Butyrate improves the metabolism of proximal tubular cells and attenuates tissue damage in oxalate-induced acute kidney injury.

Metabolic reprogramming of renal cells is closely linked to kidney injury and repair. In proximal tubular cells (PTCs), impaired mitochondrial and peroxisomal fatty acid oxidation leads to compensatory increase in glycolysis to meet energy demands. Short-chain fatty acids such as butyrate modulate cell metabolism and can attenuate inflammation through activation of the G protein-coupled receptors (GPCRs). We investigated whether butyrate influences PTC metabolism in calcium oxalate crystal (CaOx)-induced acute kidney injury (AKI). In vitro, primary murine PTCs were pretreated with sodium butyrate (NaB) and/or challenged with CaOx. In vivo, AKI was induced in wild-type (WT) and Gpr109a⁻/⁻ animals by a single intraperitoneal injection of sodium oxalate (NaOx), followed by NaOx administration in drinking water for 24 hours. Additionally, animals received NaB pretreatment, which was maintained during AKI. NaB upregulated peroxisomal gene expression and enhanced mitochondrial respiration in unstimulated PTCs. CaOx exposure impaired mitochondrial function while enhancing glycolytic potential without altering basal glycolysis, and under these conditions, NaB treatment increased proton leak. CaOx-induced AKI mice showed renal dysfunction, tubular injury, increased IL-6 mRNA, and dysregulated expression of peroxisomal metabolism genes. Disruption of renal function, tissue integrity, and peroxisome-associated pathways was more severe in mice lacking GPR109A exposed to CaOx. In WT mice, NaB improved renal function, reduced tubular injury, and partially restored the expression of genes associated with peroxisomal metabolism. In contrast, NaB had minimal protective effects in Gpr109a⁻/⁻ mice. These findings suggest that butyrate enhances PTC metabolism and mitigates CaOx-induced injury, with potential implications for human AKI.