Natriuretic peptide/natriuretic peptide receptor-A (NPR-A) system has inhibitory effects in renal fibrosis in mice.

Abstract

OBJECT:

This study was designed to examine whether natriuretic peptide/natriuretic peptide receptor-A (NPR-A) system attenuates renal fibrosis in a unilateral ureteral obstruction (UUO) model and also examined the mechanism involved.

METHODS:

Three groups were studied: untreated UUO in wild-type mice; untreated UUO in NPR-A KO mice; and ANP treated (0.05 microg/kg/min) UUO in wild-type mice. We measured histological and immunohistochemical findings (alpha-SMA and F4/80), tissue cGMP levels, various mRNA expression levels by real-time PCR analysis, and transcription factor levels (AP-1 and NF-kappaB) in renal tissue.

RESULTS:

Compared with wild-type UUO mice, NPRA-KO UUO mice had abnormal morphological findings (fibrous area: +26%, alpha-SMA expression: +30%) with lower tissue cGMP levels and increases in the mRNA expression levels of TGF-beta, collagen I, collagen III, PAI-1, renin and angiotensinogen, whereas there were no differences in F4/80 positive cells or the mRNA expression levels of ICAM-1, osteopontin, or MCP-1 between the two groups. In contrast, ANP pre-treatment significantly improved morphological changes with increase of tissue cGMP levels and reduction in the mRNA expression level of TGF-beta, collagen I, collagen III, PAI-1, ICAM-1, osteopontin, MCP-1, renin, and angiotensinogen. NPRA-KO UUO mice had higher AP-1 levels than wild-type UUO mice and ANP pre-treatment reduced AP-1 and NF-kappaB activity.

CONCLUSION:

The endogenous natriuretic peptide/NPR-A system may inhibit renal fibrosis partly via inhibition of the angiotensin/AP-1/TGF-beta/collagen pathway and exogenous ANP pre-treatment may inhibit it partly via both the angiotensin/AP-1/TGF-beta/collagen and NF-kappaB/inflammatory pathways.

• Authors: Toshio Nishikimi, Chikako Inaba-Iemura, Kimihiko Ishimura, Kazuyoshi Tadokoro, Shogo Koshikawa, Keiko Ishikawa, Kazumi Akimoto, Yoshiyuki Hattori, Kikuo Kasai, Naoto Minamino, Nobuyo Maeda, Hiroaki Matsuoka
• Journal: Regulatory peptides (Regul Pept) Vol. 154 Issue 1-3 Pg. 44-53 (Apr 10 2009) ISSN: 0167-0115 [Print] Netherlands
• PMID: 19223006 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fluorescent Dyes
• Indoles
• Natriuretic Peptides
• RNA, Messenger
• DAPI
• Receptors, Atrial Natriuretic Factor
• atrial natriuretic factor receptor A
• Cyclic GMP

Topics

• Animals
• Crosses, Genetic
• Cyclic GMP (analysis)
• Fibrosis (pathology)
• Fluorescent Dyes (metabolism)
• Immunohistochemistry
• Indoles (metabolism)
• Kidney Diseases (etiology, pathology, physiopathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Natriuretic Peptides (genetics, metabolism)
• RNA, Messenger (metabolism)
• Receptors, Atrial Natriuretic Factor (genetics, metabolism)
• Renin-Angiotensin System
• Ureteral Obstruction (complications)