Measurement of F(2)-isoprostanes unveils profound oxidative stress in aged rats.

Free radicals have been theorized to play a causative role in the normal aging process. To date, methods used to detect oxidative stress in aged experimental animals have only detected 2- to 3-fold differences or less between young and aged animals. Measurement of F(2)-isoprostanes has emerged as probably the most reliable approach to assess oxidative stress status in vivo. Therefore, we measured levels of F(2)-isoprostanes free in plasma and levels esterified in plasma lipids in young rats (3-4 months of age) and aged rats (22-24 months of age). Plasma concentrations of free F(2)-isoprostanes were increased dramatically by a mean of 20.3-fold (range 4.3 to 42.9-fold) and levels esterified in plasma lipids were also strikingly increased by a mean of 29.9-fold (range 15.8 to 50.0-fold). These findings unveil profound oxidative stress in aged rats which adds considerable support for the free radical theory of aging.

Sustained influence of the renal nerves to attenuate sodium retention in angiotensin hypertension.

Recent studies indicate that baroreflex suppression of renal sympathetic nerve activity is sustained for up to 5 days of ANG II infusion; however, steady-state conditions are not associated with ANG II hypertension of this short duration. Thus the major goal of this study was to determine whether neurally induced increments in renal excretory function during chronic intravenous infusion of ANG II are sustained under more chronic conditions when hypertension is stable and sodium balance is achieved. Experiments were conducted in five conscious dogs subjected to unilateral renal denervation and surgical division of the urinary bladder into hemibladders to allow separate 24-h urine collection from denervated (Den) and innervated (Inn) kidneys. ANG II was infused after control measurements for 10 days at a rate of 5 ng. kg(-1). min(-1). Twenty-four-hour control values for mean arterial pressure (MAP) and the ratio for urinary sodium excretion from Den and Inn kidneys (Den/Inn) were 92 +/- 4 mmHg and 0.99 +/- 0.05, respectively. On days 8-10 of ANG II infusion, MAP was stable (+30 +/- 3 mmHg) and sodium balance was achieved. Whereas equal amounts of sodium were excreted from the kidneys during the control period, throughout ANG II infusion there was a greater rate of sodium excretion from Inn vs. Den kidneys (day 10 Den/Inn sodium = 0.56 +/- 0.05), indicating chronic suppression of renal sympathetic nerve activity. The greater rate of sodium excretion in Inn vs. Den kidneys during renal sympathoinhibition also revealed a latent impairment in sodium excretion from Den kidneys. Although the Den/Inn for sodium and the major metabolites of nitric oxide (NO) decreased in parallel during ANG II hypertension, the Den/Inn for cGMP, a second messenger of NO, remained at control levels throughout this study. This disparity fails to support the notion that a deficiency in NO production and action in Den kidneys accounts for the impaired sodium excretion. Most importantly, these results support the contention that baroreflex suppression of renal sympathetic nerve activity is sustained during chronic ANG II hypertension, a response that may play an important role in attenuating the rise in arterial pressure.

Gender differences in the regulation of blood pressure.

Men are at greater risk for cardiovascular and renal disease than are age-matched, premenopausal women. Recent studies using the technique of 24-hour ambulatory blood pressure monitoring have shown that blood pressure is higher in men than in women at similar ages. After menopause, however, blood pressure increases in women to levels even higher than in men. Hormone replacement therapy in most cases does not significantly reduce blood pressure in postmenopausal women, suggesting that the loss of estrogens may not be the only component involved in the higher blood pressure in women after menopause. In contrast, androgens may decrease only slightly, if at all, in postmenopausal women. In this review the possible mechanisms by which androgens may increase blood pressure are discussed. Findings in animal studies show that there is a blunting of the pressure-natriuresis relationship in male spontaneously hypertensive rats and in ovariectomized female spontaneously hypertensive rats treated chronically with testosterone. The key factor in controlling the pressure-natriuresis relationship is the renin-angiotensin system (RAS). The possibility that androgens increase blood pressure via the RAS is explored, and the possibility that the RAS also promotes oxidative stress leading to production of vasoconstrictor substances and reduction in nitric oxide availability is proposed.

Reduced uterine perfusion pressure during pregnancy in the rat is associated with increases in arterial pressure and changes in renal nitric oxide.

