Maternal Tryptophan Supplementation Protects Adult Rat Offspring against Hypertension Programmed by Maternal Chronic Kidney Disease: Implication of Tryptophan-Metabolizing Microbiome and Aryl Hydrocarbon Receptor.

Chien-Ning Hsu,Li-Tung Huang,I-Chun Lin,Hong-Ren Yu,Mao-Meng Tiao,You-Lin Tain

doi:10.3390/ijms21124552

Abstract

Hypertension and chronic kidney disease (CKD) can originate during early-life. Tryptophan metabolites generated by different pathways have both detrimental and beneficial effects. In CKD, uremic toxins from the tryptophan-generating metabolites are endogenous ligands of the aryl hydrocarbon receptor (AHR). The interplay between AHR, nitric oxide (NO), the renin–angiotensin system (RAS), and gut microbiota is involved in the development of hypertension. We examined whether tryptophan supplementation in pregnancy can prevent hypertension and kidney disease programmed by maternal CKD in adult offspring via the aforementioned mechanisms. Sprague–Dawley (SD) female rats received regular chow or chow supplemented with 0.5% adenine for 3 weeks to induce CKD before pregnancy. Pregnant controls or CKD rats received vehicle or tryptophan 200 mg/kg per day via oral gavage during pregnancy. Male offspring were divided into four groups (n = 8/group): control, CKD, tryptophan supplementation (Trp), and CKD plus tryptophan supplementation (CKDTrp). All rats were sacrificed at the age of 12 weeks. We found maternal CKD induced hypertension in adult offspring, which tryptophan supplementation prevented. Maternal CKD-induced hypertension is related to impaired NO bioavailability and non-classical RAS axis. Maternal CKD and tryptophan supplementation differentially shaped distinct gut microbiota profile in adult offspring. The protective effect of tryptophan supplementation against maternal CKD-induced programmed hypertension is relevant to alterations to several tryptophan-metabolizing microbes and AHR signaling pathway. Our findings support interplay among tryptophan-metabolizing microbiome, AHR, NO, and the RAS in hypertension of developmental origins. Furthermore, tryptophan supplementation in pregnancy could be a potential approach to prevent hypertension programmed by maternal CKD.

Highlights

Hypertension and kidney disease are highly prevalent diseases throughout the world
Maternal chronic kidney disease (CKD) and tryptophan supplementation are associated with a higher kidney weight-to-body weight (BW) ratio (PCKD = 0.004 and PTrp = 0.01), while there was no synergistic effect
We previously reported that exogenous aryl hydrocarbon receptor (AHR) ligand TCDD induced programmed hypertension together with activation of AHR and its target genes in adult rats [10], this notion is not supported by the present observations, which showed that tryptophan-derived endogenous AHR ligands activated AHR signaling pathway but had no effect on blood pressure (BP) in adult offspring

Summary

Introduction

Hypertension and kidney disease are highly prevalent diseases throughout the world. Maternal illness and nutrition play key roles in the developmental programming of kidney disease and hypertension [1,2,3]. Women with chronic kidney disease (CKD) are at risk for adverse pregnancy-related events [4], less attention has been paid to explore the effects of maternal CKD on the adult offspring outcomes. Endogenous tryptophan metabolites (e.g., melatonin, serotonin, and kynurenines) and gut microbiota derived tryptophan metabolites (e.g., indole, indolic acid, skatole, and tryptamine) play significant roles in developing health and disease. Dietary tryptophan supplementation has shown potential benefits to the therapy of several human disorders [7,8], so far, no data supported the notion that additional tryptophan in pregnancy could be beneficial for adult offspring outcomes

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