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.