A reduction in nitric oxide (NO) synthesis has been suggested to play a role in pregnancy-induced hypertension. We have recently reported that normal pregnancy in the rat is associated with significant increases in whole-body NO production and renal protein expression of neuronal and inducible NO synthase. The purpose of this study was to determine whether whole-body and renal NO production is reduced in a rat model of pregnancy-induced hypertension produced by chronically reducing uterine perfusion pressure starting at day 14 of gestation. Chronic reductions in uterine perfusion pressure resulted in increases in arterial pressure of 20 to 25 mm Hg, decreases in renal plasma flow (<23%) and glomerular filtration rate (<40%), but no difference in urinary nitrite/nitrate excretion relative to control pregnant rats. In contrast, reductions in uterine perfusion pressure in virgin rats resulted in no significant effects on arterial pressure. Renal endothelial (<4%) and inducible (<11%) NO synthase protein expression did not decrease significantly in the chronically reduced uterine perfusion pressure rats relative to normal pregnant rats; however, significant reductions in neuronal NO synthase were observed (<30%). The results of this study indicate that the reduction in renal hemodynamics and the increase in arterial pressure observed in response to chronic decreases in uterine perfusion pressure in pregnant rats are associated with no change in whole-body NO production and a decrease in renal protein expression of neuronal NO synthase.

Oxidative stress may explain how hypertension is maintained by normal levels of angiotensin II.

It is well known that essential hypertension evolves in most patients with "near normal" levels of plasma renin activity. However, these levels appear to be responsible for the high levels of arterial pressure because they are normalized by the administration of angiotensin II converting inhibitors or angiotensin receptor antagonist. In experimental animals, hypertension can be induced by the continuous intravenous infusion of small doses of angiotensin II that are not sufficient to evoke an immediate pressor response. However, this condition resembles the characteristics of essential hypertension because the high levels of blood pressure exist with normal plasma levels of angiotensin II. It is suggested that small amounts of angiotensin whose plasma levels are inappropriate for the existing size of extracellular volume stimulate oxidative stress which binds nitric oxide forming peroxynitrite. The latter compound oxidizes arachidonic acid producing isoprostaglandin F2alpha (an isoprostane) which is characterized by a strong antinatriuretic vasoconstrictor renal effect. In this chain of reactions the vasoconstrictor effects derived from oxygen quenching of nitric oxide and increased isoprostane synthesis could explain how hypertension is maintained with normal plasma levels of renin.

Subpressor doses of angiotensin II increase plasma F(2)-isoprostanes in rats.

The present study was performed to determine whether physiologically relevant doses of angiotensin II (Ang II), which do not affect renal hemodynamics but do cause slow response hypertension, result in oxidative stress as measured by production of vasoconstrictor F(2)-isoprostane, a prostaglandin-like non-cyclooxygenase-produced arachidonic acid metabolite that is the end product of lipid peroxidation. Rats were instrumented with abdominal aortic and left femoral venous catheters, and before and throughout Ang II (or saline) infusion, all rats received enalapril (250 mg/L). Four days after the initiation of enalapril, rats were infused with Ang II (10 ng. kg(-1). min(-1), n=6) or saline (n=6) for 14 days. Mean arterial pressure was measured 24 hours per day, and on day 12, glomerular filtration rate and renal plasma flow were measured. Mean arterial pressure in control rats averaged 85+/-1 mm Hg, and with Ang II infusion, mean arterial pressure increased slowly and reached a plateau on day 3, averaging 117+/-2 mm Hg (P<0.0001 compared with enalapril alone). Glomerular filtration rate and renal plasma flow were not affected by Ang II. Free F(2)-isoprostanes in plasma increased by 54% with Ang II (P<0.01), and the production of F(2)-isoprostanes esterified in plasma lipids tended to be higher with Ang II also but did not reach significance (P=0.1). These studies suggest that low doses of Ang II are capable of producing oxidative stress in animals. Whether oxidative stress plays a causative role in Ang II-mediated slow-response hypertension or is secondary to the hypertension is not clear from these data and will require further study.

Gender differences in development of hypertension in spontaneously hypertensive rats: role of the renin-angiotensin system.

