A Novel Dipeptidyl Peptidase-4 Inhibitor DA-1229 Ameliorates Tubulointerstitial Fibrosis in Cyclosporine Nephrotoxicity in Mice

Cyclosporine A (CyA) is an immunosuppressive agent that induces nephrotoxicity with long-term treatment. The roles of DPP-4 and its inhibitors in cyclosporine nephrotoxicity are not fully understood. Therefore, we investigated the effects of a novel DPP-4 inhibitor, DA-1229, on the progression of re...

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Veröffentlicht in:Life (Basel, Switzerland) Switzerland), 2021-03, Vol.11 (3), p.251, Article 251
Hauptverfasser: Min, Hye Sook, Lee, Ji Eun, Ghee, Jung Yeon, Kang, Young Sun, Cha, Jin Joo, Han, Jee Young, Han, Sang Youb, Cha, Dae Ryong
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Sprache:eng
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Zusammenfassung:Cyclosporine A (CyA) is an immunosuppressive agent that induces nephrotoxicity with long-term treatment. The roles of DPP-4 and its inhibitors in cyclosporine nephrotoxicity are not fully understood. Therefore, we investigated the effects of a novel DPP-4 inhibitor, DA-1229, on the progression of renal disease in an experimental cyclosporine nephrotoxicity model. Chronic cyclosporine nephrotoxicity was induced in six-week-old male ICR mice by subcutaneous injections of CyA at a dose of 30 mg/kg for four weeks. Animals were treated with DA-1229 at a dose of 300 mg/kg per day in food for four weeks. Although DPP-4 activity did not increase in the kidneys of mice with induced cyclosporine nephrotoxicity, DA-1229 treatment significantly suppressed DPP-4 activity in both plasma and renal tissues. DPP-4 inhibition by DA-1229 led to significantly decreased albuminuria and urinary excretion of 8-isoprosatane. DPP-4 inhibition also substantially suppressed pro-inflammatory effects, profibrotic molecules, and macrophage infiltration, and led to the improvement in renal structural changes. Our results suggest that DPP-4 inhibition by DA-1229 provides renoprotective effects in an animal model of cyclosporine nephrotoxicity via antioxidant, anti-inflammatory, and anti-fibrotic mechanisms. DPP-4 inhibition may be a useful new therapeutic approach for the management of progressive renal disease in cyclosporine nephrotoxicity.
ISSN:2075-1729
2075-1729
DOI:10.3390/life11030251