BET Proteins Regulate Expression of Osr1 in Early Kidney Development

In utero renal development is subject to maternal metabolic and environmental influences affecting long-term renal function and the risk of developing chronic kidney failure and cardiovascular disease. Epigenetic processes have been implicated in the orchestration of renal development and prenatal programming of nephron number. However, the role of many epigenetic modifiers for kidney development is still unclear. Bromodomain and extra-terminal domain (BET) proteins act as histone acetylation reader molecules and promote gene transcription. BET family members Brd2, Brd3 and Brd4 are expressed in the nephrogenic zone during kidney development. Here, the effect of the BET inhibitor JQ1 on renal development is evaluated. Inhibition of BET proteins via JQ1 leads to reduced growth of metanephric kidney cultures, loss of the nephron progenitor cell population, and premature and disturbed nephron differentiation. Gene expression of key nephron progenitor transcription factor Osr1 is downregulated after 24 h BET inhibition, while Lhx1 and Pax8 expression is increased. Mining of BRD4 ChIP-seq and gene expression data identify Osr1 as a key factor regulated by BRD4-controlled gene activation. Inhibition of BRD4 by BET inhibitor JQ1 leads to downregulation of Osr1, thereby causing a disturbance in the balance of nephron progenitor cell self-renewal and premature differentiation of the nephron, which ultimately leads to kidney hypoplasia and disturbed nephron development. This raises questions about the potential teratogenic effects of BET inhibitors for embryonic development. In summary, our work highlights the role of BET proteins for prenatal programming of nephrogenesis and identifies Osr1 as a potential target of BET proteins.

Sex difference in blood pressure, a combinatorial consequence of the differential in RAAS components, sex hormones and time course

: The longitudinal increment of blood pressure (BP) with age is attributed to lifestyle, internal and external environments. It is not limited to systemic brain-derived neurotrophic factor (BDNF), signaling to allow the individuals to better adapt to the developmental and environmental change. This regulation is necessary for all lives, regardless of sex. Basic levels of renin-angiotensin- aldosterone system (RAAS) components in males and females define the fundamental sex difference in BP, which may be set by prenatal programming and profoundly influence BP after birth. The innate sex difference in BP is magnified during puberty growth and further modified by menopause. At the age of 70 or older, blood pressure was similar in men and women. The understanding of the prenatal setup and development of sexual dimorphism in BP may provide preventative therapeutic strategies, including timing and drugs, for individuals with abnormal BP.

Sex differences in prenatal programming of hypertension by dexamethasone

Prenatal dexamethasone has been shown to increase blood pressure in male offspring but the mechanism for the increase in blood pressure is unclear. The present study examined if prenatal programming by maternal injection of dexamethasone on days 15 and 16 of gestation affected the blood pressure comparably in female and male offspring. Our hypothesis was that males would be affected by prenatal dexamethasone to a greater extent than females and that either an increase in renal tubular transporter abundance or an increase in renin or aldosterone system would be associated with hypertension with prenatal programming. Prenatal dexamethasone increased blood pressure at two months and six months of age and resulted in proteinuria and albuminuria at six months in male but not female rat offspring. There was no effect of prenatal dexamethasone on blood pressure and proteinuria at one month in male and in female offspring. While prenatal dexamethasone increased male renal thick ascending limb sodium potassium two chloride cotransporter protein abundance at two months, prenatal dexamethasone on days 15 and 16 of gestation did not affect transporter abundance in males at other ages, nor did it affect proximal tubule sodium/hydrogen exchanger or distal convoluted tubule sodium chloride cotransporter protein abundance at any age. There was no difference in systemic renin or aldosterone in the prenatal dexamethasone group compared to same sex controls. In conclusion, male but not female offspring have an increase in blood pressure and urinary protein excretion with prenatal dexamethasone. The increase in blood pressure with prenatal programming was not associated with a consistent increase in renal tubular transporter protein abundance, nor plasma renin activity and serum aldosterone.

PERINATAL EFFECTS AND RISK OF ARTERIAL HYPERTENSION IN CHILDREN (PART 2)

The article presents data about maternal and prenatal influences lead to «programming» of arterial hypertension (AH) in the child's later life. A special group that is threatened by the development of AH at an older age is premature children and children with intrauterine development delay due to a small number of nephrons and the launch of prenatal programming of hypertension. The state of the mother's health before conception, as well as the use of assisted reproductive technologies, despite a normal pregnancy in general and the birth of a healthy newborn can provoke the development of hypertension in childhood.