Local C-type natriuretic peptide (CNP) production and CNP receptor expression have been demonstrated in glomeruli. However, the glomerular (patho-)physiological functions of CNP are largely unknown. We therefore investigated the effects of CNP on mesangial cell proliferation and matrix accumulation in the rat mesangioproliferative anti-Thy 1.1 model. Over seven days rats received a continuous infusion (1 microgram/kg/min) of either CNP (N = 6), an irrelevant control peptide (N = 3) or buffer alone (N = 6). Kidney biopsies were performed on days 2, 4 and 8. Few significant differences between the groups were noted on days 2 and 4. Compared to buffer treated rats on day 8, those receiving CNP showed a 35% reduction of glomerular mitoses, a 62% reduction of glomerular uptake of the thymidine analogue BrdU and a significant reduction in glomerular expression of PDGF B-chain. Double immunoperoxidase staining also revealed blunting of proliferating, activated mesangial cells (515 reduction of alpha-smooth muscle actin-/BrdU-positive cells) and macrophage influx. Moreover, there was a marked reduction of mesangial collagen IV and fibronectin accumulation at the protein and mRNA level. Rats receiving the control peptide were indistinguishable from buffer treated rats. Systemic blood pressure was reduced by 10 to 20% in both CNP and control peptide treated rats on day 8, excluding that the findings were due to hemodynamic effects of CNP. Our findings demonstrate that CNP is involved in the regulation of mesangial cell proliferation and matrix production in vivo. The data suggest the existence of a glomerular natriuretic peptide system that may regulate tissue homeostasis and contribute to resolution of mesangioproliferative diseases.