study, we investigated whether in vivo delivery of small interfering RNAs (siRNAs) targeting 12/15-LO can ameliorate renal injury and DN in a streptozotocin-injected mouse model of type 1 diabetes. To achieve greater in vivo access and siRNA expression in the kidney, we used double-stranded 12/15-LO siRNA oligonucleotides conjugated with cholesterol. Diabetic DBA/2J mice were injected subcutaneously with either cholesterol-tagged 12/15-LO siRNA, mismatched control siRNA, or vehicle alone, twice weekly for 7 wk. Relative to controls, mice that received 12/15-LO siRNA showed significant reduction in albuminuria, kidney-to-body weight ratios, glomerular mesangial matrix expansion, renal structural damage, and monocyte/macrophage infiltration. These effects were associated with lower renal cortical or glomerular levels of profibrotic markers transforming growth factor-beta, connective tissue growth factor, type I and type IV collagens, plasminogen activator inhibitor 1, and fibronectin. The diabetes-induced increase in glomerular cyclin-dependent kinase inhibitors that are associated with hypertrophy was also prevented by siRNA administration. Our results show for the first time that systemic delivery of cholesterol-tagged siRNAs targeting 12/15-LO has renoprotective effects under diabetic conditions and therefore could be a novel therapeutic approach for DN.
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PMID:Effects of cholesterol-tagged small interfering RNAs targeting 12/15-lipoxygenase on parameters of diabetic nephropathy in a mouse model of type 1 diabetes. 1856 37


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