INTERMITTENT FASTING MODULATES RENAL FUNCTION IN ASSOCIATION WITH ESTROUS CYCLE VARIATION AND AUTOPHAGY MECHANISMS

Introduction: Intermittent fasting (IF) is a dietary restriction used as non-pharmacological therapy of disorders including type 2 diabetes mellitus. One potential mechanism involved is autophagy. In addition, IF can lead to endocrine changes on the estrous cycle what could affect sex hormone-targeted peripheral organs, like kidneys. Moreover, estrogens modulate kidney function and autophagy. Objective: verify the potential impact of IF on renal function and autophagy, and see if the estrous cycle can possibly modulate those results. Methods: Female Wistar rats (10 weeks old) were randomly divided into two experimental groups: 1) CONT group (control, n=4), with free access to chow; and 2) IF group (n=5), rats subjected to the IF protocol [fasting: 18h (from “zeitgeber time” (ZT)=8 up to ZT=24)/ feeding: 6h (from ZT=1 up to ZT=7)] for 4 consecutive weeks (CEUA-UFMG#13-2023). Results: Compared to the CONT group, the IF group showed: 1) reduction in body weight (BW, 15%) and in visceral adipose tissue depots, with exception of brown adipose tissue. Regarding renal function, IF group showed: 1) reduced hydric balance due to increased water intake (3.0-fold) and reduction in urinary volume (64%); 2) reduced glycosuria (44%) and fractional excretion (FE) of glucose (FE_glucose); 3) increased proteins excretion (1.8-fold) and increased FE_proteins; 4) increased natriuresis (20%) associated with reduced cortical (Na⁺+K⁺) ATPase activity. No significant changes were observed in urinary kidney injury biomarkers (γ-GT and LDH) and in renal cortex structures. We found positive correlations between proteinuria, glycosuria and urinary chloride and estrous cycle in CONT group. IF group showed a difference frequency of meta estrus and diestrus phases [36.36% (IF) / 22.73% (CONT); 23.64% (IF) / 43.18% (CONT), respectively]. Histological analysis showed increased luminal tubular area and in the number of tubular epithelial cells in IF group. Regarding autophagy at renal cortex, we observed reduction in p62 and p-AKT expression as well as increased LC3B expression in IF group. Conclusions: Our findings suggest that IF modulates cortical tubule transport and autophagy pathway activation directly at the renal tissue. These effects could be associated with estrous cycle phases and its possible modulation.