Cubilin maintains blood levels of HDL and albumin

J Am Soc Nephrol. 2014 May;25(5):1028-36. doi: 10.1681/ASN.2013060671. Epub 2013 Dec 19.

Abstract

Cubilin is an endocytic receptor highly expressed in renal proximal tubules, where it mediates uptake of albumin and filtered forms of apoA-I/HDL. Cubilin deficiency leads to urinary loss of albumin and apoA-I; however, the consequences of cubilin loss on the homeostasis of blood albumin and apoA-I/HDL have not been studied. Using mice heterozygous for cubilin gene deletion (cubilin HT mice), we show that cubilin haploinsufficiency leads to reduced renal proximal tubular uptake of albumin and apoA-I and significantly increased urinary loss of albumin and apoA-I. Moreover, cubilin HT mice displayed significantly decreased blood levels of albumin, apoA-I, and HDL. The levels of albumin and apoA-I protein or mRNA expressed in the liver, kidney, or intestine of cubilin HT mice did not change significantly. The clearance rate of small HDL3 particles (density>1.13 g/ml) from the blood increased significantly in cubilin HT mice. In contrast, the rate of clearance of larger HDL2 particles from the blood did not change significantly, indicating a decreased half-life for HDL particles capable of filtering through the glomerulus. On the basis of these findings, we conclude that cubilin deficiency reduces renal salvage and delivery back to the blood of albumin and apoA-I, which decreases blood levels of albumin and apoA-I/HDL. These findings raise the possibility that therapeutic increase of renal cubilin expression might reduce proteinuria and increase blood levels of albumin and HDL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albumins / antagonists & inhibitors
  • Albumins / metabolism
  • Albuminuria / etiology*
  • Albuminuria / genetics*
  • Albuminuria / metabolism
  • Animals
  • Apolipoprotein A-I / antagonists & inhibitors
  • Apolipoprotein A-I / blood
  • Apolipoprotein A-I / urine*
  • Gene Deletion
  • Genetic Carrier Screening
  • Humans
  • Kidney Glomerulus / metabolism
  • Kidney Glomerulus / pathology
  • Lipoproteins, HDL / antagonists & inhibitors
  • Lipoproteins, HDL / biosynthesis
  • Lipoproteins, HDL / blood*
  • Lipoproteins, HDL3 / antagonists & inhibitors
  • Lipoproteins, HDL3 / blood
  • Lipoproteins, HDL3 / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Receptors, Cell Surface / deficiency
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / physiology*

Substances

  • Albumins
  • Apolipoprotein A-I
  • Lipoproteins, HDL
  • Lipoproteins, HDL3
  • Receptors, Cell Surface
  • intrinsic factor-cobalamin receptor