title: WNT Agonist Decreases Tissue Damage and Improves Renal Function After Ischemia-Reperfusion.
abstract: Renal ischemia-reperfusion (IR) injury (IRI) after shock states or transplantation causes tissue damage and delayed graft function, respectively. The Wnt/β-catenin signaling pathway plays a critical role in nephrogenesis. We therefore hypothesized that pharmacological activation of the Wnt/β-catenin signaling by the Wnt agonist, a synthetic pyrimidine, could protect kidneys from IRI. Adult male rats were subjected to bilateral clamping of the renal pedicles with microvascular clips for 60 min, followed by reperfusion. The Wnt agonist (5 mg/kg body weight) or vehicle (20% dimethyl sulfoxide in saline) was administered intravenously 1 h before ischemia. Blood and renal tissues were collected 24 h after IR for evaluation. Renal IR caused a significant reduction of β-catenin and its downstream target gene cyclin D1 by 65% and 39%, respectively, compared with the sham, whereas the Wnt agonist restored them to sham levels. The number and intensity of cells staining with the proliferation marker Ki67 in ischematized kidneys were enhanced by the Wnt agonist. The integrity of the renal histological architecture in the Wnt agonist group was better preserved than the vehicle group. The Wnt agonist significantly lowered serum levels of creatinine, aspartate aminotransferase, and lactate dehydrogenase and inhibited the production of interleukin 6 and interleukin 1β and myeloperoxidase activities. Lastly, the Wnt agonist reduced inducible nitric oxide synthase, nitrotyrosine proteins, and 4-hydroxynonenal in the kidneys by 60%, 47%, and 21%, respectively, compared with the vehicle. These results indicate that the Wnt agonist improves renal regeneration and function while attenuating inflammation and oxidative stress in the kidneys after IR. Thus, pharmacologic stimulation of the Wnt/β-catenin signaling provides a beneficial effect on the prevention of renal IRI.
authors.affiliation: *Department of Surgery, Hofstra North Shore-LIJ School of Medicine; and †Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, New York.
authors.forename: Michael
authors.initials: M
authors.lastname: Kuncewitch
authors.forename: Weng-Lang
authors.initials: WL
authors.lastname: Yang
authors.forename: Lana
authors.initials: L
authors.lastname: Corbo
authors.forename: Adam
authors.initials: A
authors.lastname: Khader
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Nicastro
authors.forename: Gene F
authors.initials: GF
authors.lastname: Coppa
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
mesh_terms: D058186:Acute Kidney Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration / Q000187:drug effects; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D012769:Shock / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D051153:Wnt Proteins / Q000819:agonists*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495268:Ctnnb1 protein, rat; D053583:Interleukin-1beta; D015850:Interleukin-6; D020011:Protective Agents; D011743:Pyrimidines; D012333:RNA, Messenger; D051153:Wnt Proteins; D051176:beta Catenin; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat