Protein and Calorie Restriction Contribute Additively to Protection from Renal Ischemia Reperfusion Injury Partly via Leptin Reduction in Male Mice.

Abstract

BACKGROUND:

Short-term dietary restriction (DR) without malnutrition preconditions against surgical stress in rodents; however, the nutritional basis and underlying nutrient/energy-sensing pathways remain poorly understood.

OBJECTIVES:

We investigated the relative contribution of protein restriction (PR) vs. calorie restriction (CR) to protection from renal ischemia reperfusion injury (IRI) and changes in organ-autonomous nutrient/energy-sensing pathways and hormones underlying beneficial effects.

METHODS:

Mice were preconditioned on experimental diets lacking total calories (0-50% CR) or protein/essential amino acids (EAAs) vs. complete diets consumed ad libitum (AL) for 1 wk before IRI. Renal outcome was assessed by serum markers and histology and integrated over a 2-dimensional protein/energy landscape by geometric framework analysis. Changes in renal nutrient/energy-sensing signal transduction and systemic hormones leptin and adiponectin were also measured. The genetic requirement for amino acid sensing via general control non-derepressible 2 (GCN2) was tested with knockout vs. control mice. The involvement of the hormone leptin was tested by injection of recombinant protein vs. vehicle during the preconditioning period.

RESULTS:

CR-mediated protection was dose dependent up to 50% with maximal 2-fold effect sizes. PR benefits were abrogated by EAA re-addition and additive with CR, with maximal benefits at any given amount of CR occurring with a protein-free diet. GCN2 was not required for functional benefits of PR. Activation and repression of nutrient/energy-sensing kinases, AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1), respectively, on PR reflected a state of negative energy balance, paralleled by 13% weight loss and an 87% decrease in leptin, independent of calorie intake. Recombinant leptin administration partially abrogated benefits of dietary preconditioning against renal IRI.

CONCLUSIONS:

In male mice, PR and CR both contributed to the benefits of short-term DR against renal IRI independent of GCN2 but partially dependent on reduced circulating leptin and coincident with AMPK activation and mTORC1 repression.

• Authors: Lauren T Robertson, J Humberto Treviño-Villarreal, Pedro Mejia, Yohann Grondin, Eylul Harputlugil, Christopher Hine, Dorathy Vargas, Hanqiao Zheng, C Keith Ozaki, Bruce S Kristal, Stephen J Simpson, James R Mitchell
• Journal: The Journal of nutrition (J Nutr) Vol. 145 Issue 8 Pg. 1717-27 (Aug 2015) ISSN: 1541-6100 [Electronic] United States
• PMID: 26041674 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2015 American Society for Nutrition.

Chemical References

• Dietary Proteins
• Leptin
• Urea
• Eif2ak4 protein, mouse
• Protein Serine-Threonine Kinases

Topics

• Acute Kidney Injury (prevention & control)
• Animals
• Area Under Curve
• Caloric Restriction
• Dietary Proteins (administration & dosage)
• Leptin (genetics, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Reperfusion Injury (prevention & control)
• Urea (blood)