Abstract-The renin-angiotensin system plays an important role in renal development. However, it is unknown whether reduction in angiotensin II effects during the nephrogenic period leads to different renal alterations in males and females during the adult age. The aim of this study was to evaluate whether the role of angiotensin II on renal development is sex dependent and whether there are sex differences in blood pressure, renal hemodynamics, and severity of renal damage during adult life when nephrogenesis is altered by blocking angiotensin II effects. Newborn Sprague-Dawley rats were treated with an angiotensin II type 1 receptor antagonist (L-158.809; 7 mg/kg per day) during the first 2 weeks of life. At 3 months of age, changes in blood pressure, albuminuria, and renal hemodynamics were assessed, and stereological and histopathologic studies were performed. Blood pressure increased (127Ϯ0.5 versus 115Ϯ0.7 mm Hg in control rats; PϽ0.05) and nephron number decreased (37%; PϽ0.05) similarly in treated males and females. However, only males had an elevation in albuminuria (5.92Ϯ1.65 versus 0.33Ϯ0.09 mg per day in control rats; PϽ0.05), a fall in glomerular filtration rate (12.6%; PϽ0.05), and a significant decrease in papillary volume (42%; PϽ0.05). Mean glomerular volume, glomerulosclerosis, arteriolar hypertrophy, and tubulointerstitial damage in cortex and medulla were also higher (PϽ0.05) in angiotensin II type 1 receptor antagonist-treated males than in treated females. The results of this study suggest that females seem to be more protected than males to the renal consequences of reducing angiotensin II effects during renal development.

Abstract-We have demonstrated that the reduction of angiotensin II effects during the nephrogenic period reduces the nephron number and induces the development of hypertension. The hypotheses examined are that this reduction of angiotensin effects leads to the development of an age-dependent sodium sensitive hypertension and that the hypertension is angiotensin II dependent. Newborn rats were treated with an angiotensin II type 1 receptor antagonist during the first 2 weeks of age. At 3 to 4 and 11 to 12 months of age, changes in systolic blood pressure, proteinuria, and renal function in response to a prolonged high sodium intake were examined. The basal blood pressure response to the administration of the angiotensin II receptor antagonist was also evaluated at both ages. Basal blood pressure was similarly elevated (PϽ0.05) in male and female treated rats, and the increment was age dependent. High sodium intake only elicited a blood pressure elevation (136Ϯ1 to 154Ϯ3 mm Hg; PϽ0.05) and a decrease in glomerular filtration rate (28%; PϽ0.05) at 11 to 12 months in treated rats. Blockade of angiotensin II receptors during renal development induced an increase (PϽ0.05) in proteinuria that was age and sex dependent, but high sodium intake only induced an elevation in proteinuria in the younger rats (50%; PϽ0.05). Hypertension was maintained by angiotensin II at both ages because blood pressure decreased to normal levels after treatment with an angiotensin II type 1 receptor antagonist. This study shows that the reduction of angiotensin II effects during the nephrogenic period modifies renal function and induces the development of an angiotensin II-dependent hypertension that becomes sodium sensitive during aging. T he importance of nephron number in the development of hypertension and renal dysfunction is supported by experimental and clinical studies [1][2][3][4][5][6][7][8][9] demonstrating that the alteration of nephrogenesis regulation leads to significant changes in arterial pressure and renal function during the adulthood. These effects of the reduction in nephron number during renal development seem to be more significant than those elicited by a decrease in nephron number later in life. 2 One mechanism that is involved in the regulation of nephrogenesis is the renin-angiotensin system (RAS). The role of RAS has been confirmed in previous studies of our group demonstrating that the blockade of the angiotensin II (Ang II) type 1 (AT 1 ) receptors during the late nephrogenic period reduces nephron number by 37%, induces the development of hypertension, and elicits important renal changes that are greater in male than in female rats. 7,8 An age-and sexdependent increment in proteinuria is observed in rats when the effects of Ang II via the AT 1 receptor are reduced during the nephrogenic period. 7,8 These rats also have a decrease in renal functional reserve, because the response to an increment in plasma amino acid levels is deteriorated, and their renal excretory ability to eliminate an acute sodium load is im...