Previous data strongly support a role for androgens in promoting the gender difference in hypertension in the spontaneously hypertensive rat(s) (SHR), but the mechanism is not clear. Because males develop higher blood pressures than do females, we hypothesize that androgens may affect the renin-angiotensin system to promote the development of hypertension in male SHR. The present study was performed to determine the effect of converting enzyme inhibition (CEI) on the development of hypertension in SHR. Male, female, castrated male, and ovariectomized (ovx) female SHR (n=10 per gender per treatment group) received enalapril (250 mg/L) in drinking water for 8 to 10 weeks. Some ovx females were also given testosterone chronically. At 17 to 19 weeks of age, 24-hour protein excretion and mean arterial pressure were measured. By 13 weeks of age, male rats had higher systolic blood pressures by tail plethysmography than did the other rats, and CEI reduced blood pressures to similar levels in all groups. At 17 to 19 weeks, the same trend was found by direct measurement of mean arterial pressure. The ovx females treated with testosterone had serum testosterone and blood pressure levels similar to those found in males. CEI reduced mean arterial pressure to similar levels in all gender groups. Untreated males and ovx females given testosterone had significantly higher levels of urinary protein excretion than did the other groups, and CEI had no effect on proteinuria in any of the rats. These data suggest that the development of hypertension in SHR regardless of sex steroids is mediated by the renin-angiotensin system. However, the data further suggest that androgens promote the exacerbation of hypertension in male SHR via a mechanism involving the renin-angiotensin system.

Gender differences in hypertension in spontaneously hypertensive rats: role of androgens and androgen receptor.

Males are at greater risk of cardiovascular and renal disease than are females. For example, male spontaneously hypertensive rats (SHR) have higher blood pressures than females. Androgens have been strongly implicated in the hypertension of male SHR, because castration attenuates the hypertension. This study determined whether the androgen receptor plays a role in hypertension in male SHR and whether testosterone alone can cause the hypertension or whether conversion to dihydrotestosterone is necessary. Male SHR, aged 10 weeks, were given the androgen receptor antagonist flutamide (8 mg/kg SC; n=8) or the 5alpha-reductase inhibitor finasteride (30 mg x kg(-1) x d(-1) SC; n=11) daily for 5 to 6 weeks. Control rats (n=10) received vehicle (20% benzyl benzoate or ethanol in castor oil). After 5 to 6 weeks, blood pressure (mean arterial pressure) and glomerular filtration rate were measured. Long-term flutamide treatment caused a reduction in mean arterial pressure (control 178+/-5 mm Hg; flutamide 159+/-3 mm Hg; P<0.01), but finasteride had no effect (180+/-5 mm Hg). There were no differences in glomerular filtration rate among the groups. These data indicate that hypertension in male SHR is mediated via the androgen receptor and does not require conversion of testosterone to dihydrotestosterone.

State-of-the-Art lecture. Role of angiotensin and oxidative stress in essential hypertension.

In this review, we examine the possibility that small increments in angiotensin II are responsible for an increase in blood pressure and maintenance of hypertension through the stimulation of oxidative stress. A low dose of angiotensin II (2 to 10 ng x kg(-1) x min(-1), which does not elicit an immediate pressor response), when given for 7 to 30 days by continuous intravenous infusion, can increase mean arterial pressure by 30 to 40 mm Hg. This slow pressor response to angiotensin is accompanied by the stimulation of oxidative stress, as measured by a significant increase in levels of 8-iso-prostaglandin F(2alpha) (F(2)-isoprostane). Superoxide radicals and nitric oxide can combine chemically to form peroxynitrite, which can then oxidize arachidonic acid to form F(2)-isoprostanes. F(2)-isoprostanes exert potent vasoconstrictor and antinatriuretic effects. Furthermore, angiotensin II can stimulate endothelin production, which also has been shown to stimulate oxidative stress. In this way, a reduction in the concentration of nitric oxide (which is quenched by superoxide) along with the formation of F(2)-isoprostanes and endothelin could potentiate the vasoconstrictor effects of angiotensin II. We hypothesize that these mechanisms, which underlie the development of the slow pressor response to angiotensin II, also participate in the production of hypertension when circulating angiotensin II levels appear normal, as occurs in many cases of essential and renovascular hypertension.

