Perinatal Resveratrol Therapy Prevents Hypertension Programmed by Maternal Chronic Kidney Disease in Adult Male Offspring: Implications of the Gut Microbiome and Their Metabolites.

Chien-Ning Hsu,Chih-Yao Hou,Sufan Lin,You-Lin Tain,Guo-Ping Chang-Chien,Hung-Wei Yang

doi:10.3390/biomedicines8120567

Abstract

The gut microbiota plays a critical role in kidney disease and hypertension; however, whether maternal chronic kidney disease (CKD)-induced offspring hypertension is associated with alterations of the microbiota and microbial metabolites remains elusive. Using rat as an animal model, we conducted a maternal adenine-induced CKD model to examine whether adult male offspring develop hypertension and kidney disease. As resveratrol has antioxidant and prebiotic properties, we also aimed to elucidate whether its use in pregnancy and lactation can benefit hypertension programmed by maternal CKD via mediation of the gut microbiota and oxidative stress. Female Sprague-Dawley rats received regular chow (C) or chow supplemented with 0.5% adenine (CKD) from 3 weeks before pregnancy until lactation. One group of the adenine-induced CKD pregnant rats received resveratrol (R; 50 mg/L) in drinking water during gestation and lactation. Male offspring were divided into three groups: C, CKD, and CKD+R. The microbial metabolites analyzed were short chain fatty acids (SCFAs) in feces and trimethylamine (TMA)/trimethylamine N-oxide (TMAO) in plasma. We found perinatal resveratrol therapy protected against maternal CKD-induced hypertension in adult male offspring. The overall microbial compositions and diversity of bacterial community in the three groups were different. Resveratrol therapy increased α-diversity, decreased the Firmicutes to Bacteroidetes ratio, and increased the abundance of the genera Lactobacillus and Bifidobacterium. Perinatal resveratrol therapy increased plasma TMA levels but decreased the plasma TMAO-to-TMA ratio. Although resveratrol had negligible effect on fecal concentrations of SCFAs, it increased G-protein coupled receptor-41 (GPR41) protein levels in the offspring’s kidneys. Additionally, resveratrol therapy increased plasma levels of L-arginine and the L-arginine-to-ADMA ratio (AAR), and decreased oxidative stress. Overall, the protective effects of resveratrol against programmed hypertension are related to gut microbiome remodeling, including an increased abundance of beneficial microbes, mediation of the TMA-TMAO pathway, and alterations of SCFA receptors. Our results highlighted that targeting the microbiome and their metabolites might be potential therapeutic strategies to prevent maternal CKD-induced adverse pregnancy and offspring outcomes.

Highlights

Chronic kidney disease (CKD) is a highly prevalent disease that affects nearly 10% of the world’s population [1]
blood pressure (BP) (SBP) from 4 to 12 weeks of age showed that maternal CKD caused increases in Systolic BP (SBP) (Figure 2), while the elevation of SBP was prevented by maternal resveratrol therapy from 6 to 12 weeks of age
At 12 weeks of age, diastolic BP and mean arterial pressure were elevated in the CKD group compared with the controls

Summary

Introduction

Chronic kidney disease (CKD) is a highly prevalent disease that affects nearly 10% of the world’s population [1]. Pregnant women with CKD are at risk of adverse maternal and perinatal outcomes [3]. We previously reported that maternal CKD increases the risks of developing hypertension and renal hypertrophy in adult male rat offspring [4]. Current evidence suggests that hypertension and CKD are interconnected, and both can originate in early life [5,6,7]. This concept, namely “developmental origins of health and disease (DOHaD)”, has been used widely to demonstrate that the developing fetus exposed to a suboptimal in utero environment increases the risk for developing many chronic diseases in adulthood [8]

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