A Scoping Review of Life-Course Psychosocial Stress and Kidney Function.

Increased exposure to maternal psychosocial stress during gestation and adverse neonatal environments has been linked to alterations in developmental programming and health consequences in offspring. A programmed low nephron endowment, among other altered pathways of susceptibility, likely increases the vulnerability to develop chronic kidney disease in later life. Our aim in this scoping review was to identify gaps in the literature by focusing on understanding the association between life-course exposure to psychosocial stress, and the risk of reduced kidney function. A systematic search in four databases (PubMed, ProQuest, Wed of Science, and Scopus) was performed, yielding 609 articles. Following abstract and full-text review, we identified 19 articles meeting our inclusion criteria, reporting associations between different psychosocial stressors and an increase in the prevalence of kidney disease or decline in kidney function, mainly in adulthood. There are a lack of studies that specifically evaluated the association between gestational exposure to psychosocial stress and measures of kidney function or disease in early life, despite the overall evidence consistent with the independent effects of prenatal stress on other perinatal and postnatal outcomes. Further research will establish epidemiological studies with clear and more comparable psychosocial stressors to solve this critical research gap.

Effect of Calcitriol on the Renal Microvasculature Differentiation Disturbances Induced by AT1 Blockade During Nephrogenesis in Rats.

Alterations in the renal vasculature during fetal programming can cause disturbances in renal structure and function that persist into adulthood. Calcitriol can affect cellular differentiation and proliferation, and promote endothelial cell maintenance, each of which is a key event in nephrogenesis. Calcitriol is a negative endocrine regulator of the renin gene. Rats exposed to renin-angiotensin system (RAS) antagonists during lactation have been shown to develop renal disorders, which demonstrated that the RAS may play an important role in mammalian kidney development. We evaluated the effects of calcitriol administration on losartan [angiotensin II receptor antagonist (ANGII), AT1]-induced changes in renal differentiation in rats during lactation. Rats treated with losartan showed alterations in renal function and structure that persisted into adulthood. These disruptions included hydronephrosis, papillary atrophy, endothelial dysfunction, and aberrant endothelial structure. These changes were mitigated by treatment with calcitriol. The results of our study showed that animals exposed to AT1 blockade during lactation exhibited altered renal microvasculature differentiation in adulthood that was attenuated by treatment with calcitriol.

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

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 AT1. 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.

Renal developmental disturbances and their long-term consequences in female pups from vitamin D-deficient mothers: involved mechanisms.

The mechanisms involved in kidney disturbances during development, induced by vitamin D3 deficiency in female rats, that persist into adulthood were evaluated in this study. Female offspring from mothers fed normal (control group, n=8) or vitamin D-deficient (Vit.D-, n=10) diets were used. Three-month-old rats had their systolic blood pressure (SBP) measured and their blood and urine sampled to quantify vitamin D3 (Vit.D3), creatinine, Na+, Ca+2 and angiotensin II (ANGII) levels. The kidneys were then removed for nitric oxide (NO) quantification and immunohistochemical studies. Vit.D- pups showed higher SBP and plasma ANGII levels in adulthood (P<0.05) as well as decreased urine osmolality associated with increases in urinary volume (P<0.05). Decreased expression of JG12 (renal cortex and glomeruli) and synaptopodin (glomeruli) as well as reduced renal NO was also observed (P<0.05). These findings showed that renal disturbances in development in pups from Vit.D- mothers observed in adulthood may be related to the development of angiogenesis, NO and ANGII alterations.

Tracking morphological complexities of organ development in culture.

Organogenesis is one of the most striking process during development. During this period, organ primordia pass throughout several stages in which the level of organisation increases in complexity to achieve the final organ architecture. Organ culture, a method in which an isolated organ is explanted and maintained ex-vivo, is an excellent tool for following the morphological dynamics during development. While most of the work has been made in early stages of development, culturing organs in mid-late stages is needed to understand the achievement of the final organ anatomy in the new-born. Here, we investigated the possibility of following morphological changes of the mice heart, lung, kidney and intestine using a filter-grid culture method for 7 days starting at E14.5. We observed that the anatomy, histology and survival of the cultured organs were indicative of a continuity of the developmental processes: they survived and morphodifferentiated during 5-7 days in culture. The exception was the heart, which started to die after 4 days. Using a second approach, we demonstrated that heart tissue can be easily cultured in body slices, together with other tissues such as the lung, with a healthier differentiation and longer survival. The culture method used here, permits a high-resolution imaging to identify the dynamic of organ architecture ex-vivo using morphovideos. We also confirmed the suitability of this system to perform lineage tracing using a vital dye in branching organs. In summary, this work tested the feasibility of monitoring and recording the anatomical changes that establish the final organ structure of the heart, lung, kidney and intestine. Additionally, this strategy allows the morphological study of organ development including fate maps with a relative long-term survival up to the onset of differentiation. This work contributes to elucidating how organs are formed, promoting the understanding of congenital malformations and to design organ replacement therapies.

Growing evidence suggests WT1 effects in the kidney development are modulated by Hsp70/NO interaction.

The study of kidney development at the cellular and molecular levels remains an active area of nephrology research. The functional integrity of the kidney depends on normal development as well as on physiological cell turnover. Apoptosis induction is essential for these mechanisms. A route to cell death revealed in the past decade shows that heat shock proteins (HSPs) and their cofactors are responsible for regulating the apoptotic pathway. Specifically, heat shock protein 70 (Hsp70), the most ubiquitous and highly conserved HSP, helps proteins adopt native conformation or regain function after misfolding. Hsp70 is an important cofactor for the function of Wilms' tumour 1 (WT1) and suggests a potential role for this chaperone during kidney differentiation. In addition, we have demonstrated that WT1 expression is modulated by nitric oxide (NO) availability and Hsp70 interaction after neonatal unilateral ureteral obstruction. NO has been identified as playing an important role in the developing kidney. These findings suggest that Hsp70 and NO may play a critical and fundamental role in the capacity to modulate both apoptotic pathway and oxidative stress during kidney development. Furthermore, the design of experimental protocols that assess renal epithelial functionality in this context, could contribute to the understanding of renal development and alterations.