Resveratrol Butyrate Ester Protects Adenine-Treated Rats against Hypertension and Kidney Disease by Regulating the Gut-Kidney Axis.

Chih-Yao Hou,You-Lin Tain,Chi-I Chang,Chien-Ning Hsu

doi:10.3390/antiox11010083

Abstract

Despite recent advances in pharma-nutritional management, chronic kidney disease (CKD) remains an increasingly prevalent disorder. Resveratrol, a pleiotropic phytochemical, has been found to reduce the risk for several chronic diseases. Considering the low bioavailability of resveratrol, we recently synthesized resveratrol butyrate ester (RBE) via the esterification of resveratrol with butyrate. The aim of this study was to examine the effectiveness of RBE as regards protection from hypertension and kidney damage and explore the underlying mechanisms using a young rat adenine-induced CKD model. Three-week-old male Sprague Dawley rats received regular or 0.5% adenine chow for three weeks. Three groups of adenine-fed CKD rats (N = 8/group) received resveratrol (50 mg/L), or a low dose (25 mg/L) or high dose (50 mg/L) of RBE in drinking water from week 6 to week 12. As compared with the controls, adenine-treated rats had markedly increased creatinine levels and blood pressure, which was associated with renal hypertrophy and decreased creatinine clearance. Treatment with resveratrol or a low or high dose of RBE, similarly protected adenine-fed rats against hypertension and kidney damage. CKD-induced hypertension is associated with an altered gut microbiota profile, dysregulated renal short chain fatty acid (SCFA) receptor expression, activation of the aryl hydrocarbon receptor (AhR) signaling pathway, and reduced nitric oxide bioavailability. We found gut microbiota compositions were shaped differentially by resveratrol and RBE treatment in adenine-treated CKD rats. The beneficial effect of high-dose RBE was associated with reduced renal expression of SCFA G protein-coupled receptor 41 (GPR41) and olfactory receptor 78 (Olfr78), antagonizing the AhR signaling pathway, and increased abundance of beneficial bacteria such as genera Akkermansia, Blautia, and Enterococcus. Our study provided the first evidence documenting RBE as a novel phytochemical supplement targeting the gut–kidney axis to protect against adenine-induced kidney damage and hypertension.

Highlights

Chronic kidney disease (CKD) is a growing global health issue that affects approximately 10% of the world’s population [1]
There was no difference in body weight between groups, while the kidney weight and kidney weight-to-Body weight (BW) ratios were lower in the CN group as compared to the other four groups
nitric oxide (NO) deficiency developed in the CKD group, and the protective effects of resveratrol and resveratrol butyrate ester (RBE) are not likely related to the NO pathway

Summary

Introduction

Chronic kidney disease (CKD) is a growing global health issue that affects approximately 10% of the world’s population [1]. CKD can originate in infancy and childhood [2]. Children with CKD are at increased risk of morbidity and mortality and are vulnerable to complications associated with CKD [3]. Hypertension is the leading complication of pediatric CKD [4]. Prior research indicated that more than half of children with CKD display blood pressure (BP) abnormalities [4], even in the early stages of CKD [5]. Early detection and management of hypertension in children with

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