On Testable Design for CMOS Logic Circuits.

Abstract

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 <i>Nod1</i> or <i>Rip2</i> in mice could prevent cardiac Ca²⁺ mishandling induced by sixth nephrectomy (Nx), a model of CKD. We examined intracellular Ca²⁺ dynamics in cardiomyocytes from <i>Wild-type</i> (<i>Wt</i>), <i>Nod1</i>^-/- and <i>Rip2^-/-</i> sham-operated or nephrectomized mice. Compared with <i>Wt</i> cardiomyocytes, <i>Wt</i>-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 <i>Nod1</i>^-/--Nx and <i>Rip2</i>^-/--Nx mice showed a significant amelioration in Ca²⁺ mishandling without modifying the kidney impairment induced by Nx. In conclusion, <i>Nod1</i> and <i>Rip2</i> 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.