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Deprecated: Implicit conversion from float 282.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Am+J+Physiol+Renal+Physiol 2015 ; 308 (10): F1135-45 Nephropedia Template TP
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Impairment of hepatic nuclear factor-4? binding to the Stim1 promoter contributes to high glucose-induced upregulation of STIM1 expression in glomerular mesangial cells #MMPMID25786776
Wang Y; Chaudhari S; Ren Y; Ma R
Am J Physiol Renal Physiol 2015[May]; 308 (10): F1135-45 PMID25786776show ga
The present study was carried out to investigate if hepatic nuclear factor (HNF)4? contributed to the high glucose-induced increase in stromal interacting molecule (STIM)1 protein abundance in glomerular mesangial cells (MCs). Western blot and immunofluorescence experiments showed HNF4? expression in MCs. Knockdown of HNF4? using a small interfering RNA approach significantly increased mRNA expression levels of both STIM1 and Orai1 and protein expression levels of STIM1 in cultured human MCs. Consistently, overexpression of HNF4? reduced expressed STIM1 protein expression in human embryonic kidney-293 cells. Furthermore, high glucose treatment did not significantly change the abundance of HNF4? protein in MCs but significantly attenuated HNF4? binding activity to the Stim1 promoter. Moreover, knockdown of HNF4? significantly augmented store-operated Ca2+ entry, which is known to be gated by STIM1 and has recently been found to be antifibrotic in MCs. In agreement with those results, knockdown of HNF4? significantly attenuated the fibrotic response of high glucose. These results suggest that HNF4? negatively regulates STIM1 transcription in MCs. High glucose increases STIM1 expression levels by impairing HNF4? binding activity to the Stim1 promoter, which subsequently releases Stim1 transcription from HNF4? repression. Since the STIM1-gated store-operated Ca2+ entry pathway in MCs has an antifibrotic effect, inhibition of HNF4? in MCs might be a potential therapeutic option for diabetic kidney disease.