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HNF4 alpha and the Ca-Channel TRPC1 are novel disease candidate genes in diabetic nephropathy

: Niehof, M.; Borlak, J.


Diabetes 57 (2008), Nr.4, S.1069-1077
ISSN: 0012-1797
Fraunhofer ITEM ()
Ca-signaling; TRPC1; PLCB1; diabetic late stage complications; Transcription factors - HNF4; genetic regulation; nephropathy; ion channel

OBJECTIVE-The nuclear receptor hepatic nuclear factor 40. (HNF4 alpha) is a master regulatory protein and an essential player in the control of a wide range of metabolic processes. Dysfunction of HNF4 alpha 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 chromatin immunoprecipitation-cloning assay and by sequencing of immunoprecipitated DNA. Expression of candidate genes was analyzed in kidney and liver of Zucker diabetic fatty (ZDF) and of streptozotocin (STZ)-administered rats and after siRNA-mediated silencing of HNF4 alpha. RESULTS-We identified the calcium-permeable nonselective transient receptor potential cation channel, subfamily C, member 1 (TRPC1) as a novel HNF4 alpha 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 a significant reduction of TRPC1 gene expression in kidney and liver of diabetic ZDF and of STZ-administered rats as a result of HNF4 alpha dysfunction. We found HNF4a 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 HNF4 alpha 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 HNF4 alpha and TRPC1 in human and rat kidney pathologies. We propose dysregulation of HNF4 alpha and TRPC1 as a possible molecular rationale in diabetic nephropathy.