Inhibiting Angiotensin-Converting Enzyme Promotes Renal Repair by Limiting Progenitor Cell Proliferation and Restoring the Glomerular Architecture

Am J Pathol. 2011 Aug;179(2):628-38. doi: 10.1016/j.ajpath.2011.04.003. Epub 2011 Jun 2.

Abstract

We previously reported that angiotensin-converting enzyme inhibitor (ACEi) renoprotection in Munich Wistar Frömter (MWF) rats, which develop progressive glomerular injury, was associated with podocyte repopulation and preservation of glomerular architecture. Here, we studied the time course of the lesions, their cellular components, and the effect of ACEi. Early glomerular lesions were synechiae, followed by extracapillary crescents and glomerulosclerosis. The majority of cells forming crescents were claudin1(+) parietal epithelial cells and, to a lesser extent, WT1(+) podocytes, both in active proliferation. In crescents, cells expressing the metanephric mesenchyme marker NCAM were also found. Three distinct populations of parietal epithelial cells were identified in the rat Bowman's capsule: NCAM(+)WT1(-) cells, also expressing progenitor cell marker CD24, and NCAM(+)WT1(+) and NCAM(-)WT1(+) cells, the latter population representing parietal podocytes. After exposure to inductive medium, cultured parietal epithelial cells that were obtained by capsulated glomeruli generated podocytes, documenting their progenitor nature. Mitotic activity of cultured renal progenitors was induced by angiotensin II through the down-regulation of cell cycle inhibitor C/EBPδ expression. Treatment with ACEi reduced number and extension of crescents and glomerulosclerosis in MWF rats. Renoprotection was accomplished through the limitation of NCAM(+) progenitor proliferation via the modulation of C/EBPδ. Thus, chaotic migration and proliferation of the Bowman's capsule progenitor cells pave the way to crescent formation and subsequent sclerosis. ACEi, by moderating progenitor cell activation, restores glomerular architecture and prevents renal disease progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / pharmacology*
  • Animals
  • Cell Proliferation
  • Creatinine / blood
  • Humans
  • Kidney / enzymology*
  • Kidney / pathology
  • Kidney Failure, Chronic / metabolism
  • Kidney Glomerulus / enzymology*
  • Kidney Glomerulus / pathology
  • Male
  • Microscopy, Immunoelectron / methods
  • Mitosis
  • Podocytes / cytology
  • Rats
  • Rats, Wistar
  • Stem Cells / cytology
  • Time Factors

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Creatinine