Proximal tubule overexpression of a locally acting IGF isoform, Igf-1Ea, increases inflammation after ischemic injury

Fiona K. Rae, Norseha Suhaimi, Joan Li, Tommaso Nastasi, Esfir Slonimsky, Nadia Rosenthal, Melissa H. Little

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6 Citations (Scopus)

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. Design: 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 24. h and 5. days 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.

Original languageEnglish
Pages (from-to)6-16
Number of pages11
JournalGrowth Hormone and IGF Research
Volume22
Issue number1
DOIs
Publication statusPublished - Feb 2012
Externally publishedYes

Keywords

  • Acute kidney injury
  • Igf-1Ea
  • IGF-1Ea
  • Ischemia reperfusion injury
  • Kidney
  • Macrophages
  • Neutrophils
  • Proximal tubules

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