Pyrrolidine dithiocarbamate reduces alloxan-induced kidney damage by decreasing nox4, inducible nitric oxide synthase, a
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ORIGINAL ARTICLE
Pyrrolidine dithiocarbamate reduces alloxan-induced kidney damage by decreasing nox4, inducible nitric oxide synthase, and metalloproteinase-2 Bruna Pinheiro Pereira 1 & Gabriel Tavares do Valle 2 & Bruno César Côrrea Salles 3 & Karla Cristinne Mancini Costa 1 & Marilene Lopes Ângelo 1 & Larissa Helena Lobo Torres 1 & Rômulo Dias Novaes 4 & Sílvia Graciela Ruginsk 5 & Carlos Renato Tirapelli 2 & Fernanda Borges de Araújo Paula 3 & Carla Speroni Ceron 1 Received: 1 April 2020 / Accepted: 10 May 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract We examined the effect of the NFκB inhibitor pyrrolidine-1-carbodithioic acid (PDTC) on inducible nitric oxide synthase (iNOS), matrix metalloproteinase-2 (MMP-2) activity, and oxidative and inflammatory kidney damage in alloxan-induced diabetes. Two weeks after diabetes induction (alloxan-130 mg/kg), control and diabetic rats received PDTC (100 mg/kg) or vehicle for 8 weeks. Body weight, glycemia, urea, and creatinine were measured. Kidney changes were measured in hematoxylin/eosin sections and ED1 by immunohistochemistry. Kidney thiobarbituric acid reactive substances (TBARS), superoxide anion (O2−), and nitrate/nitrite (NOx) levels, and catalase and superoxide dismutase (SOD) activities were analyzed. Also, kidney nox4 and iNOS expression, and NFkB nuclear translocation were measured by western blot, and MMP-2 by zymography. Glycemia and urea increased in alloxan rats, which were not modified by PDTC treatment. However, PDTC attenuated kidney structural alterations and macrophage infiltration in diabetic rats. While diabetes increased both TBARS and O2− levels, PDTC treatment reduced TBARS in diabetic and O2− in control kidneys. A decrease in NOx levels was found in diabetic kidneys, which was prevented by PDTC. Diabetes reduced catalase activity, and PDTC increased catalase and SOD activities in both control and diabetic kidneys. PDTC treatment reduced MMP-2 activity and iNOS and p65 NFκB nuclear expression found increased in diabetic kidneys. Our results show that the NFκB inhibitor PDTC reduces renal damage through reduction of Nox4, iNOS, macrophages, and MMP-2 in the alloxan-induced diabetic model. These findings suggest that PDTC inhibits alloxan kidney damage via antioxidative and anti-inflammatory mechanisms. Keywords Pyrrolidine dithiocarbamate . Alloxan-induced diabetes . Kidney damage . Matrix metalloproteinases . Oxidative stress . Inducible nitric oxide synthase
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00210-020-01906-1) contains supplementary material, which is available to authorized users. * Carla Speroni Ceron [email protected]; [email protected] 1
Departamento de Alimentos e Medicamentos, Universidade Federal de Alfenas (UNIFAL-MG), Alfenas, Minas Gerais,, Brazil
2
Escola de Enfermagem de Ribeirão Preto (EERP), Universidade de São Paulo – USP, Sao Paulo, Brazil
3
Departamento de Análises Clínicas, Universidade Federal de Alfenas (UNIFAL-MG
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