Irena Audzeyenka, Klaudia Grochowalska, Maria Szrejder, Tomasz Kulesza, Patrycja Rachubik, Dorota Rogacka, Agnieszka Piwkowska
Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Gdańsk, Poland.
Laboratory of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, Medical University of Gdansk, Gdansk, Poland.
Sci Rep. 2025 Apr 23;15(1):14162. doi: 10.1038/s41598-025-98797-0.
Lactate is a cellular product of glycolytic metabolism, serving as both an additional oxidative energy substrate and a signaling molecule in metabolic regulation. Plasma lactate levels are elevated in diabetes, and chronic extracellular lactic acidosis is recognized as a negative prognostic marker for the disease. The development of diabetic kidney disease is closely associated with podocyte injury, which forms a crucial layer of the glomerular filtration barrier. Given that high extracellular glucose concentrations also induce lactate production and excretion in podocytes, we hypothesize that an appropriate LDH expression pattern is crucial for maintaining proper podocyte metabolism and function. Our research shows that hyperglycemia significantly decreases lactate dehydrogenase activity in podocytes. Specifically, reduced LDHA expression under hyperglycemic conditions contributes to metabolic disturbances in these cells. Lower LDH activity results in decreased glycolytic activity, altered expression of monocarboxylate transporters, reduced insulin-dependent glucose uptake, and a decrease in the number of podocyte foot processes. These findings underscore the essential role of LDHA in the metabolic adaptation of podocytes to elevated glucose levels typical of diabetes. By elucidating the molecular mechanisms underlying podocyte injury, our study provides new insights into potential therapeutic targets for preventing or mitigating diabetic kidney disease.
乳酸是糖酵解代谢的细胞产物，既是一种额外的氧化能量底物，也是代谢调节中的信号分子。糖尿病患者血浆乳酸水平升高，慢性细胞外乳酸酸中毒被认为是该疾病的不良预后标志物。糖尿病肾病的发展与足细胞损伤密切相关，足细胞构成肾小球滤过屏障的关键层。鉴于高细胞外葡萄糖浓度也会诱导足细胞产生和排泄乳酸，我们推测适当的乳酸脱氢酶（LDH）表达模式对于维持足细胞正常代谢和功能至关重要。我们的研究表明，高血糖显著降低足细胞中的乳酸脱氢酶活性。具体而言，高血糖条件下LDHA表达降低导致这些细胞出现代谢紊乱。较低的LDH活性导致糖酵解活性降低、单羧酸转运体表达改变、胰岛素依赖性葡萄糖摄取减少以及足细胞足突数量减少。这些发现强调了LDHA在足细胞对糖尿病典型的高血糖水平进行代谢适应中的重要作用。通过阐明足细胞损伤的分子机制，我们的研究为预防或减轻糖尿病肾病的潜在治疗靶点提供了新的见解。
