Maternal N-Acetylcysteine Therapy Prevents Hypertension in Spontaneously Hypertensive Rat Offspring: Implications of Hydrogen Sulfide-Generating Pathway and Gut Microbiota.

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

doi:10.3390/antiox9090856

Abstract

Hypertension can come from early life. N-acetylcysteine (NAC), a hydrogen sulfide (H2S) precursor as well as an antioxidant, has antihypertensive effect. We investigated whether maternal NAC therapy can protect spontaneously hypertensive rats (SHR) male offspring against hypertension. The pregnant rats were assigned to four groups: SHRs without treatment; Wistar Kyoto (WKY) without treatment; SHR+NAC, SHRs received 1% NAC in drinking water throughout pregnancy and lactation; and, WKY+NAC, WKY rats received 1% NAC in drinking water during pregnancy and lactation. Male offspring (n = 8/group) were killed at 12 weeks of age. Maternal NAC therapy prevented the rise in systolic blood pressure (BP) in male SHR offspring at 12 weeks of age. Renal cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulphurtransferase (3MST) protein levels and H2S-releasing activity were increased in the SHR+NAC offspring. Maternal NAC therapy increased fecal H2S and thiosulfate levels in the SHR+NAC group. Additionally, maternal NAC therapy differentially shaped gut microbiota and caused a distinct enterotype in each group. The protective effect of maternal NAC therapy against hypertension in SHR offspring is related to increased phylum Actinobacteria and genera Bifidobacterium and Allobaculum, but decreased phylum Verrucomicrobia, genera Turicibacter, and Akkermansia. Several microbes were identified as microbial markers, including genera Bifidobacterium, Allobaculum, Holdemania, and Turicibacter. Our results indicated that antioxidant therapy by NAC in pregnant SHRs can prevent the developmental programming of hypertension in male adult offspring. Our findings highlight the interrelationships among H2S-generating pathway in the kidneys and gut, gut microbiota, and hypertension. The implications of maternal NAC therapy elicited long-term protective effects on hypertension in later life that still await further clinical translation.

Highlights

Hypertension is a common disease and a leading global risk for mortality [1]
Our results indicated that antioxidant therapy by NAC in pregnant spontaneously hypertensive rats (SHR) can prevent the developmental programming of hypertension in male adult offspring
Maternal NAC treatment caused an increase of body weight (BW) in the Wistar Kyoto (WKY), but not SHR offspring

Summary

Introduction

Hypertension is a common disease and a leading global risk for mortality [1]. Hypertension can originate in early life by so-called “developmental origins of health and disease” (DOHaD) [2,3].Accumulative evidence demonstrates that early-life oxidative stress can increase the risk of developing hypertension in later life [3,4,5]. Hypertension is a common disease and a leading global risk for mortality [1]. Hypertension can originate in early life by so-called “developmental origins of health and disease” (DOHaD) [2,3]. Accumulative evidence demonstrates that early-life oxidative stress can increase the risk of developing hypertension in later life [3,4,5]. Antioxidants have shown benefits in hypertension by counteracting oxidative stress [6]. The kidneys can be programmed by adverse early-life environments, namely renal programming, leading to hypertension in adulthood [7,8]. The imbalance between vasodilators, such as nitric oxide (NO), and vasoconstrictors, such as angiotensin II (Ang II), in favor of vasoconstriction can lead to hypertension [9]. We and others have demonstrated that renal NO deficiency is characterized in the prehypertensive stage of the spontaneously hypertensive rats (SHRs), a commonly used genetic hypertensive model [10,11]

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