Persson Patrik, Palm Fredrik
Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
Curr Opin Nephrol Hypertens. 2017 Sep;26(5):345-350. doi: 10.1097/MNH.0000000000000341.
Tissue hypoxia is present in kidneys from diabetic patients and constitutes a central pathway to diabetic kidney disease (DKD). This review summarizes regulation of hypoxia inducible factor (HIF) and interventions towards the same for treatment of DKD.
In the hypoxic diabetic kidney, HIF activity and the effects of HIF signaling seem to be cell-specific. In mesangial cells, elevated glucose levels induce HIF activity by a hypoxia-independent mechanism. Elevated HIF activity in glomerular cells promotes glomerulosclerosis and albuminuria, and inhibition of HIF protects glomerular integrity. However, tubular HIF activity is suppressed and HIF activation protects mitochondrial function and prevents development of diabetes-induced tissue hypoxia, tubulointerstitial fibrosis and proteinuria. No clinical treatment targeting kidney hypoxia is currently available, but development of prolyl hydroxylase inhibitors to promote HIF activity to treat renal anemia could potentially also target diabetes-induced kidney hypoxia.
Increasing HIF activity in the diabetic kidney may possess a novel target for treatment of DKD by improving kidney oxygen homeostasis. However, HIF-mediated glomerulosclerosis may be a concern. The kidney outcomes from the ongoing clinical trials using prolyl hydroxylase inhibitors may provide additional insights into the complex role of HIF signaling in the diabetic kidney.
糖尿病患者肾脏存在组织缺氧，这是糖尿病肾病（DKD）的核心发病途径。本综述总结了缺氧诱导因子（HIF）的调节机制以及针对其治疗DKD的干预措施。
在缺氧的糖尿病肾脏中，HIF活性及HIF信号传导的作用似乎具有细胞特异性。在系膜细胞中，高糖水平通过非缺氧依赖机制诱导HIF活性。肾小球细胞中HIF活性升高会促进肾小球硬化和蛋白尿，抑制HIF可保护肾小球完整性。然而，肾小管HIF活性受到抑制，激活HIF可保护线粒体功能并预防糖尿病诱导的组织缺氧、肾小管间质纤维化和蛋白尿。目前尚无针对肾脏缺氧的临床治疗方法，但开发脯氨酰羟化酶抑制剂以提高HIF活性来治疗肾性贫血，可能也适用于治疗糖尿病诱导的肾脏缺氧。
通过改善肾脏氧稳态，增加糖尿病肾脏中的HIF活性可能为DKD治疗提供新靶点。然而，HIF介导的肾小球硬化可能是一个问题。正在进行的使用脯氨酰羟化酶抑制剂的临床试验结果，可能会为HIF信号在糖尿病肾脏中的复杂作用提供更多见解。
