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Deprecated: Implicit conversion from float 263.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Am+J+Physiol+Renal+Physiol 2015 ; 309 (5): F414-28 Nephropedia Template TP
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Interactions between HIF-1? and AMPK in the regulation of cellular hypoxia adaptation in chronic kidney disease #MMPMID26136559
Li H; Satriano J; Thomas JL; Miyamoto S; Sharma K; Pastor-Soler NM; Hallows KR; Singh P
Am J Physiol Renal Physiol 2015[Sep]; 309 (5): F414-28 PMID26136559show ga
Renal hypoxia contributes to chronic kidney disease (CKD) progression, as validated in experimental and human CKD. In the early stages, increased oxygen consumption causes oxygen demand/supply mismatch, leading to hypoxia. Hence, early targeting of the determinants and regulators of oxygen consumption in CKD may alter the disease course before permanent damage ensues. Here, we focus on hypoxia inducible factor-1? (HIF-1?) and AMP-activated protein kinase (AMPK) and on the mechanisms by which they may facilitate cellular hypoxia adaptation. We found that HIF-1? activation in the subtotal nephrectomy (STN) model of CKD limits protein synthesis, inhibits apoptosis, and activates autophagy, presumably for improved cell survival. AMPK activation was diminished in the STN kidney and was remarkably restored by HIF-1? activation, demonstrating a novel role for HIF-1? in the regulation of AMPK activity. We also investigated the independent and combined effects of HIF-1? and AMPK on cell survival and death pathways by utilizing pharmacological and knockdown approaches in cell culture models. We found that the effect of HIF-1? activation on autophagy is independent of AMPK, but on apoptosis it is partially AMPK dependent. The effects of HIF-1? and AMPK activation on inhibiting protein synthesis via the mTOR pathway appear to be additive. These various effects were also observed under hypoxic conditions. In conclusion, HIF-1? and AMPK appear to be linked at a molecular level and may act as components of a concerted cellular response to hypoxic stress in the pathophysiology of CKD.