Sex differences exist in the regulation of arterial pressure and renal function by the renin-angiotensin system (RAS). This may in part stem from a differential balance in the pressor and depressor arms of the RAS. In males, the ACE/AngII/AT(1)R pathways are enhanced, whereas, in females, the balance is shifted towards the ACE2/Ang(1-7)/MasR and AT(2)R pathways. Evidence clearly demonstrates that premenopausal women, as compared to aged-matched men, are protected from renal and cardiovascular disease, and this differential balance of the RAS between the sexes likely contributes. With aging, this cardiovascular protection in women is lost and this may be related to loss of estrogen postmenopause but the possible contribution of other sex hormones needs to be further examined. Restoration of these RAS depressor pathways in older women, or up-regulation of these in males, represents a therapeutic target that is worth pursuing.

The mechanism of albuminuria is perhaps one of the most complex yet important questions in renal physiology today. Recent studies have directly demonstrated that the normal glomerulus filters substantial amounts of albumin and that charge selectivity plays little or no role in preventing this process. This filtered albumin is then processed by proximal tubular cells by two distinct pathways; dysfunction in either one of these pathways gives rise to discrete forms of albuminuria. Most of the filtered albumin is returned to the peritubular blood supply by a retrieval pathway. Albuminuria in the nephrotic range would arise from retrieval pathway dysfunction. The small quantities of filtered albumin that are not retrieved undergo obligatory lysosomal degradation before urinary excretion as small peptide fragments. This degradation pathway is sensitive to metabolic factors responsible for hypertrophy and fibrosis, particularly molecules such as angiotensin II and transforming growth factor-beta1, whose production is stimulated by hyperglycemic and hypertensive environments. Dysfunction in this degradation pathway leads to albuminuria below the nephrotic range. These new insights into albumin filtration and processing argue for a reassessment of the role of podocytes and the slit diaphragm as major direct determinants governing albuminuria, provide information on how glomerular morphology and "tubular" albuminuria may be interrelated, and offer a new rationale for drug development.

Abstract-Sexual dimorphism in arterial pressure regulation has been observed in humans and animal models. The mechanisms underlying this gender difference are not fully known. Previous studies in rats have shown that females excrete more salt than males at a similar arterial pressure. The renin-angiotensin system is a powerful regulator of arterial pressure and body fluid volume. This study examined the role of the angiotensin type 2 receptor (AT 2 R) in pressure-natriuresis in male and female rats because AT 2 R expression has been reported to be enhanced in females.Renal function was examined at renal perfusion pressures of 120, 100, and 80 mm Hg in vehicle-treated and AT 2 R antagonist-treated (PD123319; 1 mg/kg/h) groups. The pressure-natriuresis relationship was gender-dependent such that it was shifted upward in female vs male rats (PϽ0.001). AT 2 R blockade modulated the pressure-natriuresis relationship, shifting the curve downward in male (PϽ0.01) and female (PϽ0.01) rats to a similar extent. In females, AT 2 R blockade also reduced the lower end of the autoregulatory range of renal blood flow (PϽ0.05) and glomerular filtration rate (PϽ0.01). Subsequently, the renal blood flow response to graded angiotensin II infusion was also measured with and without AT 2 R blockade. We found that AT 2 R blockade enhanced the renal vasoconstrictor response to angiotensin II in females but not in males (PϽ0.05). In conclusion, the AT 2 R modulates pressure-natriuresis, allowing the same level of sodium to be excreted at a lower pressure in both genders. However, a gender-specific role for the AT 2 R in renal autoregulation was evident in females, which may be a direct vascular AT 2 R effect. (Hypertension. 2011;57:275-282.)Key Words: angiotensin type 2 receptor Ⅲ gender differences Ⅲ hypertension Ⅲ natriuresis Ⅲ renal blood flow Ⅲ sodium I t is well-established that women are protected from cardiovascular and renal disease relative to men before menopause. 1 However, the mechanisms responsible for this gender difference are poorly understood, partly because females remain underrepresented in human clinical trials and animal studies. 2,3 Evidence suggests that estrogen plays a protective role against cardiovascular disease in women, 4 and previous studies have identified gender differences in the activity of the renin-angiotensin system (RAS), 1 a major regulator of arterial pressure.Studies in rodents have also revealed major gender differences in the expression of RAS components and differences in the way males and females respond to stimulation and inhibition of the RAS under physiological and pathophysiological circumstances. [5][6][7][8] Recently, with the discovery of angiotensin-converting enzyme 2, a depressor axis to the RAS has been identified 9 that incorporates the angiotensin type 2 receptor (AT 2 R), which is upregulated by estrogen. 7,10 Previously, we have demonstrated that the vasodepressor RAS pathways are enhanced in females and that the AT 2 R has a depressor influence on the response to chronic ang...

