C-type Natriuretic Peptide Suppresses Mesangial Proliferation And Matrix Expression Via A MMIPs/TIMPs-independent Pathway In Vitro

ObjectiveC-type natriuretic peptide(CNP)acts mainly in a local,paracrine fashion to regulate vascular tone and cell proliferation.Although several in vivo studies have demonstrated that CNP could exert an inhibitory effect on mesangial matrix generation,a limited number of reports existed about the anti-extracellular matrix(ECM)accumulation effect of CNP and its underlying mechanisms in mesangial cells(MCs)in vitro.The principal aim of the present study is to probe whether the downregulation of collagen(Col)-IV synthesis in CNP-treated MCs is mediated by matrix metalloproteinases and tissue inhibitors of metalloproteinases(MMPs/TIMPs)pathway.MethodsHuman MCs were incubated in serum-containing medium in the absence or presence of CNP(0 p M,10 p M,100 p M)for 24,48,and 72 hours,respectively.Results(1)CNP significantly suppressed the growth of MCs at doses of 10 and 100 p M(P<0.05).the high-dose group showed a 11% decrease and a 35% decrease in 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2Htetrazolium(MTS)activity compared with the corresponding low-dose group at 48 and 72 hours after culture,respectively(P<0.05).CNP administration could significantly suppress MCs proliferation and Col-IV expression in a time-and dose-dependent manner.(2)CNP administration significantly decreased the secretion and expression of matrix metalloproteinase-2(MMP-2)and matrix metalloproteinase-9(MMP-9)in the cultured MCs.(3)The secretion and expression of tissue inhibitor of metalloproteinase-1(TIMP-1)progressively elevated after treatment with CNP for 24 hours and 48 hours,whereas declined at later time point.(4)CNP expression was negatively correlated with MMP-2 and MMP-9 expression.(5)The balance of MMPs/TIMPs was shifted toward the decrease in MMP-2,MMP-9 activity and/or the elevation in TIMP-1 expression,which could not account for the down-regulation of Col-IV expression in CNP-treated MCs.ConclusionCNP suppresses mesangial proliferation and ECM expression via a MMPs/TIMPs-independent pathway in vitro.