Prenatal programming of rat thick ascending limb chloride transport by low-protein diet and dexamethasone.
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.
Dagan
Amit
A
Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9063, USA.
Habib
Sabeen
S
Gattineni
Jyothsna
J
Dwarakanath
Vangipuram
V
Baum
Michel
M
D000375:Aging; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001692:Biological Transport; D001794:Blood Pressure / Q000187:drug effects; D002712:Chlorides / Q000378:metabolism*; D003907:Dexamethasone / Q000008:administration & dosage / Q000633:toxicity*; D018753:Diet, Protein-Restricted / Q000009:adverse effects*; D005260:Female; D005665:Furosemide / Q000494:pharmacology; D005865:Gestational Age; D005938:Glucocorticoids / Q000008:administration & dosage / Q000633:toxicity*; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D007274:Injections, Intraperitoneal; D007700:Kinetics; D008138:Loop of Henle / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1
D000959:Antihypertensive Agents; D002712:Chlorides; D005938:Glucocorticoids; C578716:Slc12a1 protein, rat; D049994:Sodium Potassium Chloride Symporter Inhibitors; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D005665:Furosemide; D003907:Dexamethasone