title: Proximal tubule overexpression of a locally acting IGF isoform, Igf-1Ea, increases inflammation after ischemic injury.
abstract: OBJECTIVE
  IGF-1 is an important regulator of postnatal growth in mammals. In mice, a non-circulating, locally acting isoform of IGF-1, IGF-1Ea, has been documented as a central regulator of muscle regeneration and has been shown to improve repair in the heart and skin. In this study, we examine whether local production of IGF1-Ea protein improves tubular repair after renal ischemia reperfusion injury.
  
  
  METHODS
  Transgenic mice in which the proximal-tubule specific promoter Sglt2 was driving the expression of an Igf-1Ea transgene. These animals were treated with an ischemic-reperfusion injury and the response at 24h and 5days compared with wildtype littermates.
  
  
  RESULTS
  Transgenic mice demonstrated rapid and enhanced renal injury in comparison to wild type mice. Five days after injury the wild type and low expressing Igf-1Ea transgenic mice showed significant tubular recovery, while high expressing Igf-1Ea transgenic mice displayed significant tubular damage. This marked injury was accompanied by a two-fold increase in the number of F4/80 positive macrophages and a three-fold increase in the number of Gr1-positive neutrophils in the kidney. At the molecular level, Igf-1Ea expression resulted in significant up-regulation of proinflammatory cytokines such as TNF-α and Ccl2. Expression of Nfatc1 was also delayed, suggesting reduced tubular proliferation after kidney injury.
  
  
  CONCLUSIONS
  These data indicate that, unlike the muscle, heart and skin, elevated levels of IGF-1Ea in the proximal tubules exacerbates ischemia reperfusion injury resulting in increased recruitment of macrophages and neutrophils and delays repair in a renal setting.
authors.affiliation: Institute for Molecular Bioscience, Queensland Bioscience Precinct, The University of Queensland, St. Lucia 4072, Australia.
authors.forename: Fiona K
authors.initials: FK
authors.lastname: Rae
authors.forename: Norseha
authors.initials: N
authors.lastname: Suhaimi
authors.forename: Joan
authors.initials: J
authors.lastname: Li
authors.forename: Tommaso
authors.initials: T
authors.lastname: Nastasi
authors.forename: Esfir
authors.initials: E
authors.lastname: Slonimsky
authors.forename: Nadia
authors.initials: N
authors.lastname: Rosenthal
authors.forename: Melissa H
authors.initials: MH
authors.lastname: Little
mesh_terms: D000818:Animals; D007249:Inflammation / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D007334:Insulin-Like Growth Factor I