Genetic Deletion of NOD1 Prevents Cardiac Ca(2+) Mishandling Induced by Experimental Chronic Kidney Disease

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 Ca(2+) mishandling induced by sixth nephrectomy (Nx), a model of CKD. We examined intracellular Ca(2+) 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 Ca(2+) transients, a reduction in both cell shortening and sarcoplasmic reticulum Ca(2+) load, together with an increase in diastolic Ca(2+) leak. Cardiomyocytes from Nod1(−/−)-Nx and Rip2(−/−)-Nx mice showed a significant amelioration in Ca(2+) mishandling without modifying the kidney impairment induced by Nx. In conclusion, Nod1 and Rip2 deficiency prevents the intracellular Ca(2+) 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.