Cardiovascular and Metabolic Disorders Signature Research Program, Duke-NUS Medical School, Singapore; Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Japan Society for the Promotion of Science, Tokyo, Japan.
Cardiovascular and Metabolic Disorders Signature Research Program, Duke-NUS Medical School, Singapore.
Kidney Int. 2023 Dec;104(6):1135-1149. doi: 10.1016/j.kint.2023.08.006. Epub 2023 Oct 16.
Diabetic nephropathy (DN) is characterized by abnormal kidney energy metabolism, but its causes and contributions to DN pathogenesis are not clear. To examine this issue, we carried out targeted metabolomics profiling in a mouse model of DN that develops kidney disease resembling the human disorder. We found a distinct profile of increased lactate levels and impaired energy metabolism in kidneys of mice with DN, and treatment with an angiotensin-receptor blocker (ARB) reduced albuminuria, attenuated kidney pathology and corrected many metabolic abnormalities, restoring levels of lactate toward normal while increasing kidney ATP content. We also found enhanced expression of lactate dehydrogenase isoforms in DN. Expression of both the LdhA and LdhB isoforms were significantly increased in kidneys of mice, and treatment with ARB significantly reduced their expression. Single-cell sequencing studies showed specific up-regulation of LdhA in the proximal tubule, along with enhanced expression of oxidative stress pathways. There was a significant correlation between albuminuria and lactate in mice, and also in a Southeast Asian patient cohort consisting of individuals with type 2 diabetes and impaired kidney function. In the individuals with diabetes, this association was independent of ARB and angiotensin-converting enzyme inhibitor use. Furthermore, urinary lactate levels predicted the clinical outcomes of doubling of serum creatinine or development of kidney failure, and there was a significant correlation between urinary lactate levels and biomarkers of tubular injury and epithelial stress. Thus, we suggest that kidney metabolic disruptions leading to enhanced generation of lactate contribute to the pathogenesis of DN and increased urinary lactate levels may be a potential biomarker for risk of kidney disease progression.
糖尿病肾病（DN）的特征是肾脏能量代谢异常，但导致这种异常的原因及其对 DN 发病机制的贡献尚不清楚。为了研究这个问题，我们在一种类似于人类疾病的小鼠 DN 模型中进行了靶向代谢组学分析。我们发现，DN 小鼠的肾脏中存在明显的乳酸水平升高和能量代谢受损的特征，而血管紧张素受体阻滞剂（ARB）的治疗可减少蛋白尿，减轻肾脏病理，并纠正许多代谢异常，使乳酸水平恢复正常，同时增加肾脏的 ATP 含量。我们还发现，DN 中乳酸脱氢酶同工酶的表达增强。在小鼠肾脏中，LdhA 和 LdhB 同工酶的表达均显著增加，而 ARB 的治疗可显著降低其表达。单细胞测序研究显示，LdhA 在近端小管中特异性上调，同时氧化应激途径的表达增强。在小鼠和包括 2 型糖尿病和肾功能受损的东南亚患者队列中，白蛋白尿与乳酸之间存在显著相关性。在糖尿病患者中，这种相关性独立于 ARB 和血管紧张素转换酶抑制剂的使用。此外，尿乳酸水平可预测血清肌酐倍增或肾衰竭的临床结局，并且尿乳酸水平与肾小管损伤和上皮应激的生物标志物显著相关。因此，我们认为导致乳酸生成增加的肾脏代谢紊乱可能导致 DN 的发病机制，并认为尿乳酸水平升高可能是肾脏疾病进展风险的潜在生物标志物。
