Abstract 324: Collectrin in The Kidney Determines Salt-Sensitivity

Abstract

Collectrin (Tmem27), an ACE-2 homologue and a chaperone of amino acid transporters, is expressed in the endothelium throughout the vasculature and in the renal epithelia, including the proximal tubules and collecting duct. Its renal expression is upregulated after reduction of nephron mass and during salt-sensitive hypertension (SSH). These observations raise the question of how collectrin might be functionally integrated in the ACE family in the context of blood pressure (BP) regulation. We previously reported that, on a permissive genetic background, collectrin-deficient (KO) mice have baseline hypertension (HTN) that is ameliorated by supplementation with L-arginine (L-Arg). Furthermore, they have augmented SSH that is corrected by TEMPOL, a superoxide dismutase mimetic. These phenotypes are associated with impaired cellular uptake of L-Arg, impaired endothelial-dependent relaxation, decreased levels of endothelial nitric oxide synthase dimerization (eNOS), and a rightward shift of the pressure-natriuresis relationship. Here, we demonstrate that the activity or dimerization of neuronal NOS (nNOS) in the renal medulla is also significantly decreased in KO mice. To determine the effect of renal versus extra-renal collectrin on BP regulation, we performed renal cross-transplantation (XTP) studies (through a service provided by the Duke O’Brien Center), under normal and high salt conditions, in the following groups: 1) wild-type (WT) mice with WT kidney (WT -> WT), 2) collectrin KO mice with WT kidney (WT -> KO), and 3) WT mice with collectrin KO kidney (KO -> WT). BP was measured by radiotelemetry. Collectrin KO -> WT group displayed a trend towards higher baseline systolic BP (SBP, mm Hg), but did not reach significance (WT -> WT 137.3, WT -> KO 133.5, KO -> WT 142.4, p = not significant, n = 3-5 per group). By paired analysis, all groups had significantly higher SBP on high salt diet (HSD), compared to normal salt diet. However, collectrin KO -> WT group had a statistically significantly higher SBP under HSD (WT -> WT 148.9, WT -> KO 151.6, KO -> WT 168.6, p= 0.037, one way ANOVA). In conclusion, collectrin may regulate BP by influencing renal hemodynamics and/or epithelial sodium handling through its central role in mediating cellular L-Arg uptake.