Chronic aminoguanidine attenuates renal dysfunction and injury in aging rats.

We have previously shown that aging is associated with increased lipid peroxidation, reductions in renal function, and increased glomerular sclerosis. The mechanism(s) responsible for these age-related changes are not clear. The purpose of the present studies was to determine if there was an increase in inducible nitric oxide synthase (iNOS) with aging, and if so, whether inhibition of iNOS would prevent aging injury by preventing free radical-mediated lipid peroxidation. iNOS protein expression in the kidney increased by approximately 90% by 24 months. Inhibition of iNOS by aminoguanidine (0.1% in drinking water) for 9 months, beginning at 13 months of age, reduced blood pressure, improved glomerular filtration rate by 70%, and renal plasma flow by 40%, whereas glomerular sclerosis was considerably reduced. Renal F2-isoprostanes and malondialdehyde levels, markers of oxidative stress and lipid peroxidation, were not reduced by aminoguanidine. Aminoguanidine also did not attenuate immunostaining for advanced glycosylation end products (AGE) in the kidneys. These findings suggest that aminoguanidine attenuates aging renal dysfunction by inhibiting a pathophysiologic function of iNOS that is independent of free radical-mediated lipid peroxidation or significant effects on AGE deposition.

Role of androgens in mediating hypertension and renal injury.

1. Men are generally at greater risk for cardiovascular disease than are women, particularly with regard to enhanced progression of hypertension and loss of renal function. Despite these gender differences in the progression of hypertension and renal disease in humans and animals, the mechanisms responsible are unknown. 2. Castration in males has been shown to slow the progression of hypertension and ameliorate the loss in renal function. When serum testosterone was measured in the developing male spontaneously hypertensive rat (SHR), the peak serum testosterone level at 12 weeks coincided with the time when differences in systolic blood pressure could be measured between intact male SHR and females or castrated male SHR. Ovariectomy does not affect blood pressure in female SHR but testosterone treatment of ovariectomized females for 5 weeks results in exacerbation of hypertension almost to the level found in intact male SHR. These data strongly suggest a role for androgens in mediating the gender differences in hypertension. 3. The mechanisms by which androgens could increase blood pressure are not known. We have recently shown that, at comparable renal perfusion pressures, there is a hypertensive shift in the pressure-natriuresis relationship in male SHR compared with females or castrated male SHR. Testosterone treatment of ovariectomized female SHR also causes a rightward shift in the pressure-natriuresis relationship. 4. We hypothesize that androgens increase arterial pressure by causing a hypertensive shift in the pressure-natriuresis relationship, either by having a direct effect to increase proximal tubular reabsorption or by activation of the renin-angiotensin system. We also hypothesize that the enhanced proximal tubular reabsorption leads to a tubuloglomerular feedback-mediated afferent vasodilation, which, in combination with the increase in arterial pressure, results in glomerular hypertension and renal injury.

Differential expression of renal nitric oxide synthase isoforms during pregnancy in rats.

Alterations in nitric oxide (NO) production have been suggested to play a role in mediating changes in renal function during normal pregnancy and in pregnancy-induced hypertension. Although NO production is enhanced during normal pregnancy, the mechanisms for the increase are unknown. The purpose of this study was to determine whether the elevation in NO production during pregnancy is associated with increases in renal expression of endothelial (eNOS), inducible (iNOS), and neuronal (nNOS) nitric oxide synthases. To achieve this goal we examined systemic and renal hemodynamics, urinary excretion of nitrate/nitrite, and renal protein expression of the three NOS isoforms in prepregnant rats, pregnant rats at days 6, 13, and 19 of gestation and at day 4 postpartum. Mean arterial pressure decreased by 14% in late pregnancy whereas the glomerular filtration rate and renal plasma flow increased by 21% and 24%, respectively, in mid pregnancy. Excretion of nitrate/nitrite increased throughout pregnancy with a 3.4-fold increase present at day 19 (12.2+/-0.7 to 41.1+/-1.3 micromol/24 h). Renal eNOS protein expression decreased by 39% during pregnancy with the lowest level resulting at day 19 and returning to virgin levels by day 4 post partum. In contrast, renal iNOS and nNOS protein expression increased 31% and 25%, respectively, with highest expression occurring for both at day 13 of pregnancy. These data suggest that the increased NO production and renal hemodynamics associated with pregnancy in rats may be caused by the upregulation of iNOS and nNOS in the kidney.

