Brief dietary protein dilution using carbohydrate rich drink protects from kidney ischemia and reperfusion injuries trough IGF-1

Abstract

Objective Lifelong low-protein, high-carbohydrate diets extend lifespan in rodent. Consistently in human, the administration of oral carbohydrate drinks the day before surgery might improve clinical outcome. However, the fundamental questions of what represents a macronutritionally balanced diet, and how this impact surgical stress remain unanswered. Methods Here, we induced dietary protein dilution by giving mice ad libitum access to 50% sucrose water, without any food restriction. Mice were randomized into four regimens: regular diet (17,6 % protein, Ctrl), and a low protein diet (5.6% protein, LP), with or without high sucrose water (50% sucrose) for 7 days. At the end of the preconditioning, calorimetric data, fasting blood glucose, IGF1, glucose tolerance, and finally resistance to renal failure following a bilateral renal ischemia-reperfusion was evaluated. Results We demonstrate that access to carbohydrate drinks promotes dietary protein restriction despite a total caloric intake that was twice higher. This short-term self-restriction in daily protein, independent of caloric intake, improved insulin sensitivity, reduced serum triglyceride, and enhanced mitochondrial respiration as well as energy expenditure. Importantly, a 7-day pre-conditioning protein dilution regimen promotes recovery following kidney ischemia and reperfusion (IRI), a model of surgical stress. This protection from kidney IRI inversely correlated with pre-operative protein intake, but not carbohydrate or fat. The benefit of a low protein, high-carbohydrate regimen was independent of the protein sensing pathway eIF2α/ATF4, NRF2 and hydrogen sulfide, but instead required Insulin-like growth factor 1 (IGF1) downregulation. Conclusion These results support further clinical studies of a low protein diet combined with carbohydrate drinks prior to surgery.