Regulation of Vascular Tone of Preglomerular Renal Vasculature by Caldesmon

Caldesmon is an actomyosin-tropomyosin-binding protein with pleiotropic functions that generally acts as an inhibitor of actomyosin ATPase activity. This study aims to explore the role of caldesmon in regulation of preglomerular vascular tone.

Expression of caldesmon, myosin light chain, and α-smooth muscle actin was assessed by western blot of interlobar arteries (IAs) from young and old mice or human renal arteries from patients who underwent nephrectomy or tumor enucleation. IAs were obtained from wild-type or heterozygous mice, carrying a mutant allele that ablates both caldesmon isoforms (caldesmon^+/-). In IAs, the vasoreactivity to α₁-agonist phenylephrine, the soluble guanylate cyclase activator cinaciguat, and inhibitors of RhoA-associated protein kinase Y27632 or p21-activated protein kinase 1 IPA-3 were tested by wire myography.

Caldesmon was expressed in all preglomerular vessels of mice and humans. In caldesmon^+/- IAs of young mice, caldesmon protein was 50% less than in IAs of wild-type mice. In IAs of old mice, caldesmon was less than in IAs of young mice and not significantly different between caldesmon^+/- and wild-type. Caldesmon mutation did not affect phenylephrine-induced contraction or cinaciguat sensitivity but induced a rightward shift of Y27632-induced relaxation in IAs of young and old mice and a reduction in IPA-3-induced relaxation by 50% only in IAs of young mice. In human renal arteries, caldesmon expression negatively correlated with age and the presence of renal inflammation. In the inflammation group, a reduction in estimated glomerular filtration rate was detected.

This study provides cumulative evidence that caldesmon is a marker of age and inflammation-related changes in preglomerular vascular function. Our work supports the view that in the renal vasculature, caldesmon expression is age dependent and determines its sensitivity to the RhoA-associated protein kinase/p21-activated protein kinase 1 regulatory pathway.