Background: The inhibition of dipeptidyl peptidase (DPP) IV shows protective effects on tissue injury of the heart, lung,\r\nand kidney. Forkhead box O (FoxO) transcriptional factors regulate cellular differentiation, growth, survival, the cell cycle,\r\nmetabolism, and oxidative stress. The aims of this study were to investigate whether the DPP IV inhibitor sitagliptin\r\ncould attenuate kidney injury and to evaluate the status of FoxO3a signaling in the rat remnant kidney model.\r\nMethods: Rats were received two-step surgery of 5/6 renal mass reduction and fed on an oral dose of 200 mg/kg/day\r\nsitagliptin for 8 weeks. Before and after the administration of sitagliptin, physiologic parameters were measured. After\r\n8 weeks of treatment, the kidneys were harvested.\r\nResults: The sitagliptin treatment attenuated renal dysfunction. A histological evaluation revealed that\r\nglomerulosclerosis and tubulointerstitial injury were significantly decreased by sitagliptin. Sitagliptin decreased DPP IV\r\nactivity and increased the renal expression of glucagon-like peptide-1 receptor (GLP-1R). The subtotal nephrectomy led\r\nto the activation of phosphatidylinositol 3-kinase (PI3K)-Akt and FoxO3a phosphorylation, whereas sitagliptin treatment\r\nreversed these changes, resulting in PI3K-Akt pathway inactivation and FoxO3a dephosphorylation. The renal expression\r\nof catalase was increased and the phosphorylation of c-Jun N-terminal kinase (JNK) was decreased by sitagliptin.\r\nSitagliptin treatment reduced apoptosis by decreasing cleaved caspase-3 and -9 and Bax levels and decreased\r\nmacrophage infiltration.\r\nConclusions: In rat remnant kidneys, DPP IV inhibitor attenuated renal dysfunction and structural damage. A reduction\r\nof apoptosis, inflammation and an increase of antioxidant could be suggested as a renoprotective mechanism together\r\nwith the activation of FoxO3a signaling. Therefore, DPP IV inhibitors might provide a promising approach for treating\r\nCKD, but their application in clinical practice remains to be investigated.
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