Although many experimental therapeutic roles for C-type natriuretic peptide (CNP) have been documented in the field of cardiovascular and pulmonary-vascular disease, the therapeutic uses of CNP to nephropathies are not as well documented. In this study, we established a rat model of unilateral ureteral obstruction (UUO) to observe the beneficial effects of CNP on tubulointerstitial fibrosis (TIF). In UUO rats, CNP administration induced a significant increase in plasma CNP levels, and caused a significant decrease in blood urea nitrogen and creatinine levels. In addition, CNP infusion also alleviated the pathological lesions and collagen IV accumulation in the obstructed kidneys through downregulation of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 expression. In conclusion, exogenous CNP infusion can ameliorate UUO-induced TIF in rats. However, the use of CNP as a therapeutic agent requires further evaluation before being considered for human TIF. C-type natriuretic peptide (CNP) shares sequence homology with the endocrine cardiac peptides, atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP). They comprise a ring structure of 17 amino acids linked by a cysteine disulfide bridge that is essential for receptor binding and bioactivity. However, unlike the other members of natriuretic peptide family, CNP selectively binds to the transmembrane natriuretic peptide receptor (NPR)-B and subsequently leads to a large increase in intracellular cyclic guanosine monophosphate (cGMP). 1 CNP was first isolated from pigs, 2 but CNP immunoreactivity has been found in a wide variety of tissues, such as vascular endothelium, heart, bone, adrenal, and reproductive glands. 3-7 CNP is also believed to be produced locally in the kidney. Several studies have documented a significant arteriovenous gradient for CNP across both the human and animal kidneys, indirectly indicating renal extraction of this peptide. 8,9 Our previous immunohistochemical study showed that CNP was predominantly present in tubular epithelial cells, including proximal, distal, and medullary collecting duct cells; moreover, CNP immunoreactivity was also observed in glomeruli. 10 In pathological circumstances, either urinary levels or renal tissue expression of CNP may act as a sensitive marker of nephropathies. In a recent study, we established a unilateral ureteral obstruction (UUO) model in Wistar rats, and observed that expression of CNP mRNA and protein in the obstructed kidneys tended to be higher immediately after ligation, and then declined progressively. 11 An expansion of extracellular fluid volume may account for the early elevation in CNP expression. 12 However, epithelial-mesenchymal transition, combined with the paradoxical expressions of NPR-C and neutral endopeptidase (NEP), may account for the decline of CNP in the advanced stages of nephropathies. 10,11 In contrast to regulation of blood pressure and body fluid homeostasis, the known physiological actions of CNP include local vasorelaxation, inhibition of organ re...