Tissue hypoxia has been proposed as an important factor in the pathophysiology of both chronic kidney disease (CKD) and acute kidney injury (AKI), initiating and propagating a vicious cycle of tubular injury, vascular rarefaction, and fibrosis and thus exacerbation of hypoxia. Here, we critically evaluate this proposition by systematically reviewing the literature relevant to the following six questions: (i) Is kidney disease always associated with tissue hypoxia? (ii) Does tissue hypoxia drive signalling cascades that lead to tissue damage and dysfunction? (iii) Does tissue hypoxia per se lead to kidney disease? (iv) Does tissue hypoxia precede pathology? (v) Does tissue hypoxia colocalize with pathology? (vi) Does prevention of tissue hypoxia prevent kidney disease? We conclude that tissue hypoxia is a common feature of both AKI and CKD. Furthermore, at least under in vitro conditions, renal tissue hypoxia drives signalling cascades that lead to tissue damage and dysfunction. Tissue hypoxia itself can lead to renal pathology, independent of other known risk factors for kidney disease. There is also some evidence that tissue hypoxia precedes renal pathology, at least in some forms of kidney disease. However, we have made relatively little progress in determining the spatial relationships between tissue hypoxia and pathological processes (i.e. colocalization) or whether therapies targeted to reduce tissue hypoxia can prevent or delay the progression of renal disease. Thus, the hypothesis that tissue hypoxia is a "common pathway" to both AKI and CKD still remains to be adequately tested.

Abstract-The renin-angiotensin system is a powerful regulator of arterial pressure and body fluid volume. Increasing evidence suggests that the angiotensin type 2 receptor (AT 2 R), which mediates the vasodilatory and natriuretic actions of angiotensin peptides, is enhanced in females and may, therefore, represent an innovative therapeutic target. We investigated the therapeutic potential of direct AT 2 R stimulation on renal function in 11-to 12-week-old anesthetized male and female Sprague-Dawley rats. Renal blood flow was examined in response to a graded infusion of the highly selective, nonpeptide AT 2 R agonist, compound 21 (100, 200, and 300 ng/kg per minute), in the presence and absence of AT 2 R blockade (PD123319; 1 mg/kg per hour). Direct AT 2 R stimulation significantly increased renal blood flow in both males and females, without influencing arterial pressure. This was dose dependent in females only and occurred to a greater extent in females at the highest dose of compound 21 administered (males: 13.1Ϯ2.4% versus females: 23.0Ϯ3.2% change in renal blood flow at 300 ng/kg per minute versus baseline; PϽ0.01). In addition, AT 2 R stimulation significantly increased sodium and water excretion to a similar extent in males and females (P Group ϭ0.05 and 0.005). However, there was no significant change in glomerular filtration rate in either sex, suggesting that altered tubular function may be responsible for AT 2 R-induced natriuresis rather than hemodynamic effects. Taken together, this study provides evidence that direct AT 2 R stimulation produces vasodilatory and natriuretic effects in the male and female kidney. The AT 2 R may, therefore, represent a valuable therapeutic target for the treatment of renal and cardiovascular diseases in both men and women. Key Words: angiotensin type 2 receptor Ⅲ compound 21 Ⅲ sex differences Ⅲ hypertension Ⅲ natriuresis Ⅲ renal blood flow B efore menopause, women are protected from hypertension and cardiovascular disease relative to men. However, this protection weakens after menopause, and ultimately the prevalence of hypertension in women exceeds that of men. 1 Alarmingly, sex-related differences have also been reported in the efficacy of current cardiovascular therapies, 2,3 with poorer treatment outcomes commonly reported in women. 3 The development of sex-specific approaches for the treatment of hypertension and cardiovascular disease is, therefore, of utmost importance.It is well established that the kidney plays a central role in arterial pressure control. The regulation of sodium excretion by the kidney is critical to the long-term regulation of arterial pressure given its influence on body fluid volume homeostasis. 4 In response to a rise in arterial pressure, sodium and water excretion is increased to reduce extracellular fluid volume and to restore arterial pressure to normal. Abnormal renal excretory function is, therefore, recognized as a key contributor to the development of hypertension. 5The renin-angiotensin system (RAS) plays a pivotal role in the re...

