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)

Early diabetic nephropathy is characterized by glomerular hypertrophy. Previous studies in vitro have demonstrated that mesangial cells exposed to high glucose are arrested in the G1-phase of the cell cycle and express increased levels of the cyclin-dependent kinase inhibitor p27Kip1. The present study was performed to investigate the renal expression of p27Kip1 in db/db mice, a model of diabetes mellitus type II. Glomerular p27Kip1 protein, but not mRNA expression, was strongly enhanced in diabetic db/db mice compared with non-diabetic db/+ littermates. Immunohistochemical studies revealed that this stimulated expression was mainly restricted to the nuclei of mesangial cells and podocytes, but glomerular endothelial cells occasionally also stained positively. Quantification of p27Kip1 positive glomerular cells showed a significant increase of these cells in db/db mice compared with non-diabetic db/+ animals. Although tubular cells revealed a positive staining for p27Kip1 protein, there was no difference between db/+ and db/db mice. Immunoprecipitation experiments revealed that p27Kip1 protein associates with Cdk2 and Cdk4, but not with Cdk6. To test for the influence of hyperglycemia on cell cycle arrest and p27Kip1 expression, mesangial cells were isolated from db/+ and db/db mice. There was a similar basal proliferation when these cells were grown in normal glucose-containing medium (100 mg/dl). However, raising the glucose concentration to 275 to 450 mg/dl induced cell cycle arrest in db/+ as well as db/db mesangial cells. Increasing the medium osmolarity with D-mannitol failed to induce p27Kip1 expression in mesangial cells. Transfection of cells with p27Kip1 antisense, but not missense, phosphorothioate oligonucleotides facilitated cell cycle progression equally well in db/+ and db/db mesangial cells. Furthermore, p27Kip1 expression was comparable in both cell lines in normal glucose, but increased in high glucose medium. Our studies demonstrate that p27Kip1 expression is enhanced in diabetic db/db animals. This induction appears to be due to hyperglycemia. Expression of p27Kip1 may be important in cell cycle arrest and hypertrophy of mesangial cells during early diabetic nephropathy.
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PMID:Glomerular expression of p27Kip1 in diabetic db/db mouse: role of hyperglycemia. 955 93

Alterations in proliferation and hypertrophy of renal mesangial cells are typical features of diabetic nephropathy. The HP (hexosamine pathway) has been proposed as a biochemical hypothesis to explain microvascular alterations due to diabetic nephropathy; however, involvement of HP in the regulation of mesangial cell growth or hypertrophy has been poorly studied. Although gangliosides are known to regulate cell proliferation, their potential role in mesangial cell-growth perturbations has hardly been explored. In the present study, we investigated the effects of the HP activation, mimicked by GlcN (glucosamine) treatment, on mesangial cell growth and hypertrophy and the potential implication of gangliosides in these processes. Our results indicate that GlcN induced hypertrophy of mesangial cells, as measured by an increase in the protein/cell ratio, and it caused cell-cycle arrest by an increase in the expression of cyclin-dependent kinase inhibitor p21(Waf1/Cip1). Furthermore, GlcN treatment resulted in a massive increase in the levels of gangliosides G(M2) and G(M1). Treatment of cells with exogenous G(M2) and G(M1) reproduced the effects of 0.5 mM GlcN on p21(Waf1/Cip1) expression, cell-cycle arrest and hypertrophy, suggesting that gangliosides G(M2) and G(M1) are probably involved in mediating GlcN effects. These results document a new role of the HP in the regulation of mesangial cell growth and hypertrophy. They also suggest a potential new mechanism of action of the HP through modulation of ganglioside levels.
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PMID:Glucosamine induces cell-cycle arrest and hypertrophy of mesangial cells: implication of gangliosides. 1565 67

