Dietary or pharmacological inhibition of insulin-like growth factor-1 protects from renal ischemia-reperfusion injury in mice
Arnaud Lyon,
Thomas Agius,
Michael R. Macarthur,
Kevin Kiesworo,
Louis Stavart,
Florent Allagnat,
Sarah J. Mitchell,
Leonardo V. Riella,
Korkut Uygun,
Heidi Yeh,
Sebastien Déglise,
Déla Golshayan,
Alban Longchamp
Affiliations
Arnaud Lyon
Department of Vascular Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland; Transplantation Center and Transplantation Immunopathology Laboratory, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland; Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Thomas Agius
Department of Vascular Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland; Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Michael R. Macarthur
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA
Kevin Kiesworo
Department of Vascular Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
Louis Stavart
Department of Vascular Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland; Transplantation Center and Transplantation Immunopathology Laboratory, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
Florent Allagnat
Department of Vascular Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
Sarah J. Mitchell
Ludwig Princeton Branch, Princeton University, Princeton, NJ, USA
Leonardo V. Riella
Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Korkut Uygun
Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Heidi Yeh
Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Sebastien Déglise
Department of Vascular Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
Déla Golshayan
Transplantation Center and Transplantation Immunopathology Laboratory, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland
Alban Longchamp
Department of Vascular Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland; Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Corresponding author
Summary: One-week protein restriction (PR) limits ischemia-reperfusion (IR) damages and improves metabolic fitness. Similarly, longer-term calory restriction results in increased lifespan, partly via reduced insulin-like growth factor (IGF)-1. However, the influence of short-term PR on IGF-1 and its impact on IR are unknown. PR was achieved in mice via one-week carbohydrate loading and/or through a low-protein diet. PR decreased IGF-1 circulating levels as well as renal and hepatic expression. Upon renal IR, serum IGF-1 positively correlated with renal dysfunction and tissular damages, independently of sex and age. Exogenous IGF-1 administration abrogated PR benefits during IR, while IGF-1 receptor inhibition with linsitinib was protective. IGF-1 was associated with a reduction in forkhead box O (FoxO), and AMP-activated protein kinase (AMPK) signaling pathways previously demonstrated to improve IR resilience in various organs. These data support dietary or pharmacological reduction of IGF-1 signaling to mitigate IR injury prior to solid organ transplantation and beyond.
