| First Author | Das F | Year | 2017 |
| Journal | Am J Physiol Renal Physiol | Volume | 313 |
| Issue | 2 | Pages | F291-F307 |
| PubMed ID | 28424212 | Mgi Jnum | J:280764 |
| Mgi Id | MGI:6369572 | Doi | 10.1152/ajprenal.00666.2016 |
| Citation | Das F, et al. (2017) PDGF receptor-beta uses Akt/mTORC1 signaling node to promote high glucose-induced renal proximal tubular cell collagen I (alpha2) expression. Am J Physiol Renal Physiol 313(2):F291-F307 |
| abstractText | Increased expression of PDGF receptor-beta (PDGFRbeta) has been shown in renal proximal tubules in mice with diabetes. The core molecular network used by high glucose to induce proximal tubular epithelial cell collagen I (alpha2) expression is poorly understood. We hypothesized that activation of PDGFRbeta by high glucose increases collagen I (alpha2) production via the Akt/mTORC1 signaling pathway in proximal tubular epithelial cells. Using biochemical and molecular biological techniques, we investigated this hypothesis. We show that high glucose increases activating phosphorylation of the PDGFRbeta, resulting in phosphorylation of phosphatidylinositol 3-kinase. A specific inhibitor, JNJ-10198409, and small interfering RNAs targeting PDGFRbeta blocked this phosphorylation without having any effect on MEK/Erk1/2 activation. We also found that PDGFRbeta regulates high glucose-induced Akt activation, its targets tuberin and PRAS40 phosphorylation, and finally, mTORC1 activation. Furthermore, inhibition of PDGFRbeta suppressed high glucose-induced expression of collagen I (alpha2) in proximal tubular cells. Importantly, expression of constitutively active Akt or mTORC1 reversed these processes. As a mechanism, we found that JNJ and PDGFRbeta knockdown inhibited high glucose-stimulated Hif1alpha expression. Furthermore, overexpression of Hif1alpha restored expression of collagen I (alpha2) that was inhibited by PDGFRbeta knockdown in high glucose-stimulated cells. Finally, we show increased phosphorylation of PDGFRbeta and its association with Akt/mTORC1 activation, Hif1alpha expression, and elevated collagen I (alpha2) levels in the renal cortex of mice with diabetes. Our results identify PDGFRbeta as a driver in activating Akt/mTORC1 nexus for high glucose-mediated expression of collagen I (alpha2) in proximal tubular epithelial cells, which contributes to tubulointerstitial fibrosis in diabetic nephropathy. |
