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)

Glomerular mesangial cells (MC) are believed to play a pivotal role in development of diabetic nephropathy. We employed differential display reverse transcription polymerase chain reaction (DDRT-PCR) comparing human MC grown under 25 mM and 5.5 mM D-glucose and osmolarity control as a first step to identify possible candidate genes regulated by hyperglycemia. This strategy resulted in cloning of a novel gene in human MC, human munc13 (hmunc13), a human homologue of rat munc13s with the N-terminal segment similar to munc13-1 and the C-terminal segment more similar to munc13-2. Hmunc13 is also expressed in human kidney cortical epithelial cells. By using relative RT-PCR and Northern blot, we have confirmed that expression of hmunc13 in MC is up-regulated by high D-glucose treatment. Together with previous reports that munc13s binds to diacylglycerol (DAG) and that hyperglycemia increases DAG levels, these findings point to a potential role of hmunc13 in mediating some of the acute and chronic changes in MC produced by exposure to hyperglycemia.
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PMID:Cloning of a novel gene in the human kidney homologous to rat munc13s: its potential role in diabetic nephropathy. 960 1

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease requiring dialysis in the Western world. Clinical studies reveal that stringent control of blood glucose levels reduces the risk of most diabetic complications, underscoring the importance of understanding the cellular response to hyperglycemia. Our work identifies a new pathway of potential significance in this response, linking hyperglycemia to the stimulation of constitutive protein secretion via a pathway involving munc13 and rab34. These two proteins have previously been shown to interact at the Golgi via the munc13 homology domain 2 (MHD2). In the present study, using cultured rat mesangial cells (RMC), we show that high glucose-induced upregulation of endogenous munc13-2 increases secretion of the model protein, vesicular stomatitis virus glycoprotein-green fluorescent protein (VSVG-GFP), while small interfering (si)RNA-mediated knockdown of either munc13-2 or rab34 abolishes this effect. Similarly, increased secretion of VSVG-GFP is observed following transfection of HeLa cells with wild-type munc13-2, but not when HeLa cells are transfected with a mutant protein in which the MHD2 domain is deleted. Finally, we show that high glucose-stimulated secretion of fibronectin in RMC is abolished by siRNA knockdown of munc13-2. Collectively, our results demonstrate that the mechanistic basis for our observed high glucose-induced protein secretion is through interaction of munc13 and rab34, indicating a potentially critical role for this newly described pathway in the pathogenesis of DN.
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PMID:Rab34 and its effector munc13-2 constitute a new pathway modulating protein secretion in the cellular response to hyperglycemia. 1964 Oct 95