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

Circ Res. 2016 Jan 22;118(2):222-9. doi: 10.1161/CIRCRESAHA.115.306799. Epub 2015 Nov 18.


Rationale: 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.

Objective: To uncover renin-angiotensin system-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 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.

Conclusions: 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.

Keywords: LDL receptors; cholesterol homeostasis; endocytosis; renin–angiotensin system; sortilin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Animals
  • CHO Cells
  • Chromatin Immunoprecipitation
  • Cricetulus
  • Endocytosis*
  • HEK293 Cells
  • Hep G2 Cells
  • Hepatocytes / metabolism*
  • Humans
  • Lipoproteins, LDL / metabolism*
  • Protein Processing, Post-Translational
  • Proteolysis
  • Proteomics* / methods
  • RNA Interference
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism
  • Transfection
  • Vacuolar Proton-Translocating ATPases / genetics
  • Vacuolar Proton-Translocating ATPases / metabolism*


  • ATP6AP2 protein, human
  • Adaptor Proteins, Vesicular Transport
  • LDLR protein, human
  • Lipoproteins, LDL
  • Receptors, Cell Surface
  • Receptors, LDL
  • Vacuolar Proton-Translocating ATPases
  • sortilin