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

• Published in: International journal of molecular sciences 2020-11, Vol.21 (22), p.8868
• Main Authors: Gil-Fernández, Marta, Navarro-García, José Alberto, Val-Blasco, Almudena, González-Lafuente, Laura, Martínez, José Carlos, Rueda, Angélica, Tamayo, Maria, Morgado, José Luis, Zaragoza, Carlos, Ruilope, Luis Miguel, Delgado, Carmen, Ruiz-Hurtado, Gema, Fernández-Velasco, María
• Format: Article
• Language: English
• Subjects: Ca2+ handling; Caffeine; Calcium (intracellular); Calcium (reticular); Calcium ions; Calcium signalling; Cardiac muscle; Cardiomyocytes; Cardiovascular diseases; chronic kidney disease; Immune system; Impairment; Inflammation; Inflammatory response; Intracellular; Kidney diseases; Kinases; Leak channels; Medical innovations; Nephrectomy; NOD1; Nod1 protein; Nucleotides; Oligomerization; Protein kinase; Protein-serine/threonine kinase; Proteins; Recruitment; Renal function; RIP2; RyR2; Sarcoplasmic reticulum; Surgery
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21228868

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.