Maternal Adenine-Induced Chronic Kidney Disease Programs Hypertension in Adult Male Rat Offspring: Implications of Nitric Oxide and Gut Microbiome Derived Metabolites

• Published in: International journal of molecular sciences Vol. 21; no. 19; p. 7237
• Main Authors: Hsu, Chien-Ning, Yang, Hung-Wei, Hou, Chih-Yao, Chang-Chien, Guo-Ping, Lin, Sufan, Tain, You-Lin
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-10-2020; MDPI
• Subjects: Abnormalities; Acetic acid; Adenine; Adenine - adverse effects; Adenine - metabolism; Angiotensin; Animals; asymmetric dimethylarginine; Bioavailability; chronic kidney disease; Chronic kidney failure; Composition; Creatinine; developmental origins of adult health and disease (DOHaD); Digestive system; Discriminant analysis; Disease Models, Animal; Dysbacteriosis; Dysbiosis - genetics; Dysbiosis - microbiology; Fatty acids; Feces; Female; Fetal Development - drug effects; Fetuses; Gastrointestinal Microbiome - genetics; gut microbiota; Hypertension; Hypertension - etiology; Hypertension - metabolism; Hypertension - microbiology; Hypertension - pathology; Hypertrophy; Intestinal microflora; Kidney diseases; Males; Maternal Inheritance - genetics; Metabolites; Microbiomes; Microbiota; Nitric oxide; Nitric Oxide - genetics; Nitric Oxide - metabolism; Physiological aspects; Placenta; Plasma; Pregnancy; Prenatal Exposure Delayed Effects - etiology; Prenatal Exposure Delayed Effects - metabolism; Prenatal Exposure Delayed Effects - microbiology; Prenatal Exposure Delayed Effects - pathology; Rats; Renal function; Renal Insufficiency, Chronic - etiology; Renal Insufficiency, Chronic - metabolism; Renal Insufficiency, Chronic - microbiology; Renal Insufficiency, Chronic - pathology; Renin; Renin-Angiotensin System - genetics; Trimethylamine; Trimethylamine-N-oxide; Uremia; Taiwan; trimethylamine-N-oxide; chronic kidney disease; nitric oxide; uremic toxin; developmental origins of adult health and disease (DOHaD); hypertension; asymmetric dimethylarginine; gut microbiota; renin-angiotensin system; short chain fatty acid
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21197237

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 (
= 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.