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.