Department of Internal Medicine-Nephrology, University of Michigan, Ann Arbor, Michigan, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
Department of Internal Medicine-Nephrology, University of Michigan, Ann Arbor, Michigan, USA.
J Biol Chem. 2023 Mar;299(3):102960. doi: 10.1016/j.jbc.2023.102960. Epub 2023 Feb 2.
Early diabetic kidney disease (DKD) is marked by dramatic metabolic reprogramming due to nutrient excess, mitochondrial dysfunction, and increased renal energy requirements from hyperfiltration. We hypothesized that changes in metabolism in DKD may be regulated by Sirtuin 5 (SIRT5), a deacylase that removes posttranslational modifications derived from acyl-coenzyme A and has been demonstrated to regulate numerous metabolic pathways. We found decreased malonylation in the kidney cortex (∼80% proximal tubules) of type 2 diabetic BKS db/db mice, associated with increased SIRT5 expression. We performed a proteomics analysis of malonylated peptides and found that proteins with significantly decreased malonylated lysines in the db/db cortex were enriched in nonmitochondrial metabolic pathways: glycolysis and peroxisomal fatty acid oxidation. To confirm relevance of these findings in human disease, we analyzed diabetic kidney transcriptomic data from a cohort of Southwestern American Indians, which revealed a tubulointerstitial-specific increase in Sirt5 expression. These data were further corroborated by immunofluorescence data of SIRT5 from nondiabetic and DKD cohorts. Furthermore, overexpression of SIRT5 in cultured human proximal tubules demonstrated increased aerobic glycolysis. Conversely, we observed reduced glycolysis with decreased SIRT5 expression. These findings suggest that SIRT5 may lead to differential nutrient partitioning and utilization in DKD. Taken together, our findings highlight a previously unrecognized role for SIRT5 in metabolic reprogramming in DKD.
早期糖尿病肾病 (DKD) 的特征是由于营养过剩、线粒体功能障碍和超滤引起的肾能量需求增加，导致代谢显著重编程。我们假设 DKD 中的代谢变化可能受到 Sirtuin 5 (SIRT5) 的调节，SIRT5 是一种去乙酰化酶，可去除来自酰基辅酶 A 的翻译后修饰，并且已被证明可调节多种代谢途径。我们发现 2 型糖尿病 BKS db/db 小鼠肾脏皮质（~80%近端小管）中的丙二酰化减少，伴随着 SIRT5 表达增加。我们对丙二酰化肽进行了蛋白质组学分析，发现 db/db 皮质中丙二酰化赖氨酸显著减少的蛋白质富集于非线粒体代谢途径：糖酵解和过氧化物酶体脂肪酸氧化。为了确认这些发现与人类疾病的相关性，我们分析了来自西南美洲印第安人群的糖尿病肾病转录组数据，结果显示 Sirt5 表达在肾小管间质中特异性增加。这些数据通过来自非糖尿病和 DKD 队列的 SIRT5 免疫荧光数据进一步得到证实。此外，在培养的人近端肾小管中过表达 SIRT5 可增加有氧糖酵解。相反，我们观察到 SIRT5 表达减少时糖酵解减少。这些发现表明 SIRT5 可能导致 DKD 中不同的营养分配和利用。总之，我们的研究结果强调了 SIRT5 在 DKD 代谢重编程中以前未被认识到的作用。
