Podocyte repopulation by renal progenitor cells following glucocorticoids treatment in experimental FSGS

Am J Physiol Renal Physiol. 2013 Jun 1;304(11):F1375-89. doi: 10.1152/ajprenal.00020.2013. Epub 2013 Mar 13.

Abstract

Prednisone is a mainstay of treatment for patients with focal segmental glomerulosclerosis (FSGS), a disease characterized by reduced podocyte number and glomerulosclerosis. Although the systemic immune-modulatory effects of prednisone are well-known, direct tissue effects on glomerular cells are poorly understood. Experimental FSGS was induced in mice with a cytotoxic anti-podocyte antibody, resulting in an abrupt decrease in podocyte number by day 3, proteinuria, and the development of glomerulosclerosis. Administering daily prednisone to mice with FSGS, beginning at day 3, significantly increased podocyte number at weeks 2 and 4. Podocyte number did not increase in control mice with FSGS given DMSO. The increase in podocyte number in prednisone-treated mice correlated significantly with reduced glomerulosclerosis. Prednisone reduced podocyte apoptosis measured by synaptopodin⁺/caspase-3⁺ double staining. Additionally, the number of podocyte progenitors, defined as cells expressing both a parietal epithelial cell protein and a podocyte protein, was significantly increased in prednisone-treated mice with FSGS at weeks 2 and 4. This was associated with increased phospho-ERK staining in both parietal epithelial cells (PAX2⁺/p-ERK⁺) and in podocyte progenitors (WT-1⁺/p-ERK⁺ lining Bowman's capsule). These data show that in this model of experimental FSGS, prednisone augments glomerular repair by increasing podocyte number through direct effects on both glomerular epithelial cells. Prednisone limits podocyte loss by reducing apoptosis, and it increases regeneration by augmenting the number of podocyte progenitors. The data support a direct glomerular cell action for prednisone in improving outcomes in FSGS.

Keywords: CD44; apoptosis; focal segmental glomerulosclerosis; glomerulosclerosis; parietal epithelial cell; prednisone; proteinuria; regeneration; repair.

Publication types

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

MeSH terms

  • Animals
  • Caspase 3 / analysis
  • Cell Count
  • Cell Proliferation / drug effects
  • Glomerulosclerosis, Focal Segmental / drug therapy*
  • Glomerulosclerosis, Focal Segmental / pathology*
  • Glucocorticoids / therapeutic use*
  • Hyaluronan Receptors / analysis
  • Immunoglobulin G / metabolism
  • Immunohistochemistry
  • Kidney Glomerulus / immunology
  • MAP Kinase Signaling System / drug effects
  • Mice
  • Microfilament Proteins / analysis
  • PAX2 Transcription Factor / analysis
  • Podocytes / chemistry
  • Podocytes / pathology*
  • Prednisone / therapeutic use*
  • Proteinuria
  • Sheep / immunology
  • Stem Cells / pathology
  • WT1 Proteins / analysis

Substances

  • Glucocorticoids
  • Hyaluronan Receptors
  • Immunoglobulin G
  • Microfilament Proteins
  • PAX2 Transcription Factor
  • Synpo protein, mouse
  • WT1 Proteins
  • Caspase 3
  • Prednisone