Sodium butyrate ameliorates renal tubular lipid accumulation through a protein phosphatase 2A/transcription factor EB axis in diabetic nephropathy

Background and Purpose Extensive evidence indicates that lipid accumulation causes renal tubular injury, which further contributes to diabetic nephropathy (DN) progression. Short‐chain fatty acids (SCFAs) play an important role in the maintenance of cellular metabolic health. Previous studies have found a significant deficiency of SCFAs in DN patients, although their effects on lipid accumulation in renal tubules have not been investigated. We have investigated the effect of sodium butyrate (NaB), one of the most abundant SCFAs, on renal tubular lipid accumulation in DN and elucidated its underlying protective mechanisms. Experimental Approach The effects of NaB were investigated on renal tubular lipid accumulation in vitro (using a glucolipotoxicity‐treated HK‐2 cell line) and DN progression in vivo (with streptozotocin injection combined with a high‐fat diet in C57BL/6J mice). RNA sequencing, surface plasmon resonance, pulldown MS assay, and molecular docking were applied to explore specific molecular mechanisms. Key Results Our findings revealed that serum butyrate levels were reduced in DN patients and inversely correlated with DN severity. NaB supplementation improved renal tubular lipid accumulation and injury in HK‐2 cells and DN mice. The protective effects of NaB were largely abrogated in kidney‐specific Tfeb knockout mice. NaB directly interacted with PPP2R1A to promote the formation and activation of PP2A heterotrimers, thereby facilitating the dephosphorylation of TFEB and promoting lipophagy. Conclusions and Implications NaB functions as a PP2A‐TFEB axis activator to restore lipophagy and ameliorate lipid accumulation in tubular epithelial cells, pointing to NaB as a promising protective agent against renal injury in DN patients.