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

Abstract

Environmental and nutritional factors during fetal and neonatal life can have long-lasting effects on renal functions and physiology and susceptibility to kidney disease in adulthood. All components of the renin-angiotensin system (RAS) are highly expressed in the kidneys during the period of renal development. The RAS plays a central role in the regulation of various cellular growth factors and stimulates adhesion molecules and cellular migration. The use of antagonists of this system during fetal development represents a major risk factor for hypertension, renal vascular dysfunction, and kidney medulla atrophy in adulthood. The inappropriate activation of the RAS by vitamin D (VitD) deficiency has been studied in recent years. Clinical and experimental studies have demonstrated an inverse relationship between circulating VitD levels and blood pressure, plasma and renin activity, and an increase in angiotensin II and the receptor AT 1 . These data raise new questions about the importance of the integrity of the RAS during development since RAS pathway inhibitors and VitD deficiency have opposing functions. This is a literature review on the possible mechanisms by which antagonists of the RAS and VitD deficiency during fetal development provoke disturbances in kidney structure and function. Potential mechanisms are presented and discussed, and the possible pathways by which an imbalanced maternal RAS may negatively impact fetal development and have consequences in adulthood are also explored.

Pharmacological Efficacy and Mechanism of Vitamin D in the Treatment of “Kidney-Brain” Disorders

“…Vitamin D inhibits renin expression and in turn reduces Ang II expression, thus, serving as a negative RAS regulator [29,30]. The deficiency of vitamin D activates the intrarenal RAS, thereby inducing an increase in the level of Ang II, which is an important stimulator of kidney injury [31,32]. Our study demonstrated that active vitamin D analogs paricalcitol and doxercalciferol were able to suppress RAS activation, alleviate glomerular and tubulointerstitial damage, and reduce proteinuria in streptozotocin (STZ, 40 mg/kg)-induced diabetic DBA/2 J mice [33,34].…”

Imbalance of Pro- and Anti-Angiogenic Factors Due to Maternal Vitamin D Deficiency Causes Renal Microvasculature Alterations Affecting the Adult Kidney Function

“…Vit.D has pleiotropic effects that extend beyond its traditional role in calcium homeostasis [10]. More than 200 genes with Vit.D receptor response elements (VDREs) directly or indirectly influence cell cycling, proliferation, differentiation, and apoptosis and regulation of the renin gene, which are important aspects of development [11,12,13].…”

Influência da vitamina D no desenvolvimento renal em ratos

“…Uma cascata de eventos durante o desenvolvimento renal é rigidamente regulada pelos receptores de ANGII, que são altamente expressos nos rins durante este período (Millan et al, 1989). Assim, a integridade do SRA desempenha um papel fundamental na saúde fetal (Almeida & Coimbra, 2019). O desenvolvimento do rim é um processo altamente complexo que exige uma regulação precisa da proliferação , diferenciação e apoptose celular (Almeida & Coimbra, 2019;Moore et al, 2020).…”

“…Assim, a integridade do SRA desempenha um papel fundamental na saúde fetal (Almeida & Coimbra, 2019). O desenvolvimento do rim é um processo altamente complexo que exige uma regulação precisa da proliferação , diferenciação e apoptose celular (Almeida & Coimbra, 2019;Moore et al, 2020). A distribuição temporal e espacial dos receptores de ANGII do tipo 1 e 2 e seus RNAm durante o desenvolvimento renal tem sido estudado (Gao et al, 2005;Norwood et al, 1997;Kakuchi et al, 1995).…”

“…periférica, sistema nervoso central (SNC), rins e coração (Sparks et al, 2014). A secreção e produção de renina são amplamente estimuladas pelo volume ou depleção de sal, reduções na pressão de perfusão vascular renal e atividade nervosa simpática (Hackenthal et al, 1990;Almeida et al, 2019). No presente estudo, observamos que ratos do grupo Vit.…”