C-type natriuretic peptide (CNP) possesses well-established cardiovascular properties. While present in the mammalian kidney, CNP production in the human kidney and its modulation in human renal disease remain less defined. We investigated the presence of CNP in normal human kidney and in patients with nephrotic syndrome (NS). We also addressed whether or not a low protein diet (LPD) alters plasma CNP and urinary CNP excretion in NS. In situ hybridization studies demonstrated CNP mRNA expression in tubular cells and glomeruli of normal human kidneys. CNP immunoreactivity was positive in proximal, distal and medullary collecting duct tubular cells in both controls and NS. Plasma CNP and urinary CNP to creatinine ratio were significantly higher in NS as compared to controls. Urinary CNP, but not plasma CNP, was significantly lowered in NS after LPD. Similarly, urinary protein to creatinine ratio and urinary albumin to creatinine ratio, but not urinary cGMP to creatinine ratio, decreased significantly with LPD. These data confirm and extend previous reports and demonstrate for the first time the presence of CNP in human kidney with NS. We also report increased plasma CNP concentration and urinary CNP excretion in NS and a significant reduction of CNP excretion by LPD. Our findings demonstrate that CNP metabolism is altered in NS and support the hypothesis that activation of renal CNP can be partially offset by LPD. These results underscore that the beneficial effect of LPD on protein excretion is paralleled by a substantial reduction in intrarenal CNP release.