Abnormal lactate metabolism is linked to albuminuria and kidney injury in diabetic nephropathy

蛋白尿 糖尿病肾病 内科学 内分泌学 肾脏疾病 医学 糖尿病 肌酐 乳酸脱氢酶 肾功能 肾病 急性肾损伤 生物 生物化学
作者
Kengo Azushima,Jean‐Paul Kovalik,Takahiro Yamaji,Jianhong Ching,Tze Wei Chng,Jing Guo,Jing Liu,Mien T.X. Nguyen,Rashidah Binte Sakban,Simi Elizabeth George,Puay Hoon Tan,Su Chi Lim,Susan B. Gurley,Thomas M. Coffman
出处
期刊:Kidney International [Elsevier]
卷期号:104 (6): 1135-1149 被引量:15
标识
DOI:10.1016/j.kint.2023.08.006
摘要

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.
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