Inhibiting angiotensin-converting enzyme promotes renal repair by limiting progenitor cell proliferation and restoring the glomerular architecture

Ariela Benigni, Marina Morigi, Paola Rizzo, Elena Gagliardini, Cinzia Rota, Mauro Abbate, Serena Ghezzi, Andrea Remuzzi, Giuseppe Remuzzi

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)628-638
Number of pages11
JournalAmerican Journal of Pathology
Volume179
Issue number2
DOIs
Publication statusPublished - Aug 2011

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Neural Cell Adhesion Molecules
Peptidyl-Dipeptidase A
Podocytes
Stem Cells
Angiotensin-Converting Enzyme Inhibitors
Cell Proliferation
Kidney
Bowman Capsule
Epithelial Cells
Wistar Rats
Sclerosis
Mesoderm
Angiotensin II
Population
Disease Progression
Cell Cycle
Down-Regulation
Wounds and Injuries

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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Inhibiting angiotensin-converting enzyme promotes renal repair by limiting progenitor cell proliferation and restoring the glomerular architecture. / Benigni, Ariela; Morigi, Marina; Rizzo, Paola; Gagliardini, Elena; Rota, Cinzia; Abbate, Mauro; Ghezzi, Serena; Remuzzi, Andrea; Remuzzi, Giuseppe.

In: American Journal of Pathology, Vol. 179, No. 2, 08.2011, p. 628-638.

Research output: Contribution to journalArticle

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