Abstract-Awareness of sex differences in the pathology of cardiovascular disease is increasing. Previously, we have shown a role for the angiotensin type 2 receptor (AT 2 R) in the sex differences in the arterial pressure response to Ang II. Tubuloglomerular feedback (TGF) contributes in setting pressure-natriuresis properties, and its responsiveness is closely coupled to renal Ang II levels. We hypothesize that, in females, the attenuated pressor response to Ang II is mediated via an enhanced AT 2 R mechanism that, in part, offsets Ang II-induced sensitization of the TGF mechanism. Mean arterial pressure was measured via telemetry in male and female wild-type (WT) and AT 2 R knockout (AT 2 R-KO) mice receiving Ang II (600 ng/kg per minute SC). Basal 24-hour mean arterial pressure did not differ among the 4 groups. After 10 days of Ang II infusion, mean arterial pressure increased in the male WT (28Ϯ6 mm Hg), male AT 2 R-KO (26Ϯ2 mm Hg), and female AT 2 R-KO (26Ϯ4 mm Hg) mice, however, the response was attenuated in female WT mice (12Ϯ4 mm Hg; P between sex and genotypeϭ0.016). TGF characteristics were determined before and during acute subpressor Ang II infusion (100 ng/kg per minute IV). Basal TGF responses did not differ between groups. The expected increase in maximal change in stop-flow pressure and enhancement of TGF sensitivity in response to Ang II was observed in the male WT, male AT 2 R-KO, and female AT 2 R-KO but not in the female WT mice (P between sex and genotype Ͻ0.05; both). In conclusion, these data indicate that an enhanced AT 2 R-mediated pathway counterbalances the hypertensive effects of Ang II and attenuates the Ang II-dependent resetting of TGF activity in females. Thus, the enhancement of the AT 2 R may, in part, underlie the protection that premenopausal women demonstrate against cardiovascular disease. Key Words: sex differences Ⅲ renin-angiotensin system Ⅲ Ang II Ⅲ mean arterial pressure Ⅲ hypertension Ⅲ renal hemodynamics Ⅲ tubuloglomerular feedback M en have a greater prevalence for hypertension and cardiovascular disease than premenopausal women of the same age. 1 The mechanisms underlying these differences in the pathophysiology of cardiovascular disease between men and women remain unclear. One of the suggested mechanisms underlying this sexual dimorphism is differences in the function of the renin-angiotensin system (RAS). [2][3][4] Angiotensin II (Ang II), the main effector peptide of the RAS, exerts its effects through 2 main receptor subtypes. Stimulation of the angiotensin type 1 receptor (AT 1 R) causes vasoconstriction, sodium reabsorption, and cell proliferation. The angiotensin type 2 receptor (AT 2 R) opposes the AT 1 R, causing vasodilation, sodium excretion, and apoptosis. 5,6 Earlier studies have shown that females have a greater AT 2 R:AT 1 R ratio. 7,8 We, and others, have demonstrated previously that the rise in arterial pressure in response to Ang II is blunted in females compared with males. 7,9 -11 Furthermore, we have provided evidence to suggest that arteria...

Sex hormones regulate the renin-angiotensin system. For example, estrogen enhances expression of the angiotensin type 2 receptor. We hypothesized that activation of the angiotensin type 2 receptor shifts the chronic pressure-natriuresis relationship leftward in females compared with males and that this effect is lost with age. Mean arterial pressure was measured by radiotelemetry in adult (4 mo old) and aged (14 mo old) wild-type and angiotensin type 2 receptor knockout male and female mice. Chronic pressure-natriuresis curves were constructed while mice were maintained on a normal-salt (0.26%) diet and following 6 days of high salt (5.0%) diet. Mean arterial pressure was lower in adult wild-type females than males (88 ± 1 and 97 ± 1 mmHg, respectively), a difference that was maintained with age, but was absent in adult knockout mice. In wild-type females, the chronic pressure-natriuresis relationship was shifted leftward compared with knockout females, an effect that was lost with age. In males, the chronic pressure-natriuresis relationship was not influenced by angiotensin type 2 receptor deficiency. Compared with age-matched females, the chronic pressure-natriuresis relationships in male mice were shifted rightward. Renal expression of the angiotensin type 2 receptor was fourfold greater in adult wild-type females than males. With age, the angiotensin type 2 receptor-to-angiotensin type 1 receptor balance was reduced in females. Conversely, in males, angiotensin receptor expression did not vary significantly with age. In conclusion, the angiotensin type 2 receptor modulates the chronic pressure-natriuresis relationship in an age- and sex-dependent manner.

The complex role of the renin-angiotensin-system (RAS) in arterial pressure regulation has been well documented. Recently, we demonstrated that chronic low-dose angiotensin II (ANG II) infusion decreases arterial pressure in female rats via an AT(2)R-mediated mechanism. Estrogen can differentially regulate components of the RAS and is known to influence arterial pressure regulation. We hypothesized that AT(2)R-mediated depressor effects evident in females were estrogen dependent and thus would be abolished by ovariectomy and restored by estrogen replacement. Female Sprague-Dawley rats underwent ovariectomy or sham surgery and were treated with 17β-estradiol or placebo. Mean arterial pressure (MAP) was measured via telemetry in response to a 2-wk infusion of ANG II (50 ng·kg(-1)·min(-1) sc) or saline. MAP significantly decreased in females treated with ANG II (-10 ± 2 mmHg), a response that was abolished by ovariectomy (+4 ± 2 mmHg) and restored with estrogen replacement (-6 ± 2 mmHg). Cardiac and renal gene expression of components of the RAS was differentially regulated by estrogen, such that overall, estrogen shifted the balance of the RAS toward the vasodilatory axis. In conclusion, estrogen-dependent mechanisms offset the vasopressor actions of ANG II by enhancing RAS vasodilator pathways in females. This highlights the potential for these vasodilator pathways as therapeutic targets, particularly in women.