Proteinuria and increased renal reabsorption of NaCl characterize the nephrotic syndrome. Here, we show that protein-rich urine from nephrotic rats and from patients with nephrotic syndrome activate the epithelial sodium channel (ENaC) in cultured M-1 mouse collecting duct cells and in Xenopus laevis oocytes heterologously expressing ENaC. The activation depended on urinary serine protease activity. We identified plasmin as a urinary serine protease by matrix-assisted laser desorption/ ionization time of-flight mass spectrometry. Purified plasmin activated ENaC currents, and inhibitors of plasmin abolished urinary protease activity and the ability to activate ENaC. In nephrotic syndrome, tubular urokinase-type plasminogen activator likely converts filtered plasminogen to plasmin. Consistent with this, the combined application of urokinase-type plasminogen activator and plasminogen stimulated amiloride-sensitive transepithelial sodium transport in M-1 cells and increased amiloride-sensitive whole-cell currents in Xenopus laevis oocytes heterologously expressing ENaC. Activation of ENaC by plasmin involved cleavage and release of an inhibitory peptide from the ENaC ␥ subunit ectodomain. These data suggest that a defective glomerular filtration barrier allows passage of proteolytic enzymes that have the ability to activate ENaC.

V ascular smooth muscle cell (VSMC) activation and phenotypic switching are critical for remodeling processes in vascular proliferative disorders, including intimal hyperplasia. Both the migratory and proliferative activities of VSMCs, as well as the interplay between the extracellular matrix (ECM) and integrin receptors essentially, contribute to neointimal hyperplasia and restrictive remodeling processes in the vessels.1 Among integrins, the particular role of integrin α V β 3 in the induction of VSMC responses has been shown both in vivo and in vitro.

Little is known about prostaglandin F2␣ in cardiovascular homeostasis. Prostaglandin F2␣ dose-dependently elevates blood pressure in WT mice via activation of the F prostanoid (FP) receptor. The FP is expressed in preglomerular arterioles, renal collecting ducts, and the hypothalamus. Deletion of the FP reduces blood pressure, coincident with a reduction in plasma renin concentration, angiotensin, and aldosterone, despite a compensatory upregulation of AT1 receptors and an augmented hypertensive response to infused angiotensin II. Plasma and urinary osmolality are decreased in FP KOs that exhibit mild polyuria and polydipsia. Atherogenesis is retarded by deletion of the FP, despite the absence of detectable receptor expression in aorta or in atherosclerotic lesions in Ldlr KOs. Although vascular TNF ␣, inducible nitric oxide enzyme and TGF ␤ are reduced and lesional macrophages are depleted in the FP/Ldlr double KOs, this result reflects the reduction in lesion burden, as the FP is not expressed on macrophages and its deletion does not alter macrophage cytokine generation. Blockade of the FP offers an approach to the treatment of hypertension and its attendant systemic vascular disease.hypertension ͉ renin ͉ PGF2␣ receptor ͉ juxtaglomerular granular cell ͉ water metabolism C ontrol of hypertension has contributed to a decline of cardiovascular morbidity and mortality. Therapies have targeted neurohumoral mechanisms, such as the sympathoadrenal and renin-angiotensin-aldosterone systems (RAAS) as well as downstream effectors and volume control. Elevated blood pressure (BP) cosegregates with clinical cardiovascular events and randomized trials have revealed the efficacy of antihypertensive drugs to reduce the risk of stroke and myocardial infarction (1). Angiotensin II activates and up-regulates NADPH oxidase (2), augmenting oxidant stress and vascular dysfunction. Both pharmacological and genetic disruption of elements of the RAAS decreases BP and retards atherogenesis (3-5).Prostaglandins (PGs) also contribute to BP homeostasis. Elevation of BP complicates the use of nonsteroidal antiinflammatory drugs and relates to the degree of inhibition of cyclooxygenase (COX)-2 and the selectivity with which it is attained (6). Genetic and pharmacological manipulations suggest that products of COX-1 may elevate BP (7), although the impact of manipulating the PG cascade is conditioned by genetic background in mice (8). Prostacyclin (PGI 2 ) is a potent renin secretagogue (9), and its biosynthesis is increased markedly in pregnancy, a high-renin but hypotensive condition; its biosynthesis is depressed in pregnancy-induced hypertension (10). Deletion of its I prostanoid receptor (the IP) reduces BP in renoprival models of high-renin hypertension in rodents (11). PGI 2 is also a vasodilator and promotes sodium excretion; indeed, salt-sensitive hypertension characterizes IP-KO mice in some genetic backgrounds (12). PGF 2␣ is derived mainly from COX-1 in the female reproductive system, where it is required for normal parturition ...

We investigated the localization of cAMP-coupled prostaglandin E(2) EP2 and EP4 receptor expression in the rat kidney. EP2 mRNA was restricted to the outer and inner medulla in rat kidney, as determined by RNase protection assay. RT-PCR analysis of microdissected resistance vessels and nephron segments showed EP2 expression in descending thin limb of Henle's loop (DTL) and in vasa recta of the outer medulla. The EP4 receptor was expressed in distal convoluted tubule (DCT) and cortical collecting duct (CCD) in preglomerular vessels, and in outer medullary vasa recta. Butaprost, an EP2 receptor-selective agonist, dose dependently raised cAMP levels in microdissected DTL and outer medullary vasa recta specimens but had no effect in EP2-negative outer medullary collecting duct segments. Dietary salt intake did not alter EP2 expression in the kidney medulla. These results suggest that PGE(2) may act in the resistance vessels and in the DTL and DCT-CCD segments as a paracrine, cAMP-dependent regulator of vascular resistance and tubular transport, respectively.