Renal impairment induced by prenatal exposure to angiotensin II in male rat offspring

Abstract

Suboptimal conditions during prenatal ontogeny can impair development of several physiological systems and result in cardiometabolic diseases in adulthood. The kidney has been identified as one of the most sensitive organs for developmental programming, but underlying mechanisms are not fully understood. Therefore, in our study we explored the consequences of prenatally increased angiotensin II (Ang II) on the structural development of the kidney and its damage by infiltrated immune cells under normal diet and after an increased salt intake, as a second insult representing a lifestyle factor in humans. Female rats were implanted with osmotic mini-pumps continuously releasing Ang II of dose 2 µg/kg/h during last two weeks of pregnancy, whereas control females were sham operated. Immunohistological and ultrastructural evaluations of the kidneys and their infiltration with immune cells were performed in mature male progeny kept either on a standard or increased salt (2% NaCl) diet. Glomerular volume decreased and the cortical tubulointerstitial injury increased in the offspring prenatally exposed to Ang II with no additional effect of increased salt. Ultrastructural examination demonstrated degenerative changes in proximal tubules, mainly fewer and shorter microvilli in the brush border, enlarged mitochondria, and an increased number of lysosomes in the epithelial cells in the progeny prenatally exposed to Ang II. Moreover, the treatment resulted in increased infiltration of T-cells and macrophages in the renal cortex compared to controls. These changes paralleled with reduced numbers of cytotoxic T-cells in circulation and higher oxidative burst of neutrophils in the progeny of Ang II-treated mothers compared to controls. Altogether, results suggest that prenatally increased Ang II promoted infiltration of immune cells in the kidney and subsequent oxidative stress, which induced a damage of renal glomerular and tubular system entailing negative consequences on the cardiovascular system. Impact statement Suboptimal prenatal conditions can contribute to development of cardiovascular diseases and an altered renin-angiotensin-aldosterone system (RAAS) can be involved in the process. In our study, increased angiotensin II in pregnant female rats resulted in renal cortical interstitial damage, and renal ultrastructural changes in the glomeruli, the brush border of proximal tubules and mitochondria in mature male offspring. The treatment promoted infiltration of T cells and macrophages in the kidneys and primed an oxidative burst of circulating neutrophils, indicating a pro-inflammatory state in the progeny of angiotensin II-treated mothers. Deregulated RAAS of mothers is involved in developmental programming of hypertension in adult male offspring via damaging kidney morphology and function. These findings suggest that preventing the activation of RAAS and oxidative stress during perinatal development might protect against hypertension development in adult male progeny.

Hydration in relation to water insecurity, heat index, and lactation status in two small‐scale populations in hot‐humid and hot‐arid environments

“…Apart from the potential effects of dehydration on the health and well‐being of pregnant and lactating mothers, dehydration could also impact that long‐term health of offspring who were exposed to dehydration in utero. Animal studies, for example, have suggested that water deprivation during pregnancy could negatively impact birth weight (Ross & Desai, 2005), renal morphology and function (Svitok, Okuliarova, Varga, & Zeman, 2019), and the renin‐angiotensin system (Guan et al, 2009; Zhang et al, 2011) of offspring, potentially influencing their long‐term risk for hypertension and cardiovascular disease. There is likewise reason to hypothesize that prenatal exposures to water deficits could alter offspring's own ability to regulate water balance (Rosinger, 2020), which is why we tested for an association with birth season.…”

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 ].…”

“…Collectively, these studies support the impact of oxidative stress on low nephron endowment. 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 ).…”

When Less or More Isn't Enough: Renal Maldevelopment Arising From Disequilibrium in the Renin-Angiotensin System

“…Svitok et al (59) directly analyzed the effects of increased ANGII during the prenatal period in offspring. ANGII was administrated to pregnant rats via osmotic mini-pumps and analyzed postnatal development via blood pressure control.…”