Genetic Deletion of NOD1 Prevents Cardiac Ca2+ Mishandling Induced by Experimental Chronic Kidney Disease

Abstract

© 2020 by the authors.Risk of cardiovascular disease (CVD) increases considerably as renal function declines in chronic kidney disease (CKD). Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) has emerged as a novel innate immune receptor involved in both CVD and CKD. Following activation, NOD1 undergoes a conformational change that allows the activation of the receptor-interacting serine/threonine protein kinase 2 (RIP2), promoting an inflammatory response. We evaluated whether the genetic deficiency of Nod1 or Rip2 in mice could prevent cardiac Ca2+ mishandling induced by sixth nephrectomy (Nx), a model of CKD. We examined intracellular Ca2+ dynamics in cardiomyocytes from Wild-type (Wt), Nod1−/− and Rip2−/− sham-operated or nephrectomized mice. Compared with Wt cardiomyocytes, Wt-Nx cells showed an impairment in the properties and kinetics of the intracellular Ca2+ transients, a reduction in both cell shortening and sarcoplasmic reticulum Ca2+ load, together with an increase in diastolic Ca2+ leak. Cardiomyocytes from Nod1−/−-Nx and Rip2−/−-Nx mice showed a significant amelioration in Ca2+ mishandling without modifying the kidney impairment induced by Nx. In conclusion, Nod1 and Rip2 deficiency prevents the intracellular Ca2+ mishandling induced by experimental CKD, unveiling new innate immune targets for the development of innovative therapeutic strategies to reduce cardiac complications in patients with CKD.This work was supported by Spanish Ministry of Economy and Competitiveness and European Regional Development Fund (SAF-2017-84777R), Institute of Health Carlos III (PI17/01093 and PI17/01344), Sociedad Española de Cardiología, Proyecto Traslacional 2019, Fundación Renal Íñigo Álvarez de Toledo (FRIAT), Fondo Europeo de Desarrollo Regional (FEDER), FSE, and CIBER-CV, a network funded by ISCIII. M.F.-V. is Miguel Servet II researcher of ISCIII (MSII16/00047 Carlos III Health Institute). G.R.-H. is Miguel Servet I researcher of ISCIII (CP15/00129 Carlos III Health Institute). M.T. is a PhD student funded by the FPU program of the Spanish Ministry of Science, Innovation and Universities (FPU17/06135). A.R. was supported by Fondo SEP-Cinvestav project #601410 FIDSC 2018/2; and Fondo SEP-Conacyt Ciencia Básica A1-S-9082