PRAS40 acts as a nodal regulator of high glucose-induced TORC1 activation in glomerular mesangial cell hypertrophy.

Journal of Cellular Physiology
Nirmalya DeyGoutam Ghosh Choudhury

Abstract

Diabetic nephropathy manifests aberrant activation of TORC1, which senses key signals to modulate protein synthesis and renal hypertrophy. PRAS40 has recently been identified as a raptor-interacting protein and is a component and a constitutive inhibitor of TORC1. The mechanism by which high glucose stimulates TORC1 activity is not known. PRAS40 was identified in the mesangial cells in renal glomeruli and in tubulointerstitium of rat kidney. Streptozotocin-induced diabetic renal hypertrophy was associated with phosphorylation of PRAS40 in the cortex and glomeruli. In vitro, high glucose concentration increased PRAS40 phosphorylation in a PI 3 kinase- and Akt-dependent manner, resulting in dissociation of raptor-PRAS40 complex in mesangial cells. High glucose augmented the inactivating and activating phosphorylation of 4EBP-1 and S6 kinase, respectively, with concomitant induction of protein synthesis and hypertrophy. Expression of TORC1-nonphosphorylatable mutant of 4EBP-1 and dominant-negative S6 kinase significantly inhibited high glucose-induced protein synthesis and hypertrophy. PRAS40 knockdown mimicked the effect of high glucose on phosphorylation of 4EBP-1 and S6 kinase, protein synthesis, and hypertrophy. To elucidate t...Continue Reading

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Citations

Jul 25, 2013·The International Journal of Biochemistry & Cell Biology·Wei LiuHuijun Duan
Jan 5, 2011·The Journal of Biological Chemistry·Chandi Charan MandalNandini Ghosh-Choudhury
May 27, 2011·The Journal of Biological Chemistry·Nirmalya DeyGoutam Ghosh Choudhury
Jun 12, 2012·PloS One·Nirmalya DeyGoutam Ghosh Choudhury
Mar 1, 2014·Archives of Physiology and Biochemistry·Claudia WizaD Margriet Ouwens
Dec 19, 2013·Journal of Cellular Physiology·Jun HaoHuijun Duan
May 29, 2013·Cellular Signalling·Claudia WizaD Margriet Ouwens
Apr 18, 2016·Drug Discovery Today·Zhao Zhong Chong
Jul 15, 2016·Molecular Neurodegeneration·Ramon VelazquezSalvatore Oddo
Dec 17, 2017·Scientific Reports·Karim Colin Hassan DhananiAdrienne Lesley Edkins
Apr 21, 2017·American Journal of Physiology. Renal Physiology·Falguni DasGoutam Ghosh Choudhury
Apr 28, 2019·The Journal of Biological Chemistry·Falguni DasGoutam Ghosh Choudhury
Oct 6, 2017·Oncotarget·Dan LvLin Huang
Jan 8, 2016·American Journal of Physiology. Cell Physiology·Falguni DasGoutam Ghosh Choudhury
Feb 23, 2012·American Journal of Physiology. Endocrinology and Metabolism·Claudia WizaD Margriet Ouwens
Aug 10, 2019·Molecular Cancer Therapeutics·Mario I VegaAlan Lichtenstein
Jan 29, 2021·Journal of Drug Targeting·Qun ZhouLinxi Chen

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