Lactate induces renal lipid accumulation and aggravates renal fibrosis by inhibiting the PPARα signaling pathway and fatty acid oxidation.

Chronic kidney disease (CKD) is characterized by renal fibrosis as its core pathological feature, and lipid metabolism disorders are a key driver of disease progression. However, the specific pathological significance of elevated lactate levels in patients with CKD remains unclear. This study aimed to verify the hypothesis that lactate exacerbates renal fibrosis by inhibiting the PPARα/FAO pathway. A total of 15 healthy controls and 75 CKD patients were enrolled. Serum lactate levels were measured, and their correlations with Scr, BUN, eGFR, and lipid metabolism parameters (triglycerides [TG], total cholesterol [TCH]) were analyzed. Meanwhile, unilateral ureteral obstruction (UUO) mouse models and transforming growth factor-β1 (TGF-β1)-induced human proximal tubular epithelial cells (HK-2 cells) were used to validate the regulatory role of lactate in renal fibrosis. Results showed that serum lactate levels in CKD patients significantly increased with disease stage progression, and were positively correlated with Scr, BUN, TG, and TCH (p < 0.05), while negatively correlated with eGFR (p < 0.0001). RNA sequencing and Western blot confirmed that UUO mouse kidney tissues exhibited lactate accumulation, downregulation of the PPARα/FAO pathway, lipid accumulation, and aggravated renal fibrosis. Exogenous lactate supplementation exacerbated TGF-β1-induced fibrosis and lipid disorders in HK-2 cells, whereas inhibition of lactate production by oxamic acid sodium significantly reversed these pathological effects. In conclusion, lactate disrupts renal lipid homeostasis and exacerbates renal fibrosis by inhibiting the PPARα/FAO pathway. This study provides an important theoretical basis for elucidating the pathological mechanism of CKD and developing novel therapeutic targets.