title: Ouabain Contributes to Kidney Damage in a Rat Model of Renal Ischemia-Reperfusion Injury.
abstract: Warm renal ischemia performed during partial nephrectomy has been found to be associated with kidney disease. Since endogenous ouabain (EO) is a neuro-endocrine hormone involved in renal damage, we evaluated the role of EO in renal ischemia-reperfusion injury (IRI). We measured plasma and renal EO variations and markers of glomerular and tubular damage (nephrin, KIM-1, Kidney-Injury-Molecule-1, α1 Na-K ATPase) and the protective effect of the ouabain inhibitor, rostafuroxin. We studied five groups of rats: (1) normal; (2) infused for eight weeks with ouabain (30 µg/kg/day, OHR) or (3) saline; (4) ouabain; or (5) saline-infused rats orally treated with 100 µg/kg/day rostafuroxin for four weeks. In group 1, 2-3 h after IRI, EO increased in ischemic kidneys while decreased in plasma. Nephrin progressively decreased and KIM-1 mRNA increased starting from 24 h. Ouabain infusion (group 2) increased blood pressure (from 111.7 to 153.4 mmHg) and ouabain levels in plasma and kidneys. In OHR ischemic kidneys at 120 h from IRI, nephrin, and KIM-1 changes were greater than those detected in the controls infused with saline (group 3). All these changes were blunted by rostafuroxin treatment (groups 4 and 5). These findings support the role of EO in IRI and suggest that rostafuroxin pre-treatment of patients before partial nephrectomy with warm ischemia may reduce IRI, particularly in those with high EO.
authors.affiliation: Division of Experimental Oncology/Unit of Urology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. villa.luca@hsr.it.
authors.forename: Luca
authors.initials: L
authors.lastname: Villa
authors.affiliation: Division of Experimental Oncology/Unit of Urology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. buono@usc.edu.
authors.forename: Roberta
authors.initials: R
authors.lastname: Buono
authors.affiliation: Prassis Sigma-Tau Research Institute, Settimo Milanese, 20019 Milan, Italy. mara.ferrandi@gmail.com.
authors.forename: Mara
authors.initials: M
authors.lastname: Ferrandi
authors.affiliation: Prassis Sigma-Tau Research Institute, Settimo Milanese, 20019 Milan, Italy. isabella.molinari8@gmail.com.
authors.forename: Isabella
authors.initials: I
authors.lastname: Molinari
authors.affiliation: Division of Experimental Oncology/Unit of Urology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. benigni.fabio@hsr.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Benigni
authors.affiliation: Division of Experimental Oncology/Unit of Urology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. bettiga.arianna@hsr.it.
authors.forename: Arianna
authors.initials: A
authors.lastname: Bettiga
authors.affiliation: Division of Experimental Oncology/Unit of Urology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. colciago.giorgia@hsr.it.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Colciago
authors.affiliation: Renal Research Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico & Fondazione D'Amico, 20122 Milan, Italy. aquamarine0321@libero.it.
authors.forename: Masami
authors.initials: M
authors.lastname: Ikehata
authors.affiliation: Division of Genetics and Cell Biology, Genomics of Renal Diseases and Hypertension Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. messaggio.elisabetta@hsr.it.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Messaggio
authors.affiliation: Renal Research Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico & Fondazione D'Amico, 20122 Milan, Italy. mariapia.rastaldi@policlinico.mi.it.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rastaldi
authors.affiliation: Division of Experimental Oncology/Unit of Urology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. montorsi.francesco@hsr.it.|Chair of Urology, Università Vita Salute San Raffaele, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. montorsi.francesco@hsr.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Montorsi
authors.affiliation: Division of Experimental Oncology/Unit of Urology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. salonia.andrea@hsr.it.|Chair of Urology, Università Vita Salute San Raffaele, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. salonia.andrea@hsr.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Salonia
authors.affiliation: Division of Genetics and Cell Biology, Genomics of Renal Diseases and Hypertension Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. manunta.paolo@hsr.it.|Chair of Nephrology, Università Vita Salute San Raffaele, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. manunta.paolo@hsr.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Manunta
mesh_terms: D000732:Androstanols / Q000627:therapeutic use*; D000818:Animals; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D009392:Nephrectomy; D010042:Ouabain / Q000097:blood / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology
chemical_list: D000732:Androstanols; D010042:Ouabain; C106263:rostafuroxin
keywords: Na-K ATPase; nephrin; ouabain; renal damage; rostafuroxin; warm ischemia