title: Urinary Proteolytic Activation of Renal Epithelial Na+ Channels in Chronic Heart Failure.
abstract: One of the key mechanisms involved in renal Na(+) retention in chronic heart failure (CHF) is activation of epithelial Na(+) channels (ENaC) in collecting tubules. Proteolytic cleavage has an important role in activating ENaC. We hypothesized that enhanced levels of proteases in renal tubular fluid activate ENaC, resulting in renal Na(+) retention in rats with CHF. CHF was produced by left coronary artery ligation in rats. By immunoblotting, we found that several urinary serine proteases were significantly increased in CHF rats compared with sham rats (fold increases: furin 6.7, prostasin 23.6, plasminogen 2.06, and plasmin 3.57 versus sham). Similar increases were observed in urinary samples from patients with CHF. Whole-cell patch clamp was conducted in cultured renal collecting duct M-1 cells to record Na(+) currents. Protease-rich urine (from rats and patients with CHF) significantly increased the Na(+) inward current in M-1 cells. Two weeks of protease inhibitor treatment significantly abrogated the enhanced diuretic and natriuretic responses to ENaC inhibitor benzamil in rats with CHF. Increased podocyte lesions were observed in the kidneys of rats with CHF by transmission electron microscopy. Consistent with these results, podocyte damage markers desmin and podocin expressions were also increased in rats with CHF (increased ≈2-folds). These findings suggest that podocyte damage may lead to increased proteases in the tubular fluid, which in turn contributes to the enhanced renal ENaC activity, providing a novel mechanistic insight for Na(+) retention commonly observed in CHF.
authors.affiliation: From the Department of Cellular and Integrative Physiology (H.Z., X.L., N.M.S., K.P.P.) and Department of Emergency Medicine (Y.L.), University of Nebraska Medical Center, Omaha; and Department of Internal Medicine II, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany (R.U.P.).
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.affiliation: From the Department of Cellular and Integrative Physiology (H.Z., X.L., N.M.S., K.P.P.) and Department of Emergency Medicine (Y.L.), University of Nebraska Medical Center, Omaha; and Department of Internal Medicine II, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany (R.U.P.).
authors.forename: Xuefei
authors.initials: X
authors.lastname: Liu
authors.affiliation: From the Department of Cellular and Integrative Physiology (H.Z., X.L., N.M.S., K.P.P.) and Department of Emergency Medicine (Y.L.), University of Nebraska Medical Center, Omaha; and Department of Internal Medicine II, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany (R.U.P.).
authors.forename: Neeru M
authors.initials: NM
authors.lastname: Sharma
authors.affiliation: From the Department of Cellular and Integrative Physiology (H.Z., X.L., N.M.S., K.P.P.) and Department of Emergency Medicine (Y.L.), University of Nebraska Medical Center, Omaha; and Department of Internal Medicine II, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany (R.U.P.).
authors.forename: Yulong
authors.initials: Y
authors.lastname: Li
authors.affiliation: From the Department of Cellular and Integrative Physiology (H.Z., X.L., N.M.S., K.P.P.) and Department of Emergency Medicine (Y.L.), University of Nebraska Medical Center, Omaha; and Department of Internal Medicine II, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany (R.U.P.).
authors.forename: Rainer U
authors.initials: RU
authors.lastname: Pliquett
authors.affiliation: From the Department of Cellular and Integrative Physiology (H.Z., X.L., N.M.S., K.P.P.) and Department of Emergency Medicine (Y.L.), University of Nebraska Medical Center, Omaha; and Department of Internal Medicine II, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany (R.U.P.). kpatel@unmc.edu.
authors.forename: Kaushik P
authors.initials: KP
authors.lastname: Patel
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D006333:Heart Failure / Q000473:pathology / Q000652:urine*; D006801:Humans; D007685:Kidney Tubules, Collecting / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018408:Patch-Clamp Techniques; D051381:Rats; D057057:Serine Proteases / Q000652:urine*
chemical_list: D053503:Epithelial Sodium Channels; D057057:Serine Proteases
keywords: Na+ and water retention; heart failure; podocyte; protease; renal function