title: Conditional knockout of proximal tubule mitofusin 2 accelerates recovery and improves survival after renal ischemia.
abstract: Proximal tubule (PT) cells are critical targets of acute ischemic injury. Elimination of the mitochondrial fusion protein mitofusin 2 (Mfn2) sensitizes PT cells to apoptosis in vitro. However, the role of PT Mfn2 in ischemic AKI in vivo is unknown. To test its role, we evaluated the effects of conditional KO of PT Mfn2 (cKO-PT-Mfn2) on animal survival after transient bilateral renal ischemia associated with severe AKI. Forty-eight hours after ischemia, 28% of control mice survived compared with 86% of cKO-PT-Mfn2 animals (P<0.001 versus control). Although no significant differences in histologic injury score, apoptosis, or necrosis were detected between genotypes, cKO-PT-Mfn2 kidneys exhibited a 3.5-fold increase in cell proliferation restricted to the intrarenal region with Mfn2 deletion. To identify the signals responsible for increased proliferation, primary PT cells with Mfn2 deficiency were subjected to stress by ATP depletion in vitro. Compared with normal Mfn2 expression, Mfn2 deficiency significantly increased PT cell proliferation and persistently activated extracellular signal-regulated kinase 1/2 (ERK1/2) during recovery from stress. Furthermore, stress and Mfn2 deficiency decreased the interaction between Mfn2 and Ras detected by immunoprecipitation, and purified Mfn2 dose-dependently decreased Ras activity in a cell-free assay. Ischemia in vivo also reduced the Mfn2-RAS interaction and increased both RAS and p-ERK1/2 activity in the renal cortical homogenates of cKO-PT-Mfn2 mice. Our results suggest that, in contrast to its proapoptotic effects in vitro, selective PT Mfn2 deficiency accelerates recovery of renal function and enhances animal survival after ischemic AKI in vivo, partly by increasing Ras-ERK-mediated cell proliferation.
authors.affiliation: Renal Section and.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Gall
authors.affiliation: Renal Section and.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Renal Section and.
authors.forename: Ramon G
authors.initials: RG
authors.lastname: Bonegio
authors.affiliation: Renal Section and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Havasi
authors.affiliation: The Obesity Center, Boston Medical Center, Boston, Massachusetts.
authors.forename: Marc
authors.initials: M
authors.lastname: Liesa
authors.affiliation: Renal Section and.
authors.forename: Pradheep
authors.initials: P
authors.lastname: Vemula
authors.affiliation: Renal Section and sborkan@bu.edu.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Borkan
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism* / Q000401:mortality; D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D007511:Ischemia / Q000150:complications / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008297:Male; D018345:Mice, Knockout; D020127:Recovery of Function; D012038:Regeneration
chemical_list: D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse
keywords: acute renal failure; apoptosis; cell signaling; mitochondria