Sexual Dimorphism in Urinary Angiotensinogen Excretion During Chronic Angiotensin II−Salt Hypertension

Abstract

Background The intrarenal renin–angiotensin system contributes to hypertension by regulating sodium and water reabsorption throughout the nephron. Sex differences in the intrarenal components of the renin–angiotensin system have been involved in the greater incidence of high blood pressure and progression to kidney damage in males than females. Objective This study investigated whether there is a sex difference in the intrarenal gene expression and urinary excretion of angiotensinogen (AGT) during angiotensin II (Ang II)–dependent hypertension and high-salt (HS) diet. Methods Male and female Sprague-Dawley rats were divided into 5 groups for each sex: Normal-salt control, HS diet (8% NaCl), Ang II–infused (80 ng/min), Ang II–infused plus HS diet, and Ang II–infused plus HS diet and treatment with the Ang II receptor blocker, candesartan (25 mg/L in the drinking water). Rats were evaluated for systolic blood pressure (SBP), kidney AGT mRNA expression, urinary AGT excretion, and proteinuria at different time points during a 14-day protocol. Results Both male and female rats exhibited similar increases in urinary AGT, with increases in SBP during chronic Ang II infusion. HS diet greatly exacerbated the urinary AGT excretion in Ang II–infused rats; males had a 9-fold increase over Ang II alone and females had a 2.5-fold increase. Male rats displayed salt-sensitive SBP increases during Ang II infusion and HS diet, and female rats did not. In the kidney cortex, males displayed greater AGT gene expression than females during all treatments. During Ang II infusion, both sexes exhibited increases in AGT gene message compared with same-sex controls. In addition, HS diet combined with Ang II infusion exacerbated the proteinuria in both sexes. Concomitant Ang II receptor blocker treatment during Ang II infusion and HS diet decreased SBP and urinary AGT similarly in both sexes; however, the decrease in proteinuria was greater in the females. Conclusion During Ang II–dependent hypertension and HS diet, higher intrarenal renin-angiotensin system activation in males, as reflected by higher AGT gene expression and urinary excretion, indicates a mechanism for greater progression of high blood pressure and might explain the sex disparity in development of salt-sensitive hypertension.

6β-Hydroxytestosterone, a Cytochrome P450 1B1-Testosterone–Metabolite, Mediates Angiotensin II–Induced Renal Dysfunction in Male Mice

“…34,50 Ang II infusion increased renal expression and urinary excretion of AGT in male rats, suggesting that there is an increased AGT availability for conversion to Ang II in kidneys. 13,34,51–54 In Dahl-salt sensitive male rats, a high salt diet increased intrarenal AGT expression, BP, proteinuria and glomerolosclerosis, which were prevented by castration and restored by administering testosterone, suggesting that Ang II-induced intrarenal AGT production depends on androgens. 55 Our previous study showing that Ang II stimulated production of testosterone metabolite 6β-OHT via CYP1B1 33 together with the demonstration that the Ang II-induced increase in urinary excretion of AGT was inhibited by Cyp1b1 gene disruption or castration in Cyp1b1 +/+ mice, and that treatment with 6β-OHT restored the increase in urinary excretion of AGT in these mice suggest that 6β-OHT contributes to Ang II- induced intrarenal AGT production.…”

“…4–10 Testosterone stimulates the expression of renal angiotensinogen (AGT) or urinary excretion of AGT in SHRs and in Ang II-high salt (HS) diet-induced hypertension. 11–13 Moreover, castration decreases expression of renal renin and AGT and hepatic AGT in male SHRs. 11,12 Ang II infusion also increases Ang II type 1 receptor (AT1a) expression in male SHRs 14 or alters the Ang II type 2 receptor (AT2) to AT1a receptor balance in kidneys of male SHRs.…”

The accumulation of brain water-free sodium is associated with ischemic damage independent of the blood pressure in female rats

“…Rands et al (2012) reported that male rats display salt-sensitive BP increases during Ang II infusion and the ingestion of HSD while female rats do not. Their findings support our observation of sex differences in salt sensitivity.…”

“…Although the detailed mechanisms underlying this sex difference remain obscure, they may involve disturbance of the function of the renin-angiotensin-aldosterone system (RAAS) (Rands et al, 2012) and oxidative stress (Sartori-Valinotti et al, 2008). Estrogen deficiency exacerbates experimental ischemic brain damage in rats (Shimada et al, 2011).…”

Salt Loading Promotes Kidney Injury via Fibrosis in Young Female Ren2 Rats

“…Our use of the transgenic female Ren2 rat suggests that salt requires excess Ang II and/or aldosterone to precipitate impaired handling of protein. Previous work in this area suggests that increases in proteinuria under conditions of Ang II infusion require 8% of salt intake over 2 weeks [20], while in congenic Ren2:Lewis rats treatment with an agonist of the G protein-coupled estrogen receptor 30 improved proteinuria under a 4%-salt diet [21]. Data from this same study also suggests a higher level of immunostaining of G protein-coupled estrogen receptor 30 in the proximal tubule in this model of excess tissue Ang II, which would support a role for estrogen in Ang II-dependent proximal tubule handling of protein.…”