Role of the kidney in the prenatal and early postnatal programming of hypertension

Abstract

Epidemiologic studies from several different populations have demonstrated that prenatal insults, which adversely affect fetal growth, result in an increased incidence of hypertension when the offspring reaches adulthood. It is now becoming evident that low-birth-weight infants are also at increased risk for chronic kidney disease. To determine how prenatal insults result in hypertension and chronic kidney disease, investigators have used animal models that mimic the adverse events that occur in pregnant women, such as dietary protein or total caloric deprivation, uteroplacental insufficiency, and prenatal administration of glucocorticoids. This review examines the role of the kidney in generating and maintaining an increase in blood pressure in these animal models. This review also discusses how early postnatal adverse events may have repercussions in later life. Causes for the increase in blood pressure by perinatal insults are likely multifactorial and involve a reduction in nephron number, dysregulation of the systemic and intrarenal renin-angiotensin system, increased renal sympathetic nerve activity, and increased tubular sodium transport. Understanding the mechanism for the increase in blood pressure and renal injury resulting from prenatal insults may lead to therapies that prevent hypertension and the development of chronic kidney and cardiovascular disease.

Fig. 1.

Effect of prenatal dexamethasone (Dex) on blood pressure and glomerular number in the rat. Prenatal dexamethasone was administered to pregnant rats on the specific days of gestation noted (0.2 mg/kg body wt daily for 2 days). Blood pressure (BP) and glomerular number were measured in adult male rats. As is evident, there was a discrete period of time when prenatal dexamethasone programs hypertension and a reduction in nephron number. [From Ortiz LA et al. (100).]

Fig. 2.

Effect of prenatal low-protein diet on blood pressure in rats of various ages. Systolic blood pressure was measured by tail cuff in adult male (top) and female (bottom) rats whose mothers were fed a low-protein diet (6%) during the last half of pregnancy and compared with rats fed a normal protein diet (20%). There was a progressive increase of blood pressure with age in the low-protein group. Data are means ± SE; *P < 0.05; ***P < 0.001 [From Vehaskari et al. (137).]

Fig. 3.

Effect of prenatal dexamethasone and prenatal dietary protein deprivation on thick ascending limb chloride transport. Medullary thick ascending limb (MTAL) chloride transport (J_Cl) from adult rats whose mothers were exposed either to prenatal dexamethasone (0.2 mg/kg body wt daily on days 15–18 gestation) or a low-protein diet during the last half of pregnancy. Both prenatal dexamethasone and dietary protein deprivation programmed an increase in MTAL chloride transport in adult rats compared with control when studied using in vitro microperfusion. [From Dagan et al. (35).]

Fig. 4.

Effect of furosemide on blood pressure control and rats whose mothers were fed a low-protein diet. Blood pressure was measured in control male rats and male rats whose mothers were fed a low-protein diet during the last half of pregnancy. Furosemide was then added to the drinking water, and the blood pressure was measured the next day. There was no effect of furosemide on blood pressure in control rats, but blood pressure decreased in the prenatal low-protein group. Veh, vehicle. [From Dagan et al. (35).]

Fig. 5.

Effect of renal denervation on blood pressure in rats exposed to prenatal dexamethasone. Rats whose mothers were treated with prenatal dexamethasone (0.2 mg/kg body wt) daily on days 15–18 of gestation or vehicle underwent either a sham operation or renal denervation at 6 wk of age and blood pressure was measured at 8 wk. Prenatal dexamethasone caused an increase in blood pressure that was prevented by renal denervation. [From Dagan et al. (36).]

Fig. 6.

Effect of renal denervation on Na⁺/H⁺ exchanger (NHE3), bumetanide-sensitive cotransporter (NKCC2), and thiazide-sensitive cotransporter (NCC) protein abundance in rats exposed to prenatal dexamethasone. Adult rats whose mothers were treated with prenatal dexamethasone (0.2 mg/kg body wt daily) on days 15–18 of gestation or vehicle underwent either a sham operation or renal denervation at 6 wk of age. Renal NHE3, NKCC2, and NCC protein abundance were determined by immunoblot. Prenatal dexamethasone increased the abundance of each of these transporters in adult rats, and the abundance decreased to control levels with denervation. There was no effect of prenatal dexamethasone or denervation on epithelial sodium channel protein abundance (not shown). [From Dagan et al. (36).]