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Published on: November 20, 2015
Prenatal programming of rat thick ascending limb chloride transport by low-protein diet and dexamethasone
Amit Dagan1, Sabeen Habib, Jyothsna Gattineni
1Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9063, USA.
Insights
Prenatal exposure to dexamethasone or a low-protein diet programs adult offspring hypertension by increasing kidney sodium transport. This study reveals how fetal insults alter kidney function, leading to high blood pressure later in life.
Area of Science:
- Nephrology
- Developmental Biology
- Endocrinology
Background:
- Prenatal exposure to dexamethasone and low-protein diets are known to cause adult-onset hypertension in offspring.
- The underlying mechanisms, particularly concerning renal transport, remain largely unknown.
Purpose of the Study:
- To investigate the prenatal programming of thick ascending limb (TAL) transport in the kidneys.
- To determine if fetal insults affect sodium-potassium-2-chloride cotransporter (NKCC2) expression and TAL chloride transport.
Main Methods:
- Rat dams received dexamethasone or a low-protein diet during gestation.
- Offspring were assessed as adults for blood pressure, medullary and cortical NKCC2 protein abundance, and TAL chloride transport.
- Transepithelial potential difference and furosemide's effect on blood pressure were also measured.
Main Results:
- Both prenatal dexamethasone and low-protein diet increased offspring blood pressure.
- Low-protein diet increased medullary NKCC2, while dexamethasone showed a non-significant trend.
- Both interventions elevated medullary TAL chloride transport and lumen-positive transepithelial potential difference.
Conclusions:
- Fetal insults can program altered renal sodium transport, contributing to hypertension.
- Increased tubular sodium reabsorption in the TAL is a likely mechanism for dexamethasone- and low-protein diet-induced hypertension.
Abstract:
Prenatal administration of dexamethasone and a low-protein diet has been shown to result in hypertension in the offspring when they are adults. The cause for the hypertension is unknown. The purpose of this study was to examine whether there was prenatal programming of thick ascending limb transport. Rats were administered either dexamethasone for 4 days (0.2 mg/kg body wt) by intraperitoneal injection daily between the 15th and 18th day of gestation, or they were fed a low-protein diet (6% protein) or an isocaloric normal protein diet (20% protein) from day 12 gestation until birth. The offspring were studied as adults. Prenatal dexamethasone and dietary protein deprivation resulted in an increase in blood pressure. Offspring of mothers fed a low-protein diet had an increase in medullary but not cortical bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) protein abundance (P < 0.01). There was not a statistically significant increase in medullary NKCC2 by prenatal dexamethasone (P = 0.07). Both prenatal administration of dexamethasone and a low-protein diet resulted in an increase in medullary thick ascending limb chloride transport compared with control (298 +/- 33 pmoles x mm(-1) x min(-1), 280 +/- 26 pmoles x mm(-1) x min(-1), and 191 +/- 21 pmoles x mm(-1) x min(-1), respectively P < 0.05). There was a higher lumen-positive transepithelial potential difference in the prenatal dexamethasone and low-protein group compared with control as well. Administration of furosemide for 24 h resulted in a decrease in blood pressure in the low-protein group but not the control group. This study demonstrates that insults administered to the fetus can program altered sodium transport. Increased tubular sodium transport is a likely cause for the hypertension by prenatal programming.
