TY - JOUR
T1 - Identification of the (Pro)renin Receptor as a Novel Regulator of Low-Density Lipoprotein Metabolism
AU - Lu, Xifeng
AU - Meima, Marcel E.
AU - Nelson, Jessica K.
AU - Sorrentino, Vincenzo
AU - Loregger, Anke
AU - Scheij, Saskia
AU - Dekkers, Dick H. W.
AU - Mulder, Monique T.
AU - Demmers, Jeroen A. A.
AU - M-Dallinga-Thie, Geesje
AU - Zelcer, Noam
AU - Danser, A. H. Jan
PY - 2016
Y1 - 2016
N2 - The (pro)renin receptor ([P]RR) interacts with (pro)renin at concentrations that are >1000× higher than observed under (patho)physiological conditions. Recent studies have identified renin-angiotensin system-independent functions for (P)RR related to its association with the vacuolar H(+)-ATPase. To uncover renin-angiotensin system-independent functions of the (P)RR. 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 coimmunoprecipitation of endogenous (P)RR and SORT1. Functionally, silencing (P)RR expression in hepatocytes decreased SORT1 and low-density lipoprotein (LDL) receptor protein abundance and, as a consequence, resulted in severely attenuated cellular LDL uptake. In contrast to LDL, endocytosis of epidermal growth factor or transferrin remained unaffected by silencing of the (P)RR. Importantly, reduction of LDL receptor and SORT1 protein abundance occurred in the absence of changes in their corresponding transcript level. Consistent with a post-transcriptional event, degradation of the LDL receptor induced by (P)RR silencing could be reversed by lysosomotropic agents, such as bafilomycin A1. Our study identifies a renin-angiotensin system-independent function for the (P)RR in the regulation of LDL metabolism by controlling the levels of SORT1 and LDL receptor
AB - The (pro)renin receptor ([P]RR) interacts with (pro)renin at concentrations that are >1000× higher than observed under (patho)physiological conditions. Recent studies have identified renin-angiotensin system-independent functions for (P)RR related to its association with the vacuolar H(+)-ATPase. To uncover renin-angiotensin system-independent functions of the (P)RR. 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 coimmunoprecipitation of endogenous (P)RR and SORT1. Functionally, silencing (P)RR expression in hepatocytes decreased SORT1 and low-density lipoprotein (LDL) receptor protein abundance and, as a consequence, resulted in severely attenuated cellular LDL uptake. In contrast to LDL, endocytosis of epidermal growth factor or transferrin remained unaffected by silencing of the (P)RR. Importantly, reduction of LDL receptor and SORT1 protein abundance occurred in the absence of changes in their corresponding transcript level. Consistent with a post-transcriptional event, degradation of the LDL receptor induced by (P)RR silencing could be reversed by lysosomotropic agents, such as bafilomycin A1. Our study identifies a renin-angiotensin system-independent function for the (P)RR in the regulation of LDL metabolism by controlling the levels of SORT1 and LDL receptor
U2 - https://doi.org/10.1161/CIRCRESAHA.115.306799
DO - https://doi.org/10.1161/CIRCRESAHA.115.306799
M3 - Article
C2 - 26582775
SN - 0009-7330
VL - 118
SP - 222
EP - 229
JO - Circulation Research
JF - Circulation Research
IS - 2
ER -