<i>HNF4</i>α and the Ca-Channel <i>TRPC1</i> Are Novel Disease Candidate Genes in Diabetic Nephropathy

Niehof, Monika; Borlak, Jürgen

doi:10.2337/db07-1065

Cited by 65 publications

(48 citation statements)

References 38 publications

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“…A previous study by Xie et al (54) reported that levels of HNF4␣ protein and mRNA were decreased in the liver of db/db mice (type II diabetes model) but increased in streptozotocin-treated mice (type I diabetes model). A recent study by Niehof and Borlak (32) showed that HNF4␣ protein expression was repressed in kidneys of both diabetic rats and humans and that the reduced HNF4␣ might contribute to diabetic nephropathy by inhibiting canonical transient receptor potential (TRP)C1 protein in the kidney (32). Since TRPC1 is a Ca 2ϩ -permeable channel expressed in kidney cells (10), the results of Niehof and Borlak's study suggest that HNF4␣ may affect diabetic renal changes by regulating renal cell Ca 2ϩ signaling.…”

mentioning

confidence: 76%

“…Previous studies revealed that HNF4␣ regulates "drug" transporters during development of the kidney proximal tubule (15,29), stimulates the mesenchymal-epithelial transition in early nephrogenesis (24), and suppresses renal cell carcinoma (28). Recently, Niehof and Borlak (32) reported that HNF4␣ protein was significantly reduced in kidneys from diabetic rats and humans. The decrease in HNF4␣ in the diabetic kidney downregulated expression of TRPC1 protein, a Ca 2ϩ channel that regulates Ca 2ϩ signals in kidney cells (10).…”

Section: Discussionmentioning

confidence: 99%

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Impairment of hepatic nuclear factor-4α binding to theStim1promoter contributes to high glucose-induced upregulation of STIM1 expression in glomerular mesangial cells

Wang

Chaudhari

Ren

et al. 2015

American Journal of Physiology-Renal Physiology

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Wang Y, Chaudhari S, Ren Y, Ma R. Impairment of hepatic nuclear factor 4␣ binding to the Stim1 promoter contributes to high glucoseinduced upregulation of STIM1 expression in glomerular mesangial cells. Am J Physiol Renal Physiol 308: F1135-F1145, 2015. First published March 18, 2015 doi:10.1152/ajprenal.00563.2014.-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 Ca 2ϩ 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 storeoperated Ca 2ϩ entry pathway in MCs has an antifibrotic effect, inhibition of HNF4␣ in MCs might be a potential therapeutic option for diabetic kidney disease. hepatic nuclear factor 4␣; stromal interacting molecule 1; storeoperated Ca 2ϩ entry; mesangial cells; high glucose; diabetic nephropathy STORE-OPERATED Ca 2ϩ entry (SOCE) via store-operated Ca 2ϩ channels (SOCs) is a ubiquitous signaling mechanism in both nonexcitable and excitable cells. This Ca 2ϩ signaling regulates diverse cellular functions ranging from cell proliferation and gene expression to cell contraction and secretion (35). Although SOCE was originally described over two decades ago, its molecular mediators were unknown until recently. By high-throughput RNA inhibition screening, two protein families, stromal interacting molecule (STIM) (27, 36) and Orai (13, 48, 59), were identified as required components of SOCE. STIM1 is a single-pass transmembrane protein located primarily in the endoplasmic reticulum (ER) membrane and functions as an ER Ca 2ϩ sensor to sense the ER luminal Ca 2ϩ concentration. Orai1 is a small plasma membrane protein and is believed to be the pore-forming unit of SOCs. Upon depletion of ER Ca 2ϩ , STIM1 aggregates and translocates to ER-plasma membrane junctions, where it physically associates and subsequently activates Orai1 and causes Ca 2ϩ entry into the cytosol (...

