C-Type Natriuretic Peptide Inhibits Proliferation and Monocyte Chemoattractant Protein-1 Secretion in Cultured Human Mesangial Cells

Abstract

Background: Mesangial cell proliferation and matrix accumulation are hallmarks of various progressive glomerular diseases. We examined whether C-type natriuretic peptide (CNP) that is known to regulate the proliferation of vascular smooth muscle cells could modulate these pathological processes using human glomerular mesangial cells (GMCs) in culture. Methods: Proliferation of GMCs cultured with different concentrations of CNP-22 for 48 h was determined by a colorimetric assay using a tetrazorium salt. Monocyte chemoattractant protein-1 (MCP-1) and type IV collagen secretion into the culture media by GMCs in the presence or absence of CNP-22 were evaluated by ELISA. Expression of mRNA for natriuretic peptide receptor B (NPR-B), a specific receptor for CNP, was examined by reverse transcription polymerase chain reaction (RT-PCR). Results: CNP-22 (1–10 µM) inhibited serum-induced GMC growth in a dose-dependent manner. The amount of MCP-1 in the culture supernatant was increased approximately 2.4-fold by 5 µg/ml of lipopolysaccharide. This increase was inhibited by CNP-22 at 0.1–1 µM in a dose-dependent fashion. CNP-22 (10 µM) inhibited GMC type IV collagen secretion stimulated by 20 ng/ml of platelet-derived growth factor. Expression of NPR-B mRNA was confirmed in GMCs by RT-PCR. Conclusions: CNP suppresses GMC proliferation and MCP-1 and type IV collagen secretion by GMCs. It may have a therapeutic potential against human proliferative glomerular diseases, especially those with the involvement of monocytes.

Urinary C-type natriuretic peptide excretion: a potential novel biomarker for renal fibrosis during aging

“…Additionally, fibrosis was also further increased in the cortex and medulla at 20 mo, and, despite decreased plasma CNP and GFR, urinary CNP excretion remained elevated in association with these renal structural alterations. Interestingly, normal glomeruli predominantly synthesize type IV collagen (1), which is a major structural component of basement membranes (2), and its production has been shown to be suppressed by CNP (4,24). Therefore, we postulate that the maintenance of this elevation in urinary CNP excretion at 20 mo may in part serve as a compensatory protective mechanism to suppress the production of various types of renal collagen, which is consistent with other studies involving renal injury (4,24).…”

“…Furthermore, in vitro studies have demonstrated that CNP possesses robust antifibrotic and antiproliferative properties in young rat and adult human cardiac fibroblasts (16,29). Moreover, others have reported that CNP suppresses human glomerular mesangial cell proliferation and type IV collagen secretion in vitro (24) and potently inhibits glomerular mesangial cell proliferation and matrix accumulation of type IV collagen after renal injury in vivo (4), which is highly relevant to the current study.…”

Release of C-type natriuretic peptide accounts for the biological activity of endothelium-derived hyperpolarizing factor

“…CNP possesses a number of cardiovascular actions that combine to exert a potent antiatherogenic influence. This study has defined an important role for endothelial-derived CNP in the regulation of vascular smooth muscle tone and local blood flow; CNP is also a potent inhibitor of vascular smooth muscle mitogenesis (16,40), and NPR activation has been shown to regulate the reactivity of leukocytes (41,42). Moreover, CNP mRNA is increased in response to shear stress (43,44), and plasma levels of CNP are elevated in inflammatory cardiovascular pathologies (45).…”

C-type natriuretic peptide attenuates bleomycin-induced pulmonary fibrosis in mice

“…Immunohistochemical examination also demonstrated that CNP infusion significantly inhibited infiltration of macrophages into the alveolar and interstitial regions. A recent study has shown that CNP suppresses the expression of monocyte chemoattractant protein-1, which induces migration and activation of macrophages (16). Considering that IL-1␤ is mainly produced by activated alveolar macrophages, it is interesting to speculate that CNP inhibits IL-1␤ production via inactivation of macrophages.…”