Li Hui, Satriano Joseph, Thomas Joanna L, Miyamoto Satoshi, Sharma Kumar, Pastor-Soler Núria M, Hallows Kenneth R, Singh Prabhleen
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California;
Division of Nephrology and Hypertension, Department of Medicine, University of California and Veterans Affairs San Diego Healthcare System, San Diego, California; and.
Am J Physiol Renal Physiol. 2015 Sep 1;309(5):F414-28. doi: 10.1152/ajprenal.00463.2014. Epub 2015 Jul 1.
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.
肾缺氧会导致慢性肾脏病（CKD）进展，这在实验性和人类CKD中均得到验证。在疾病早期，氧消耗增加导致氧需求/供应不匹配，进而引发缺氧。因此，在CKD早期靶向氧消耗的决定因素和调节因子可能会在永久性损伤发生之前改变疾病进程。在此，我们聚焦于缺氧诱导因子-1α（HIF-1α）和AMP激活的蛋白激酶（AMPK），以及它们促进细胞缺氧适应的机制。我们发现，在CKD的肾次全切除（STN）模型中，HIF-1α激活可限制蛋白质合成、抑制细胞凋亡并激活自噬，推测这有助于提高细胞存活率。STN肾中的AMPK激活减弱，而HIF-1α激活可使其显著恢复，这表明HIF-1α在调节AMPK活性方面具有新作用。我们还通过在细胞培养模型中采用药理学和基因敲低方法，研究了HIF-1α和AMPK对细胞存活和死亡途径的独立及联合作用。我们发现，HIF-1α激活对自噬的影响独立于AMPK，但对细胞凋亡的影响部分依赖于AMPK。HIF-1α和AMPK激活通过mTOR途径抑制蛋白质合成的作用似乎具有相加性。在缺氧条件下也观察到了这些不同的作用。总之，HIF-1α和AMPK在分子水平上似乎存在联系，并且可能作为CKD病理生理学中对缺氧应激协同细胞反应的组成部分发挥作用。
