Fetal Programming of Renal Dysfunction and High Blood Pressure by Chronodisruption

Abstract

Adverse prenatal conditions are known to impose significant trade-offs impinging on health and disease balance during adult life. Among several deleterious factors associated with complicated pregnancy, alteration of the gestational photoperiod remains largely unknown. Previously, we reported that prenatal manipulation of the photoperiod has adverse effects on the mother, fetus, and adult offspring; including cardiac hypertrophy. Here, we investigated whether chronic photoperiod shifting (CPS) during gestation may program adult renal function and blood pressure regulation. To this end, pregnant rats were subjected to CPS throughout pregnancy to evaluate the renal effects on the fetus and adult offspring. In the kidney at 18 days of gestation, both clock and clock-controlled gene expression did not display a daily pattern, although there were recurrent weaves of transcriptional activity along the 24 h in the control group. Using DNA microarray, significant differential expression was found for 1,703 transcripts in CPS relative to control fetal kidney (835 up-regulated and 868 down-regulated). Functional genomics assessment revealed alteration of diverse gene networks in the CPS fetal kidney, including regulation of transcription, aldosterone-regulated Na+ reabsorption and connective tissue differentiation. In adult offspring at 90 days of age, circulating proinflammatory cytokines IL-1β and IL-6 were increased under CPS conditions. In these individuals, CPS did not modify kidney clock gene expression but had effects on different genes with specific functions in the nephron. Next, we evaluated several renal markers and the response of blood pressure to 4%NaCl in the diet for 4 weeks (i.e., at 150 days of age). CPS animals displayed elevated systolic blood pressure in basal conditions that remained elevated in response to 4%NaCl, relative to control conditions. At this age, CPS modified the expression of Nhe3, Ncc, Atp1a1, Nr3c1 (glucocorticoid receptor), and Nr3c2 (mineralocorticoid receptor); while Nkcc, Col3A1 , and Opn were modified in the CPS 4%+NaCl group. Furthermore, CPS decreased protein expression of Kallikrein and COX-2, both involved in sodium handling. In conclusion, gestational chronodisruption programs kidney dysfunction at different levels, conceivably underlying the prehypertensive phenotype observed in the adult CPS offspring.

Light Environment Influences Developmental Programming of the Metabolic and Visual Systems in Mice

“…3), although the glucose results may be due to disruption and timing of sample collection rather than mean differences since we did not take multiple measurements at specific time intervals. In offspring, maternal environmental circadian disruption causes increased adiposity, hyperleptinemia, 22 altered glucose handling, 22,31 anxiety-like behavior, 6 and increased blood pressure 31,52 ; however, previous studies have not characterized the effects on the visual system. In this study, metabolic outcomes exhibited clear sex differences (see Figs.…”

Chronodisruption: A Poorly Recognized Feature of CKD

“…However, in a Korean study, the risk of CKD was two-fold higher in female shift workers than in female non-shift workers, although there were no differences in males [66]. In experimental animals, maternal chronic photoperiod shifting during gestation led to kidney gene expression changes in the offsprings, including the expression of sodium handling genes subject to circadian rhythms, and higher blood pressure values [27].…”

“…They additionally proposed that assessment of melatonin levels in saliva, urine and blood may be a robust biomarker of chronodisruption. While in some fields the concept was immediately grasped (In 2007, the International Agency for Research on Cancer classified shift-work that involves circadian disruption as probably carcinogenic to humans), it was not until 2013 that the term chronodisruption was used in the context of CKD [26] and only in 2019 was a second manuscript published on the topic [27]. While this is surprising given the chronic nature of CKD, its similarities with aging and the widely known fact that circadian rhythms may be disturbed in CKD, it does not mean that the nephrological community is not aware of disruption of circadian rhythms in CKD.…”

Effects of sleep modulation during pregnancy in the mother and offspring: Evidences from preclinical research

“…Likewise, chronodisruption during pregnancy is also associated with increased blood pressure and renal dysfunction (Mendez et al, 2019).…”