Intrarenal Renin Angiotensin System Imbalance During Postnatal Life Is Associated With Increased Microvascular Density in the Mature Kidney

Abstract

Environmental stress during early life is an important factor that affects the postnatal renal development. We have previously shown that male rats exposed to maternal separation (MatSep), a model of early life stress, are normotensive but display a sex-specific reduced renal function and exacerbated angiotensin II (AngII)-mediated vascular responses as adults. Since optimal AngII levels during postnatal life are required for normal maturation of the kidney, this study was designed to investigate both short- and long-term effect of MatSep on (1) the renal vascular architecture and function, (2) the intrarenal renin-angiotensin system (RAS) components status, and (3) the genome-wide expression of genes in isolated renal vasculature. Renal tissue and plasma were collected from male rats at different postnatal days (P) for intrarenal RAS components mRNA and protein expression measurements at P2, 6, 10, 14, 21, and 90 and microCT analysis at P21 and 90. Although with similar body weight and renal mass trajectories from P2 to P90, MatSep rats displayed decreased renal filtration capacity at P90, while increased microvascular density at both P21 and P90 ( p < 0.05). MatSep increased renal expression of renin, and angiotensin type 1 (AT1) and type 2 (AT2) receptors ( p < 0.05), but reduced ACE2 mRNA expression and activity from P2-14 compared to controls. However, intrarenal levels of AngII peptide were reduced ( p < 0.05) possible due to the increased degradation to AngIII by aminopeptidase A. In isolated renal vasculature from neonates, Enriched Biological Pathways functional clusters (EBPfc) from genes changed by MatSep reported to modulate extracellular structure organization, inflammation, and pro-angiogenic transcription factors. Our data suggest that male neonates exposed to MatSep could display permanent changes in the renal microvascular architecture in response to intrarenal RAS imbalance in the context of the atypical upregulation of angiogenic factors.

Involvement of the Renin-Angiotensin System in Stress: State of the Art and Research Perspectives

“…Adequate levels of Ang II in postnatal development are necessary for normal maturation of the kidney [ 143 , 144 ]. Male rats exposed to maternal separation continued normotensive but expressed higher sex-specific renal function reduction and higher Ang II-mediated vascular reactions during adulthood [ 145 , 146 ]. In order to understand further short- and long-term effects of these stress mechanisms, Dalmasso et al .…”

“…In order to understand further short- and long-term effects of these stress mechanisms, Dalmasso et al . (2020) [ 146 ] analyzed the renal tissue from rats submitted to maternal separation and observed lower renal filtration capacity and increased renal expression of AT 1 and AT 2 receptors, which were associated with a reduction of Ang II intrarenal levels. These effects were hypothesized as being caused by Ang III increased degradation by amino peptidase A, but this theory still requires further elucidation.…”

“…Moreover, it was identified an increase in ACE expression and a decrease in ACE2 expression and activity, along with the attenuation of the known anti-angiogenic effects of Ang-(1-7) [ 147 - 149 ]. The authors suggested that rats exposed to maternal separation might have further changes within the renal microvascular response to intrarenal RAS imbalance due to unusual upregulation of angiogenic factors [ 146 ]. In summary, RAS components play a role in neonatal isolation stress effects by influencing cardiovascular and metabolic responses.…”

Epididymal Fat-Derived Sympathoexcitatory Signals Exacerbate Neurogenic Hypertension in Obese Male Mice Exposed to Early Life Stress

“…After 15 weeks on HF, mice were subjected to a transcutaneous glomerular filtration rate measurement as described previously. 33 Then, mice were implanted with radiotelemeters (TAA11PA−C10; Data Sciences International, New Brighton, MN). After a 10-day recovery period, systolic, diastolic, MAP, and heart rate (HR) baselines were measured for 5 consecutive days in a 10-second sampling period, recorded and averaged every 5 minutes.…”