Increased mesangial cell proliferation is one of the major pathologic features in the early stage of diabetic nephropathy (DN). Carnosine is an endogenously synthesized dipeptide that has been reported as a protective factor in diabetic nephropathy. However, the underlying mechanism involved in this effect remains to be elucidated. In this study, the effect of carnosine on cell proliferation and its underlying mechanisms were investigated in cultured rat mesangial cells by the methylthiazoletetrazolium (MTT) assay, the 5-bromo-2-deoxy-uridine (BrdU) cell proliferation assay, flow cytometry and western blotting. The results showed that pretreatment of mesangial cells with carnosine significantly inhibited cell proliferation and DNA synthesis in a dose-dependent manner by increasing the cell population in G1 and reducing that in S-phase. In addition, carnosine could reverse high glucose-induced down-regulation of cyclin-dependent kinase inhibitor p21 but not that of p27. Furthermore, carnosine could reduce the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK). Taken together, these results suggest that carnosine can inhibit mesangial cell proliferation by modulating cell cycle progress, indicating that carnosine could be a potential therapeutic agent for the prevention of DN in the early stage.
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PMID:Carnosine inhibits high glucose-induced mesangial cell proliferation through mediating cell cycle progression. 1915 60

Although deficiency of the small leucine-rich proteoglycan decorin aggravates diabetic nephropathy in mice, the precise mechanisms of action are not fully understood. In the present study we used decorin-deficient mice (Dcn(-/-)) to further elucidate the molecular mechanisms involved in the protective action of decorin in diabetes. We discovered that streptozotocin-induced diabetes in Dcn(-/-) mice led to increased proteinuria associated with enhanced cyclin-dependent kinase inhibitor p27Kip1 in podocytes and tubular epithelial cells. Furthermore, lack of decorin increased the rate of apoptosis and caused overexpression of the IGF-IR in tubular epithelial cells of diabetic kidneys. In vitro experiments using human proximal renal epithelial cells showed that recombinant decorin was bound to the IGF-IR and protected against high glucose-mediated apoptosis. Furthermore, overexpression of TGFbeta1 and CTGF triggered by decorin deficiency resulted in enhanced accumulation of extracellular matrix in diabetic kidneys. Notably, diabetic Dcn(-/-) kidneys revealed marked upregulation of the proinflammatory proteoglycan biglycan and enhanced infiltration of mononuclear cells. Collectively, our results indicate that decorin is a protective agent during the development of diabetic nephropathy. Future therapeutic approaches that would either enhance the endogenous production of decorin or deliver recombinant decorin to the diseased kidney might improve the outcome of patients with diabetic nephropathy.
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PMID:Decorin deficiency in diabetic mice: aggravation of nephropathy due to overexpression of profibrotic factors, enhanced apoptosis and mononuclear cell infiltration. 2008 46

Diabetic nephropathy is the commonest cause of end-stage renal disease. Inordinate kidney growth and glomerular hyperfiltration at the very early stages of diabetes are putative antecedents to this disease. The kidney is the only organ that grows larger with the onset of diabetes mellitus, yet there remains confusion about the mechanism and significance of this growth. Here we show that kidney proximal tubule cells in culture transition to senescence in response to oxidative stress. We further determine the temporal expression of G(1) phase cell cycle components in rat kidney cortex at days 4 and 10 of streptozotocin diabetes to evaluate changes in this growth response. In diabetic rats we observe increases in kidney weight-to-body weight ratios correlating with increases in expression of the growth-related proteins in the kidney at day 4 after induction of diabetes. However, at day 10 we find a decrease in this profile in diabetic animals coincident with increased cyclin-dependent kinase inhibitor expressions. We observe no change in caspase-3 expression in the diabetic kidneys at these early time points; however, diabetic animals demonstrate reduced kidney connexin 43 and increased plasminogen activator inhibitor-1 expressions and increased senescence-associated beta-galactosidase activity in cortical tubules. In summary, diabetic kidneys exhibit an early temporal induction of growth phase components followed by their suppression concurrent with the induction of cyclin-dependent kinase inhibitors and markers of senescence. These data delineate a phenotypic change in cortical tubules early in the pathogenesis of diabetes that may contribute to further downstream complications of the disease.
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PMID:Transition of kidney tubule cells to a senescent phenotype in early experimental diabetes. 2050 38