Interactions between HIF-1α and AMPK in the regulation of cellular hypoxia adaptation in chronic kidney disease

Abstract

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-1α (HIF-1α) and AMP-activated protein kinase (AMPK) and on the mechanisms by which they may facilitate cellular hypoxia adaptation. We found that HIF-1α 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-1α activation, demonstrating a novel role for HIF-1α in the regulation of AMPK activity. We also investigated the independent and combined effects of HIF-1α 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-1α activation on autophagy is independent of AMPK, but on apoptosis it is partially AMPK dependent. The effects of HIF-1α 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-1α 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.

Obesity-induced kidney injury is attenuated by amelioration of aberrant PHD2 activation in proximal tubules

“…Using models for renal disease, Li et al showed that HIF-1α and AMPK were linked at a molecular level during the response to hypoxic stress in the pathophysiology of CKD. AMPK activation was decreased in the subtotal nephrectomy model and was markedly restored by HIF-1α activation41. In our study, we speculate that HIF-1α did not function normally and AMPK may not have been fully restored by HIF-1α to facilitate cellular adaptation to hypoxia, resulting in cellular hypertrophy.…”

AKI on CKD: heightened injury, suppressed repair, and the underlying mechanisms

“…Autophagy regulation in other CKD models or conditions is less clear. In the 5/6 th nephrectomy model of CKD, Li H et al showed evidence of autophagy suppression in kidneys, including decreases in LC3II and accumulation of P62 140 . However, in the same model Fedorova et al detected the up-regulation of autophagy genes (eg.…”

Renal Oxygenation and Hemodynamics in Kidney Injury

“…Another important molecular regulator of renal oxygenation is hypoxia inducible factor-1 alpha (HIF-1α). This transcription factor regulates several downstream proteins in oxygen delivery and consumption and plays an important role in the cellular response to hypoxia [7]. …”