Chor Ho Jo1, Sua Kim1, Joon-Sung Park2, Gheun-Ho Kim1,2. 1. Institute of Biomedical Science, Hanyang University College of Medicine, Seoul, Republic of Korea. 2. Division of Nephrology, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea.
Abstract
BACKGROUND/AIMS: Dipeptidyl peptidase-4 (DPP4) inhibitors are known to have a protective effect on diabetic kidney disease, possibly via reduction of oxidative stress and inflammation in the kidney. However, whether these potential mechanisms play a role in non-diabetic proteinuric kidney diseases is not clear. METHODS: Two different animal experiments were carried out using sitagliptin and linagliptin for DPP4 inhibition. In each experiment, male Sprague-Dawley rats were uninephrectomized and randomly divided into vehicle-treated and doxorubicin-treated rats, with or without DPP4 inhibition. Administration of a DPP4 inhibitor was performed daily by oral gavage over six weeks. RESULTS: A single intravenous injection of doxorubicin resulted in hypertension and remarkable proteinuria. Linagliptin, but not sitagliptin, lowered systolic blood pressure in rats with doxorubicin nephropathy. By contrast, sitagliptin ameliorated tubulointerstitial injury, inflammatory cell infiltration, and interstitial fibrosis in rat kidneys with doxorubicin nephropathy. Quantitative polymerase chain reaction analysis revealed that mRNA expression of NLRP3, caspase-1, ASC, and IL-1β was remarkably increased in rat kidneys with doxorubicin nephropathy, and that this upregulation of the major components of the NLRP3 inflammasome was effectively suppressed by treatment with either sitagliptin or linagliptin. Additionally, upregulation of IL-6 was reversed by linagliptin, but not by sitagliptin. On the other hand, sitagliptin, but not linagliptin, reversed the increase in mRNA expression of gp91phox, p47phox, and p67phox in rat kidneys with doxorubicin nephropathy. CONCLUSION: NLRP3 inflammasome activation was shown in our rat model of doxorubicin nephropathy. DPP4 inhibitors can suppress the activity of NLRP3, with or without relieving NADPH oxidase 2-related oxidative stress.
BACKGROUND/AIMS: Dipeptidyl peptidase-4 (DPP4) inhibitors are known to have a protective effect on diabetic kidney disease, possibly via reduction of oxidative stress and inflammation in the kidney. However, whether these potential mechanisms play a role in non-diabetic proteinuric kidney diseases is not clear. METHODS: Two different animal experiments were carried out using sitagliptin and linagliptin for DPP4 inhibition. In each experiment, male Sprague-Dawley rats were uninephrectomized and randomly divided into vehicle-treated and doxorubicin-treated rats, with or without DPP4 inhibition. Administration of a DPP4 inhibitor was performed daily by oral gavage over six weeks. RESULTS: A single intravenous injection of doxorubicin resulted in hypertension and remarkable proteinuria. Linagliptin, but not sitagliptin, lowered systolic blood pressure in rats with doxorubicinnephropathy. By contrast, sitagliptin ameliorated tubulointerstitial injury, inflammatory cell infiltration, and interstitial fibrosis in rat kidneys with doxorubicinnephropathy. Quantitative polymerase chain reaction analysis revealed that mRNA expression of NLRP3, caspase-1, ASC, and IL-1β was remarkably increased in rat kidneys with doxorubicinnephropathy, and that this upregulation of the major components of the NLRP3 inflammasome was effectively suppressed by treatment with either sitagliptin or linagliptin. Additionally, upregulation of IL-6 was reversed by linagliptin, but not by sitagliptin. On the other hand, sitagliptin, but not linagliptin, reversed the increase in mRNA expression of gp91phox, p47phox, and p67phox in rat kidneys with doxorubicinnephropathy. CONCLUSION:NLRP3 inflammasome activation was shown in our rat model of doxorubicinnephropathy. DPP4 inhibitors can suppress the activity of NLRP3, with or without relieving NADPH oxidase 2-related oxidative stress.
Authors: Javier Donate-Correa; Carla M Ferri; Fátima Sánchez-Quintana; Atteneri Pérez-Castro; Ainhoa González-Luis; Ernesto Martín-Núñez; Carmen Mora-Fernández; Juan F Navarro-González Journal: Front Med (Lausanne) Date: 2021-01-22
Authors: Javier Donate-Correa; Desirée Luis-Rodríguez; Ernesto Martín-Núñez; Víctor G Tagua; Carolina Hernández-Carballo; Carla Ferri; Ana Elena Rodríguez-Rodríguez; Carmen Mora-Fernández; Juan F Navarro-González Journal: J Clin Med Date: 2020-02-07 Impact factor: 4.241