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

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.

N-Acetylcysteine and Hydrogen Sulfide in Coronavirus Disease 2019

“…Interestingly, an animal study using a maternal suramin-induced programmed hypertension model demonstrated that maternal NAC treatment protected male rat offspring against hypertension, which was associated with an increased protein level of 3-MST and H 2 S synthesis in the kidney (92). Another rodent model showed similar results, this time involving NAC-induced enhancement of renal 3-MST and CBS (but not CSE) protein levels, as well as H 2 S-releasing activity in offspring kidneys of hypertensive mothers (44). Taurine is a metabolite of cysteine and strongly boosts the CSE enzyme, and thereby contributes to increase the endogenous H 2 S level in humans (90,114).…”

Preventing Developmental Origins of Cardiovascular Disease: Hydrogen Sulfide as a Potential Target?

“…Conversely, approaches including probiotics, prebiotics, postbiotics (e.g., SCFAs), or microbial inhibitors that target specific pathways (e.g., TMAO), have shown beneficial cardiovascular effects [121]. Our previous research demonstrated that supplementation with prebiotic inulin, probiotics Lactobacillus casei, or postbiotics acetate during pregnancy and lactation can protect adult offspring against hypertension programmed by a variety of maternal insults [122][123][124].…”

Developmental Origins of Kidney Disease: Why Oxidative Stress Matters?

“…We confined this review to antioxidants implemented mainly during gestation and lactation which are critical periods for kidney development. As listed in Table 2 , we summarize current knowledge on perinatal use of antioxidants used as a reprogramming strategy to protect offspring against renal programming in various animal models [ 29 , 30 , 31 , 33 , 34 , 35 , 36 , 59 , 60 , 62 , 63 , 67 , 70 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 ]. As the DOHaD research is a flourishing field, this list is likely to grow rapidly.…”

“…In the prenatal dexamethasone and postnatal high-fat diet model, the beneficial effects of NAC against offspring hypertension were associated with increased H 2 S-generating enzyme expression, increased plasma glutathione level, and reduction of renal 8-OHdG expression [ 36 ]. In another study, perinatal use of NAC also protected SHR offspring against hypertension via increased expression and activity of renal H 2 S-generating enzymes and activity [ 97 ]. Furthermore, NAC therapy in pregnancy and lactation prevented hypertension programmed by maternal suramin administration, which coincided with increased GSH and restoration of NO [ 33 ].…”