Abstract
Maternal chronic kidney disease (CKD) during pregnancy causes adverse fetal programming. Nitric oxide (NO) deficiency, gut microbiota dysbiosis, and dysregulated renin-angiotensin system (RAS) during pregnancy are linked to the development of hypertension in adult offspring. We examined whether maternal adenine-induced CKD can program hypertension and kidney disease in adult male offspring. We also aimed to identify potential mechanisms, including alterations of gut microbiota composition, increased trimethylamine-N-oxide (TMAO), reduced NO bioavailability, and dysregulation of the RAS. To construct a maternal CKD model, female Sprague-Dawley rats received regular chow (control group) or chow supplemented with 0.5% adenine (CKD group) for 3 weeks before pregnancy. Mother rats were sacrificed on gestational day 21 to analyze placentas and fetuses. Male offspring (n = 8/group) were sacrificed at 12 weeks of age. Adenine-fed rats developed renal dysfunction, glomerular and tubulointerstitial damage, hypertension, placental abnormalities, and reduced fetal weights. Additionally, maternal adenine-induced CKD caused hypertension and renal hypertrophy in adult male offspring. These adverse pregnancy and offspring outcomes are associated with alterations of gut microbiota composition, increased uremic toxin asymmetric and symmetric dimethylarginine (ADMA and SDMA), increased microbiota-derived uremic toxin TMAO, reduced microbiota-derived metabolite acetate and butyrate levels, and dysregulation of the intrarenal RAS. Our results indicated that adenine-induced maternal CKD could be an appropriate model for studying uremia-related adverse pregnancy and offspring outcomes. Targeting NO pathway, microbiota metabolite TMAO, and the RAS might be potential therapeutic strategies to improve maternal CKD-induced adverse pregnancy and offspring outcomes.
Highlights
Chronic kidney disease (CKD) is a highly prevalent disease worldwide, as at least 3–4% of childbearing-aged women’s lives are complicated by this condition [1,2]
Adenine-treated chronic kidney disease (CKD) group had greater degrees of glomerular (Figure 1F) and tubulointerstitial injury (Figure 1G) than controls. These data indicate that mother rats developed CKD before pregnancy, which is characterized by impaired renal function (~30% of normal renal function), renal hypertrophy, glomerular and tubulointerstitial injuries, and hypertension
This study provides a new insight into the mechanisms underlying maternal CKD-induced hypertension in adult male offspring with particular emphasis on gut microbiota metabolites, Nitric oxide (NO) pathway, and the renin-angiotensin system (RAS)
Summary
Chronic kidney disease (CKD) is a highly prevalent disease worldwide, as at least 3–4% of childbearing-aged women’s lives are complicated by this condition [1,2]. Environmental factors such as maternal illness play a key role in the developmental programming of kidney disease and hypertension [3,4]. Disturbance of normal gut microbiota could link early-life environmental insults to later risk of adult diseases [8]. Recent studies have identified several possible interconnected mechanisms between gut dysbiosis and hypertension [9,10], such as altered microbial composition, increased production of microbiota-derived trimethylamine-N-oxide (TMAO), changes of short chain fatty acids (SCFAs) and their receptors, impaired nitric oxide (NO) pathway, and dysregulation of the renin-angiotensin system (RAS). In CKD, uremic toxin accumulation plays a crucial role in cardiovascular risk. In addition to microbiota-related TMAO [11], asymmetric and symmetric dimethylarginine (ADMA and SDMA, endogenous inhibitors of NO synthase) are major uremic toxins that contribute to the pathogenesis of cardiovascular disease [12]
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