This study was designed to test the hypothesis that blockade of angiotensin II effects during renal development accelerates the aging-related changes in renal hemodynamics and proteinuria, and that these changes are sex dependent. It has also been examined whether the deterioration of urinary concentrating ability elicited by angiotensin II blockade is sex and/or aging dependent. Newborn Sprague-Dawley rats were treated with vehicle or an AT(1) angiotensin II receptor antagonist (ARA) during the first 14 postnatal days. Blood pressure, glomerular filtration rate, proteinuria, and urinary concentrating ability in response to dehydration were examined in conscious rats at 3 and 11 mo of age. ARA treatment elicited a similar increment in blood pressure in males and females that was greater (P < 0.05) at 11 than at 3 mo of age. Glomerular filtration rate only decreased (P < 0.05) in 11-mo-old male ARA-treated rats (0.59 +/- 0.07 vs. 0.80 +/- 0.07 ml.min(-1).g(-1) in control group). At 3 mo of age, proteinuria increased in male (107%) but not in female ARA-treated rats. However, at 11 mo of age, proteinuria increased in both sexes, but the increment was greater (P < 0.05) in male (244%) than in female (138%) ARA-treated rats. Renal ability to concentrate urine in response to prolonged water dehydration was only reduced in ARA-treated males. The reduction of urinary concentrating ability was accentuated by aging. Therefore, we conclude that blockade of angiotensin II effects during renal development elicits an important deterioration of cortical and medullary function that is sex and aging dependent.

The aim was to evaluate whether blockade of ANG II effects during renal development modifies the renal response to an increment of plasma amino acid concentration. It was also examined in anesthetized rats whether the reduction of the renal ability to eliminate an acute volume expansion (VE), elicited by blockade of ANG II during renal development, is sex and/or age dependent. Newborn Sprague-Dawley rats were treated with vehicle or an AT1-receptor antagonist (ARA) during postnatal nephrogenesis. Amino acid infusion induced increments ( P < 0.05) of glomerular filtration rate (31 ± 6%) and renal plasma flow (26 ± 5%) in male but not in female vehicle-treated rats. Natriuretic and diuretic responses to amino acid infusion were similar in male and female vehicle-treated rats. These renal hemodynamics and excretory responses to amino acid infusion were abolished in ARA-treated rats. Renal responses to VE were evaluated at 3–4 and 9–10 mo of age in vehicle and ARA-treated rats. VE-induced natriuresis and diuresis were reduced by more than 38% ( P < 0.05) in 3- to 4-mo-old male and female ARA-treated rats. An age-dependent reduction ( P < 0.05) in the renal ability to eliminate VE was found in male but not in female rats treated with ARA. Our results demonstrate that the renal effects induced by an increment in amino acids are abolished when ANG II effects have been reduced during nephrogenesis. In addition, this reduction of ANG II effects elicits an impairment of the renal ability to eliminate an acute VE in males and females, which is aggravated by age only in male rats.

Fructose consumption has increased because of widespread use of high-fructose corn syrup by the food industry. Renal proximal tubules are thought to reabsorb fructose. However, fructose reabsorption (Jfructose) by proximal tubules has not yet been directly demonstrated, nor the effects of dietary fructose on Jfructose. This segment expresses Na+- and glucose-linked transporters (SGLTs) 1, 2, 4, and 5 and glucose transporters (GLUTs) 2 and 5. SGLT4 and -5 transport fructose, but SGLT1 and -2 do not. Knocking out SGLT5 increases urinary fructose excretion. We hypothesize that Jfructose in the S2 portion of the proximal tubule is mediated by luminal entry via SGLT4/5 and basolateral exit by GLUT2 and that it is enhanced by a fructose-enriched diet. We measured Jfructose by proximal straight tubules from rats consuming either tap water (Controls) or 20% fructose (FRU). Basal Jfructose in Controls was 14.1 ± 1.5 pmol·mm−1·min−1. SGLT inhibition with phlorizin reduced Jfructose to 4.9 ± 1.4 pmol·mm−1·min−1 ( P < 0.008), whereas removal of Na+ diminished Jfructose by 86 ± 5% ( P < 0.0001). A fructose-enriched diet increased Jfructose from 12.8 ± 2.5 to 19.3 ± 0.5 pmol·mm−1·min−1, a 51% increase ( P < 0.03). Using immunofluorescence, we detected luminal SGLT4 and SGLT5 and basolateral GLUT2; GLUT5 was undetectable. The expression of apical transporters SGLT4 and SGLT5 was higher in FRU than in Controls [137 ± 10% ( P < 0.01) and 38 ± 14% ( P < 0.04), respectively]. GLUT2 was also elevated by 88 ± 27% ( P < 0.02) in FRU. We conclude that Jfructose by proximal tubules occurs primarily via Na+-linked cotransport processes, and a fructose-enriched diet enhances reabsorption. Transport across luminal and basolateral membranes is likely mediated by SGLT4/5 and GLUT2, respectively.