Increased tubular proliferation as an adaptive response to glomerular albuminuria

J Am Soc Nephrol. 2012 Mar;23(3):429-37. doi: 10.1681/ASN.2011040396. Epub 2011 Dec 22.

Abstract

Renal tubular atrophy accompanies many proteinuric renal diseases, suggesting that glomerular proteinuria injures the tubules. However, local or systemic inflammation and filtration of abnormal proteins known to directly injure tubules are also present in many of these diseases and animal models; therefore, whether glomerular proteinuria directly causes tubular injury is unknown. Here, we examined the renal response to proteinuria induced by selective podocyte loss. We generated mice that express the diphtheria toxin receptor exclusively in podocytes, allowing reproducible dose-dependent, specific ablation of podocytes by administering diphtheria toxin. Ablation of <20% of podocytes resulted in profound albuminuria that resolved over 1-2 weeks after the re-establishment of normal podocyte morphology. Immediately after the onset of albuminuria, proximal tubule cells underwent a transient burst of proliferation without evidence of tubular damage or increased apoptosis, resulting in an increase in total tubular cell numbers. The proliferative response coincided with detection of the growth factor Gas6 in the urine and phosphorylation of the Gas6 receptor Axl in the apical membrane of renal tubular cells. In contrast, ablation of >40% of podocytes led to progressive glomerulosclerosis, profound tubular injury, and renal failure. These data suggest that glomerular proteinuria in the absence of severe structural glomerular injury activates tubular proliferation, potentially as an adaptive response to minimize the loss of filtered proteins.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Albuminuria / metabolism
  • Albuminuria / pathology
  • Albuminuria / physiopathology*
  • Animals
  • Cell Proliferation*
  • Disease Models, Animal
  • Female
  • Heparin-binding EGF-like Growth Factor
  • Integrases / genetics
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Kidney Glomerulus / metabolism
  • Kidney Glomerulus / pathology
  • Kidney Glomerulus / physiopathology*
  • Kidney Tubules, Proximal / pathology*
  • Male
  • Membrane Proteins / genetics
  • Mice
  • Mice, Transgenic
  • Podocytes / pathology*
  • Proteinuria / metabolism
  • Proteinuria / pathology
  • Proteinuria / physiopathology*
  • Proto-Oncogene Proteins / metabolism
  • Receptor Protein-Tyrosine Kinases / metabolism

Substances

  • Hbegf protein, mouse
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NPHS2 protein
  • Proto-Oncogene Proteins
  • growth arrest-specific protein 6
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase
  • Cre recombinase
  • Integrases