Prenatal programming of rat thick ascending limb chloride transport by low-protein diet and dexamethasone

Abstract

Dagan A, Habib S, Gattineni J, Dwarakanath V, Baum M. Prenatal programming of rat thick ascending limb chloride transport by low-protein diet and dexamethasone. Am J Physiol Regul Integr Comp Physiol 297: R93-R99, 2009. First published April 29, 2009 doi:10.1152/ajpregu.91006.2008.-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 Ͻ 0.01). There was not a statistically significant increase in medullary NKCC2 by prenatal dexamethasone (P ϭ 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 Ϯ 33 pmoles ⅐ mm Ϫ1 ⅐ min Ϫ1 , 280 Ϯ 26 pmoles ⅐ mm Ϫ1 ⅐ min Ϫ1 , and 191 Ϯ 21 pmoles ⅐ mm Ϫ1 ⅐ min Ϫ1 , respectively P Ͻ 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. prenatal programming; hypertension; microperfusion; furosemide PRENATAL INSULTS TO THE DEVELOPING fetus have been shown to cause hypertension and cardiovascular disease in later life (2-5, 43, 43). Animal models have been used to elucidate the pathogenesis of the hypertension, as well as other sequela of prenatal insults. The two best studied prenatal insults that cause postnatal hypertension in rodents are maternal dietary protein deprivation and prenatal administration of glucocorticoids (14, 15, 28, 30 -34, 38, 40 -42). In both prenatal dietary protein deprivation and prenatal administration of dexamethasone, there are distinct times during gestation when these insults are associated with hypertension. We have shown that prenatal dexamethasone-programmed hypertension in rats when administered between 15 and 18 days of gestation, but not before or after this time (41). Similarly, dietary protein deprivation results in hypertension when administered in the second half, bu...

Segmental sodium reabsorption by the renal tubule in prenatally programmed hypertension in the rat

“…If the reported increase in NKCC2 in the LP kidney [14][15][16] was associated with greater sodium reabsorption, one might expect to see a reduction in FE Na distal in LP rats infused with AM+BF (i.e., outflow from the TAL). This was not the case.…”

“…Dexamethasone exposure is associated with an increase in tubular expression of the sodium:hydrogen exchanger type-3 (NHE3 located in the proximal tubule), the bumetanide-sensitive sodium:potassium:chloride (Na + : K + :2Cl -) cotransporter [NKCC2 or BSC1, located in the thick ascending limb (TAL)], and the thiazide-sensitive Na + :Cl -cotransporter (NCC or TSC, located in the distal tubule); however, the amiloride (AM)-sensitive epithelial sodium channel (ENaC, located in the collecting duct) is unaltered [12,13]. In the LP model, NHE-3 and ENaC are unaltered but NKCC2 and, in some reports, NCC are increased [14][15][16]. One group also described increased renal Na + :K + adenosine triphosphatase (ATPase_-α 1 and-β 1 subunit messenger RNA (mRNA) expression in LP rat kidneys [17], whereas we have shown that whole-kidney Na + :K + ATPase pump activity and expression of the α 1 subunit in the inner medulla are reduced markedly [15].…”

Effect of Postnatal Maternal Protein Intake on Prenatal Programming of Hypertension

“…46,47 Finally, previous studies have shown that maternal dietary protein deprivation programs an increase in NKCC2 and NCC in adult offspring and prenatal dexamethasone increases these transporters as well as NHE3. 8,12,14,18 In the previous studies, the mothers were reared by the same mothers administered a low-protein diet or prenatal dexamethasone. As shown in …”

“…[1][2][3] Many animal studies have shown that prenatal insults leading to small for gestational age offspring result in hypertension and a reduction in glomerular number when offspring are studied as adults. [4][5][6][7][8][9][10][11][12] The pathogenesis of the hypertension resulting from prenatal insults has been shown to be multifactorial and involves more than just a reduction in nephron number. [12][13][14][15] Factors such as activation of the renin-angiotensin system, an increase in renal sodium transport, and an increase in sympathetic tone may contribute to the hypertension with prenatal programming.…”

Luminal angiotensin II stimulates rat medullary thick ascending limb chloride transport in the presence of basolateral norepinephrine

“…At least four measurements were carried out per period, and the mean of the collections in each period was used to represent the chloride absorption for that period. We have previously demonstrated that passive chloride transport in mTAL is not detectable (11).…”