Identification of the (Pro)renin Receptor as a Novel Regulator of Low-Density Lipoprotein Metabolism

RATIONALE:: The (pro)renin receptor [(P)RR] interacts with (pro)renin at concentrations that are >1000 times higher than observed under (patho)physiological conditions. Recent studies have identified renin-angiotensin-system (RAS)-independent functions for (P)RR related to its association with the vacuolar H+-ATPase (V-ATPase). OBJECTIVE:: To uncover RAS-independent functions of the (P)RR. METHODS AND RESULTS:: We used a proteomics-based approach to purify and identify (P)RR-interacting proteins. This resulted in identification of sortilin-1 (SORT1) as a high-confidence (P)RR-interacting protein, a finding which was confirmed by co-immunoprecipitation of endogenous (P)RR and SORT1. Functionally, silencing (P)RR expression in hepatocytes decreased SORT1 and low-density-lipoprotein (LDL) receptor (LDLR) protein abundance and, as a consequence, resulted in severely attenuated cellular LDL uptake. In contrast to LDL, endocytosis of EGF or transferrin remained unaffected by silencing of the (P)RR. Importantly, reduction of LDLR and SORT1 protein abundance occurred in the absence of changes in their corresponding transcript level. Consistent with a post-transcriptional event, degradation of the LDLR induced by (P)RR silencing could be reversed by lysosomotropic agents, such as bafilomycin A1. CONCLUSIONS:: Our study identifies a RAS-independent function for the (P)RR in the regulation of LDL metabolism by controlling the levels of SORT1 and LDLR.

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