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Metabolic reprogramming of proximal tubular epithelial cells (PTECs) is associated with kidney injury. PTECs with impaired mitochondrial respiration increase glycolysis to compensate for the lack of ATP. Short-chain fatty acids as acetate, propionate and butyrate regulate the metabolism of immune and nonimmune cells. Butyrate inhibits histone deacetylases (HDACs) and reduces kidney injury and inflammation by signaling through the metabolite-sensing G protein receptor (GPR)109a. We investigated whether butyrate interferes with the metabolism of PTECs and reduces renal injury in calcium oxalate crystal (CaOx)-induced AKI.
Primary murine PTECs received 3.2 mM sodium butyrate (NaB) and CaOx crystals (1000 µg/ml, 1–2 µm size) for 6 hours. Oxygen consumption rate and extracellular acidification rate were assessed with Seahorse XFe96 Analyzer. AKI was induced in wild-type (WT), NaB-pretreated WT (400 mg/kg/day, i.p, for 4 consecutive days), and Gpr109a-/- mice by a single i.p. injection of sodium oxalate (NaOx, 100mg/kg) and 3% NaOx in drinking water for 24hr before sacrifice. Kidney function, injury, and metabolism were assessed.
PTECs exposed to CaOx had lower basal and maximal mitochondrial respiration and less ATP production, while glycolysis was not changed. NaB treatment increased glycolysis in PTECs exposed to CaOx. WT mice underwent intrarenal CaOx deposition had decreased renal expression of Gpr109a and acyl-CoA oxidase 2 (ACOX2, enzyme involved in β-oxidation of fatty acids), increased serum levels of creatinine and urea, as well as increased renal HDAC activity and neutrophil gelatinase-associated lipocalin (NGAL, marker of tubular injury) expression. CaOx-induced decrease in renal function and ACOX2 expression and increase in tubular injury were significantly accentuated in Gpr109a-/- mice. Pretreatment with NaB ameliorated renal function and tubular injury, as well as normalized renal HDAC and mRNA ACOX2 in WT mice undergoing CaOx-induced AKI.
Butyrate increases glycolysis in PTECs with CaOx-induced impaired mitochondrial respiration and ameliorates kidney function/injury in CaOx-induced AKI. (FAPESP 2019/02893-9 and 2017/05264-7, CNPq, and CAPES)