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

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.

Developmental Origins of Kidney Disease: Why Oxidative Stress Matters?

“…The present review is simply restricted to environmental insults starting in pregnancy and lactation period, with a focus on oxidative stress-related renal programming. Table 1 shows a range of adverse conditions during pregnancy and lactation may affect kidney development, resulting in morphological changes, functional adaption, and adverse renal outcomes in adulthood [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ].…”

“…Another factor interfering with renal programming is exposure to environmental toxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [ 62 ], bisphenol A [ 63 ], di-n-butyl phthalate [ 67 ], and smoking [ 69 ]. Additionally, maternal illness, such as diabetes [ 32 ], preeclampsia [ 33 , 34 ], CKD [ 60 ], reduced uterine perfusion [ 64 ], hypertension [ 66 ], and inflammation [ 67 ] have all been reported to affect kidney development and contribute to developmental programming of kidney disease. Additionally, renal programming can be triggered by medication like glucocorticoid [ 35 , 57 , 61 , 71 ].…”

“…However, reduced nephron number per se does not appear to mediate all programmed processes underlying developmental origins of kidney disease, as nephron number can be unaltered [ 66 ], or even increased in response to renal programming [ 75 ]. In addition to reduced nephron number, glomerular hypertrophy [ 29 , 30 , 60 , 68 ] and tubulointerstitial injury [ 29 , 30 , 32 , 66 , 68 ] are major morphological deficits associated with renal programming ( Table 1 ).…”

“…On the other hand, the most common phenotype of renal programming being studied is hypertension [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 56 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 67 , 71 ]. Albuminuria has been demonstrated in offspring mice born of dams with high-fat intake [ 69 ] or maternal smoking exposure [ 70 ].…”

“…Albuminuria has been demonstrated in offspring mice born of dams with high-fat intake [ 69 ] or maternal smoking exposure [ 70 ]. Additionally, renal function was not affected in most models of renal programming [ 29 , 30 , 32 , 59 , 60 ], except one report demonstrated blood creatinine level was elevated in 12-week-old offspring born to dams received dexamethasone administration during lactation [ 57 ]. Our review implicates that the renal programming does not rely on one particular factor exposure and it show a variety of phenotypes.…”