Nutritional Programming via Maternal Protein Restriction Mitigates Long-Term Consequences of Acute Kidney Injury

Abstract

The kidney is highly sensitive to prenatal and early-life environmental influences. Maternal protein restriction (MPR) can alter renal development and may modify susceptibility to chronic kidney disease (CKD) following acute kidney injury (AKI). We investigated whether MPR during gestation and/or lactation influences the progression from AKI to CKD after renal ischemia–reperfusion (IR) in rat offspring. Fifty Wistar pregnant rats were fed a control (20% casein) or protein-restricted (10% casein) diet during gestation, with diets maintained or switched during lactation, generating four maternal nutritional groups (CC, CR, RC, and RR). At 280–330 g body weight, offspring from these groups were randomly assigned to left renal IR plus right nephrectomy (CC + IR, CR + IR, RC + IR, and RR + IR) or right nephrectomy alone (CC, CR, RC, and RR). Renal outcomes were assessed in two independent cohorts of rats at 7 days and 5 months after surgery. Offspring from MPR during gestation and/or lactation (CR + IR, RC + IR, and RR + IR) showed reduced susceptibility to AKI-to-CKD progression compared to the CC + IR group, characterized by attenuated proteinuria, absence of glomerular hypertrophy, and minimal renal fibrosis. This protective phenotype was associated with reduced oxidative stress and endoplasmic reticulum stress, as indicated by lower 4-HNE, CHOP, and BiP, together with enhanced post-ischemic repair reflected by lower urinary KIM-1 and Hsp72 excretion. MPR during gestation and/or lactation induces a persistent renal phenotype in the offspring that confers resistance to AKI-to-CKD progression, potentially through modulation of oxidative and endoplasmic reticulum stress. These findings highlight developmental nutritional programming as a previously underappreciated determinant of renal resilience in offspring after AKI and provide a basis for investigating nutritional and developmental mechanisms that may be targeted to prevent CKD after AKI.