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Upregulation of renal BSC1 and TSC in prenatally programmed hypertension
Jennifer Manning1, Kathleen Beutler, Mark A Knepper
1Division of Pediatric Nephrology, Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70118, USA.
Insights
Prenatal protein restriction in rats programs adult hypertension by increasing renal sodium transporters. Specifically, the bumetanide-sensitive Na-K-2Cl cotransporter (BSC1) and thiazide-sensitive Na-Cl cotransporter (TSC) show elevated levels and mRNA, suggesting transcriptional upregulation.
Area of Science:
- Nephrology
- Developmental Biology
- Cardiovascular Physiology
Background:
- Prenatal factors, particularly intrauterine growth retardation, are linked to adult essential hypertension.
- The underlying mechanisms connecting prenatal conditions to hypertension remain largely unknown.
- Renal sodium reabsorption is a key regulator of blood pressure.
Purpose of the Study:
- To investigate the role of renal sodium transporters in the prenatal programming of hypertension.
- To examine the impact of a maternal low-protein diet during pregnancy on offspring kidney function.
- To identify specific sodium transporters involved in the early pathogenesis of hypertension.
Main Methods:
- Utilized an experimental rat model of prenatal hypertension programming via maternal low-protein diet.
- Assessed the abundance of key renal sodium transporters (NHE3, BSC1, TSC, ENaC) using semiquantitative immunoblotting.
- Quantified specific mRNA levels of BSC1 and TSC via ELISA-linked RT-PCR at various ages.
Main Results:
- Offspring from protein-restricted pregnancies showed significantly increased abundance of BSC1 (302%) and TSC (157%) in kidneys before hypertension onset.
- Elevated BSC1 mRNA levels were observed at 1 day, 4 weeks, and 8 weeks of age.
- Increased TSC mRNA was detected at 4 weeks of age in the experimental group.
- No significant differences in NHE3 or ENaC subunit abundance were found between groups.
Conclusions:
- Prenatal programming of hypertension involves the upregulation of sodium transport in the thick ascending limb and distal convoluted tubule.
- Transcriptional changes in BSC1 and TSC contribute to the early development of hypertension.
- This study provides insights into the molecular mechanisms linking prenatal nutrition to adult cardiovascular health.
Abstract:
Prenatal factors, especially intrauterine growth retardation, have been shown to correlate with the risk of essential hypertension in adult life, but the mechanisms are unknown. An experimental model of prenatal programming of hypertension in the rat, induced by a maternal low-protein diet during pregnancy, was employed to study the role of renal Na reabsorption in the pathogenesis. The abundance of the apical Na transporter type III Na/H exchanger (NHE3), bumetanide-sensitive Na-K-2Cl cotransporter (BSC1), thiazide-sensitive Na-Cl cotransporter (TSC), and the amiloride-sensitive epithelial Na channel (ENaC) was determined by semiquantitative immunoblotting in kidneys from the offspring at 4 wk of age, before hypertension became manifest. There were no significant differences between the experimental and control rats in the abundance of NHE3 or any of the ENaC subunits. In contrast, the quantity of BSC1 in the experimental group was increased to 302% of control (P < 0.001) and that of TSC to 157% of control (P < 0.05). Determination of specific mRNA levels by ELISA-linked RT-PCR revealed a significantly increased BSC1 mRNA at 1 day (P < 0.01), 4 wk (P < 0.01), and 8 wk (P < 0.001) of age, and a significantly increased TSC mRNA at 4 wk of age (P < 0.05) in the experimental group. The results suggest that prenatal programming of hypertension involves transcriptional upregulation of Na transport in thick ascending limb and distal convoluted tubule.