Empagliflozin Attenuates Renal Fibrosis Through the DsbA-L-CASSTING Pathway in Unilateral Ureteral Obstruction Model
Abstract
Background: Calpains (CAPN) are intracellular cysteine proteases that play an important role in multiple biological processes linked to tissue damage and repair mechanisms, such as epithelial-mesenchymal transition and fibrosis. These two phenomena are critical in the development of chronic kidney disease (CKD), but a relationship between them and CAPN in CKD has not been definitively proved. The aim of this study was to investigate the possible role of CAPN in the development of CKD and renal fibrosis in an experimental model of CKD induced by adenine and in human kidney proximal tubular cells (HK-2). Methods: Tubulointerstitial damage resembling that is observed in human CKD was induced in mice fed an adenine-rich diet (0.2%, for 5 days and 2 weeks). In vitro experiments were performed in TGF-b HK-2 treated cells (1 ng/ml, different times), and two CAPN inhibitors (calpeptin, calpain inhibitor III, 50 µ M). Mice renal function was assessed by measuring plasma BUN and creatinine. Fibrosis markers (collagen type I and fibronectin) were determined by RT-qPCR. Protein content of CAPN 2 and 5 were analyzed by western blot. CAPN activity was analyzed by fluorescence assays. Results: Our results show a progressive worsening of renal function and fibrosis in adenine-fed mice, with increased BUN, creatinine, COL I and FN mRNA expression, being significantly higher at 2 weeks of treatment. Protein content of CAPN 2 and 5 was significantly higher in animals that received adenine for…
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