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mentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Impairment of hepatic nuclear factor-4α binding to theStim1promoter contributes to high glucose-induced upregulation of STIM1 expression in glomerular mesangial cells

Wang

Chaudhari

Ren

et al. 2015

American Journal of Physiology-Renal Physiology

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“…Of particular interest to the question of the cellular basis of high glucose (HG)-induced endothelial dysfunction is the report from Kumar et al (28) that an increase in vascular smooth muscle TRPC1 expression was associated with enhanced Ca 2ϩ entry in human and animal vascular injury models and that the vascular injury associated with enhanced Ca 2ϩ entry was reduced by an isoform-specific antibody against TRPC1. Finally, the TRPC1 gene, localized on human chromosome 3q22-24, a region closely associated with diabetic nephropathy, has been identified as a possible candidate gene in diabetic nephropathy (35).…”

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confidence: 99%

Glucose enhances expression of TRPC1 and calcium entry in endothelial cells

Bishara

Ding

2010

American Journal of Physiology-Heart and Circulatory Physiology

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Hyperglycemia is a major risk factor for endothelial dysfunction and vascular disease, and in the current study, the link to glucose-induced abnormal intracellular Ca2+ (Cai2+) homeostasis was explored in bovine aortic endothelial cells in high glucose (HG; 25 mmol/l) versus low glucose (LG; 5.5 mmol/l; control). Transient receptor potential 1 (TRPC1) ion channel protein, but not TRPC3, TRPC4, or TRPC6 expression, was significantly increased in HG versus LG at 72 h. HG for 4, 24, and 72 h did not change basal Cai2+ or ATP-induced Cai2+ release; however, the amplitude of sustained Cai2+ was significantly increased at 24 and 72 h and reduced by low concentration of the putative, but nonspecific, TRPC blockers, gadolinium, SKF-96365, and 2-aminoethoxydiphenyl borate. Treatment with TRPC1 antisense significantly reduced TRPC1 protein expression and ATP-induced Ca2+ entry in bovine aortic endothelial cells. Although the link between HG-induced changes in TRPC1 expression, enhanced Ca2+ entry, and endothelial dysfunction require further study, the current data are suggestive that targeting these pathways may reduce the impact of HG on endothelial function.

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“…There is evidence that HNF4α gene expression is reduced in the kidney of patients with diabetic nephropathy (Niehof and Borlak, 2008) (Nitsch et al, 1993;Nishiyori et al, 1994), we considered that HNF4α could play a role in the transcriptional control of mALT gene.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte Nuclear Factor 4α Transactivates the Mitochondrial Alanine Aminotransferase Gene in the Kidney of Sparus aurata

et al. 2011

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Alanine aminotransferase (ALT) plays an important role in amino acid metabolism and gluconeogenesis. The preference of carnivorous fish for protein amino acids instead of carbohydrates as a source of energy lead us to study the transcriptional regulation of the mitochondrial ALT (mALT) gene and to characterize the enzyme kinetics and modulation of mALT expression in kidney of gilthead sea bream (Sparus aurata) under different nutritional and hormonal conditions. 5'-deletion analysis of mALT promoter in transiently transfected HEK293 cells, site-directed mutagenesis and electrophoretic mobility shift assays allowed us to identify HNF4α as a new factor involved in the transcriptional regulation of mALT expression. Quantitative RT-PCR assays showed that starvation and the administration of streptozotocin (STZ) decreased HNF4α levels in the kidney of S. aurata, leading to down-regulation of mALT transcription. Analysis of the tissue distribution showed that kidney, liver and intestine were the tissues with higher mALT and HNF4α expression. Kinetic analysis indicates that mALT enzyme is more efficient in catalyzing the conversion of L-alanine to pyruvate than the reverse reaction. From these results we conclude that HNF4α transactivates the mALT promoter and that the low levels of mALT expression found in the kidney of starved and STZ-treated fish result from a decreased expression of HNF4α. Our findings suggest that the mALT isoenzyme plays a major role in oxidazing dietary amino acids, and points to ALT as a target for a biotechnological action to spare protein and optimize the use of dietary nutrients for fish culture.3

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HNF4α and the Ca-Channel TRPC1 Are Novel Disease Candidate Genes in Diabetic Nephropathy

Cited by 65 publications

References 38 publications

Impairment of hepatic nuclear factor-4α binding to theStim1promoter contributes to high glucose-induced upregulation of STIM1 expression in glomerular mesangial cells

Impairment of hepatic nuclear factor-4α binding to theStim1promoter contributes to high glucose-induced upregulation of STIM1 expression in glomerular mesangial cells

Glucose enhances expression of TRPC1 and calcium entry in endothelial cells

Hepatocyte Nuclear Factor 4α Transactivates the Mitochondrial Alanine Aminotransferase Gene in the Kidney of Sparus aurata

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