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Hepatic nuclear factor 4 alpha and the Ca-channel TRPC1 are novel disease candidate genes in diabetic nephropathy

¹Fraunhofer Institute of Toxicology and Experimental Medicine, Center of Molecular Medicine and Medical Biotechnology, Hannover, Germany
²Center of Pharmacology and Toxicology, Medical School of Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany

Objective: The nuclear receptor HNF4alpha is a master regulatory protein and an essential player in the control of a wide range of metabolic processes. Dysfunction of HNF4alpha is associated with metabolic disorders including diabetes. We were particularly interested in investigating molecular causes associated with diabetic nephropathy.

Research Design and Methods: Novel disease candidate genes were identified by the ChIP-cloning assay and by sequencing of immunoprecipitated DNA. Expression of candidate genes was analysed in kidney and liver of ZDF and of streptozotocin-treated rats and after siRNA-mediated silencing of HNF4alpha.

Results: We identified the calcium permeable non-selective cation channel TRPC1 as a novel HNF4alpha gene target. Strikingly, TRPC1 is localized on human chromosome 3q22-24, i.e. a region considered to be a hotspot for diabetic nephropathy. We observed significant reduction of TRPC1 gene expression in kidney and liver of diabetic ZDF and of STZ-treated rats as a result of HNF4alpha dysfunction. We found HNF4alpha and TRPC1 protein expression to be repressed in kidneys of diabetic patients diagnosed with nodular glomerulosceloris as evidenced by immunohistochemistry. Finally, siRNA mediated functional knock down of HNF4alpha repressed TRPC1 gene expression in cell culture experiments.

Conclusions: Taken collectively results obtained from animal studies could be translated to human diabetic nephropathy; there is evidence for a common regulation of HNF4alpha and of TRPC1 in human and rat kidney pathologies. We propose dysregulation of HNF4alpha and of TRPC1 as a possible molecular rationale in diabetic nephropathy.

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