SIRT3 deficiency leads to induction of abnormal glycolysis in diabetic kidney with fibrosis.
SIRT3 deficiency leads to induction of abnormal glycolysis in diabetic kidney with fibrosis.
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DOI：
10.1038/s41419-018-1057-0
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发表时间：
2018-09-24
影响因子：
9
通讯作者：
Koya D
中科院分区：
文献类型：
--
作者：
Srivastava SP;Li J;Kitada M;Fujita H;Yamada Y;Goodwin JE;Kanasaki K;Koya D
糖尿病相关性肾纤维化中糖代谢异常的调控机制尚不清楚。在这项研究中，我们发现糖尿病肾脏中SIRT 3蛋白水平的抑制，显示与异常糖酵解相关的纤维化编程的责任，并且这种异常糖酵解是糖尿病相关肾纤维化的治疗靶点。当分析不同品系的链脲佐菌素诱导的糖尿病小鼠模型（纤维化模型：CD-1，较少纤维化模型：C57 B16）时，我们发现SIRT 3抑制与纤维化CD-1中的肾纤维化相关;通过全身施用SIRT 3 siRNA在糖尿病小鼠中进一步抑制SIRT 3，在肾中显示出显著的纤维化表型。SIRT 3的这种抑制与转化生长因子-β（TGF-β）/smad信号传导的诱导、更高水平的HIF 1 α积累和PKM 2二聚体形成相关;这些改变随后导致体内和体外异常糖酵解和相关的异常间充质转化。这种异常糖酵解的抑制抑制了纤维化编程，也恢复了SIRT 3水平。这种异常糖酵解在进行性糖尿病肾病的小鼠模型KK/Ta-Ins 2秋田小鼠中得到证实。这些数据表明SIRT 3缺乏促进异常糖酵解，这是糖尿病肾脏纤维化途径的原因。SIRT 3的恢复可能是通过抑制异常糖酵解来对抗糖尿病相关肾纤维化的替代策略。
The regulation of aberrant glucose metabolism in diabetes associated-kidney fibrosis is not well known. In this study we found the suppression of SIRT3 protein level in diabetic kidney, displays responsibility in fibrogenic programming associated with aberrant glycolysis and such abnormal glycolysis is the therapeutic target in diabetes associated-kidney fibrosis. When analyzing different strains of streptozotocin-induced diabetic mice model (fibrotic model: CD-1, less fibrotic model: C57Bl6), we found SIRT3 suppression was associated with kidney fibrosis in fibrotic CD-1; further SIRT3 suppression by systemic administration of SIRT3 siRNA in the diabetic mice, showed profound fibrogenic phenotype in the kidney. Such suppression in SIRT3 was associated with the induction of transforming growth factor-β (TGF-β)/smad signaling, higher level of HIF1α accumulation and PKM2 dimer formation; these alterations subsequently led to abnormal glycolysis and linked abnormal mesenchymal transformations in vivo and in vitro. Inhibition of such aberrant glycolysis suppressed fibrogenic programming and restored SIRT3 level as well. Such aberrant glycolysis was confirmed in the KK/Ta-Ins2Akita mouse, the mouse model of progressive diabetic kidney disease. These data demonstrate that SIRT3 deficiency promotes abnormal glycolysis which is responsible for the fibrogenic pathway in diabetic kidney. Restoration of SIRT3 could be an alternative strategy in combating diabetes associated-kidney fibrosis via inhibition of aberrant glycolysis.