A signature of renal stress resistance induced by short-term dietary restriction, fasting, and protein restriction

F Jongbloed,S Imholz,J L A Pennings,T C Saat,M E T Dollé,C T Van Oostrom,J H J Hoeijmakers,S Van Den Engel,R W F De Bruin,M Verweij,J N M Ijzermans,G Ambagtsheer,H Van Steeg,C Payan-Gomez

doi:10.1038/srep40901

Abstract

During kidney transplantation, ischemia-reperfusion injury (IRI) induces oxidative stress. Short-term preoperative 30% dietary restriction (DR) and 3-day fasting protect against renal IRI. We investigated the contribution of macronutrients to this protection on both phenotypical and transcriptional levels. Male C57BL/6 mice were fed control food ad libitum, underwent two weeks of 30%DR, 3-day fasting, or received a protein-, carbohydrate- or fat-free diet for various periods of time. After completion of each diet, renal gene expression was investigated using microarrays. After induction of renal IRI by clamping the renal pedicles, animals were monitored seven days postoperatively for signs of IRI. In addition to 3-day fasting and two weeks 30%DR, three days of a protein-free diet protected against renal IRI as well, whereas the other diets did not. Gene expression patterns significantly overlapped between all diets except the fat-free diet. Detailed meta-analysis showed involvement of nuclear receptor signaling via transcription factors, including FOXO3, HNF4A and HMGA1. In conclusion, three days of a protein-free diet is sufficient to induce protection against renal IRI similar to 3-day fasting and two weeks of 30%DR. The elucidated network of common protective pathways and transcription factors further improves our mechanistic insight into the increased stress resistance induced by short-term DR.

Highlights

Short- and long-term Dietary restriction (DR) is based on the reduction of calories per se, or specific nutrients, was first investigated in fruit flies, in which long-term protein restriction contributed more to lifespan extension than a reduction in carbohydrates[18]
We showed that the absence of protein for three days is sufficient to induce resistance against renal ischemia-reperfusion injury (IRI) and revealed common pathways and transcription factors that are implicated in the protective effect of calorie restriction, induced by two weeks of 30%DR, three days of fasting, and protein restriction
Since the discovery of the beneficial effects of short-term dietary restriction (DR) on stress resistance, optimizing its duration and content to eventually lead to a clinical applicable DR regimen has been an important part of the body of literature about DR2,11,19

Summary

Introduction

Short- and long-term DR is based on the reduction of calories per se, or specific nutrients, was first investigated in fruit flies, in which long-term protein restriction contributed more to lifespan extension than a reduction in carbohydrates[18]. Glucose supplementation did not interfere with fasting-induced protection against renal IRI, which points towards a role for specific (macro-)nutrients in inducing acute stress resistance[11]. We investigated the role of specific macronutrients in inducing resistance against renal IRI by unrestricted feeding of protein-, carbohydrate-, and fat-free diets. We showed that the absence of protein for three days is sufficient to induce resistance against renal IRI and revealed common pathways and transcription factors that are implicated in the protective effect of calorie restriction, induced by two weeks of 30%DR, three days of fasting, and protein restriction

Methods

Results

Conclusion