No abstract

C-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 exerts an inhibitory effect on mesangial matrix generation, a limited number of reports exist about the anti-extracellular matrix (ECM) accumulation effect of CNP and its underlying mechanisms in mesangial cells (MCs) in vitro. In this study, human MCs were incubated in serum-containing medium in the absence or presence of CNP (0, 10 and 100 pM) for 24, 48 and 72 h, respectively. CNP administration significantly suppresses MCs proliferation and collagen (Col)-IV expression in a time- and dose-dependent manner. In addition, the study presented herein was designed as a first demonstration of the regulative effects of CNP on the metabolisms of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in MCs in vitro, and found that: (1) CNP administration significantly decreased the secretion and expression of MMP-2 and MMP-9 in the cultured MCs; (2) the secretion and expression of TIMP-1 progressively elevated after treatment with CNP for 24 and 48 h, whereas declined at later time point; (3) CNP expression was negatively correlated with MMP-2 and MMP-9 expression; (4) the balance of MMPs/TIMPs was shifted toward the reduction in MMP-2 and MMP-9 activity and/or the increment in TIMP-1 expression, which could not account for the down-regulation of Col-IV expression in CNP-treated MCs. In conclusion, CNP suppresses mesangial proliferation and ECM expression via a MMPs/TIMPs-independent pathway in vitro.

No abstract

The initiation and progression of renal interstitial fibrosis (RIF) is a complicated process in which many factors may play an activate role. Among these factors, C-type natriuretic peptide (CNP) is an endothelium-derived hormone and acts in a local, paracrine fashion to regulate vascular smooth muscle tone and proliferation. In this study, we established a rat model of unilateral ureteral obstruction (UUO). CNP expression tends to be higher immediately after ligation and declined at later time points, occurring predominantly in tubular epithelial cells. A high-level CNP may contribute to the elevated expression of natriuretic peptide receptor (NPR)-B in the early phase of UUO. However, the sustained expression of NPR-C and neutral endopeptidase (NEP) observed throughout the study period (that is up to 3 months) helps to, at least partly, explain the subsequent decline of CNP. Thus, NEP and NPRs participate in the regulation of CNP expression in RIF.

Renal osteodystrophy (ROD) occurs as early as chronic kidney disease (CKD) stage 2 and seems ubiquitous in almost all pediatric patients with CKD stage 5. Fibroblast growth factor (FGF)-23, a bone-derived endocrine regulator of phosphate homeostasis, is overexpressed in CKD and disturbs osteoblast differentiation and matrix mineralization. In contrast, C-type natriuretic peptide (CNP) acts as a potent positive regulator of bone growth. In the present study, we infused CNP into uremic rats and observed whether CNP could attenuate ROD through the inhibition of FGF-23 cascades. In uremic rats, CNP administration significantly alleviated renal dysfunction, calcium phosphate metabolic disorders, hypovitaminosis D, secondary hyperparathyroidism, the decrease in bone turnover markers and retarded bone pathological progression. More importantly, within FGF-23/mitogen-activated protein kinase (MAPK) signaling, the fibroblast growth factor receptor-1, Klotho and alternative (STAT-1/phospho-STAT-1) elements were upregulated by CNP, whereas FGF-23, RAF-1/phospho-RAF-1, and downstream (ERK/phospho-ERK and P38/phospho-P38) elements were paradoxically underexpressed in bone tissue. Therefore, CNP exerts a therapeutic effect on ROD through inhibition of FGF-23/MAPK signaling at the RAF-1 level.