Role of nitric oxide in modulating renal function and arterial pressure during chronic aldosterone excess.

Chronic aldosterone (Aldo) excess is associated with transient sodium retention, extracellular fluid volume expansion, renal vasodilation, and hypertension. The purpose of this study was to determine the role of nitric oxide (NO) in mediating the renal vasodilation and the escape from the sodium-retaining actions of Aldo. To achieve this goal, we examined the long-term effects of Aldo (15 microgram. kg-1. min-1 for 7 days) in conscious, chronically instrumented control dogs (n = 9) and in dogs (n = 12) pretreated with the NO synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10 microgram. kg-1. min-1). In control dogs, Aldo caused a transient sodium retention (126 +/- 6 to 56 +/- 2 meq/day) followed by a return of sodium excretion to normal levels. Aldo also increased renal plasma flow by 15% (205 +/- 13 to 233 +/- 16 ml/min), glomerular filtration rate by 20% (72 +/- 3 to 87 +/- 5 ml/min), and arterial pressure from 90 +/- 3 to 102 +/- 3 mmHg. Aldo increased urinary nitrate/nitrite excretion by 60% in the control dogs. Although the sodium-retaining (144 +/- 7 to 56 +/- 7 meq/day) and arterial pressure (122 +/- 6 to 136 +/- 5 mmHg) responses to Aldo were the same in dogs pretreated with L-NAME compared with control, the renal hemodynamic response was markedly attenuated. The results of this study suggest that NO plays an important role in mediating the renal vasodilation during chronic Aldo excess.

Vitamin E ameliorates enhanced renal lipid peroxidation and accumulation of F2-isoprostanes in aging kidneys.

Aging results in progressive glomerular sclerosis and reductions in glomerular filtration rate (GFR). Oxidative stress may be an important mechanism for the aging process, but to date the role of oxidative stress on renal aging has not been determined. The present study was performed to determine whether age-related alterations in renal hemodynamics and morphology were associated with oxidative stress and whether this could be attenuated by chronic administration of vitamin E. Rats, aged 13 mo, were given either control diet containing vitamin E 50 IU/kg (n = 6) or a high-vitamin E diet (5,000 IU/kg; n = 6) for 9 mo. Another group of rats (3-4 mo old; n = 7) served as young controls. Aging was accompanied by a 60% reduction in GFR, a threefold increase in renal F2 isoprostanes, newly discovered vasoconstrictive F2-like prostaglandins generated by free radical-mediated lipid peroxidation. Renal aging was also associated with an increase in oxidant-sensitive heme oxygenase, advanced glycosylation end products (AGEs), and the AGE receptor, RAGE. AGE-RAGE interaction has been shown to induce oxidative stress. With high-vitamin E diet, GFR was increased by 50%, F2 isoprostanes were suppressed, and expression of heme oxygenase and RAGE was attenuated. There was also a tendency for glomerular sclerosis to be attenuated. These data demonstrate that age-related decline in renal function is accompanied by oxidative stress and that administration of antioxidants, such as vitamin E, could attenuate the decline in renal function.

Gender differences in the renal nitric oxide (NO) system: dissociation between expression of endothelial NO synthase and renal hemodynamic response to NO synthase inhibition.

Many studies have shown that nitric oxide (NO) production is higher in the systemic vasculature of females than males and is stimulated during pregnancy, a high estrogen state. The present study was performed in rats to determine whether females had a greater expression of endothelial NO synthase (eNOS) in kidneys than did males; whether there were gender differences in the excretion of NO metabolites, nitrate/nitrite; and whether there were gender differences in the renal hemodynamic response to NO synthase inhibition. The renal levels of eNOS mRNA (as measured by ribonuclease protection assays) and protein (as measured by Western blot) were 80% higher in kidneys from females than from males (P < .001). Urinary excretion of NO metabolites, nitrate/nitrite, were not different between males and females. To inhibit eNOS, rats were treated with nitro-L-arginine methyl ester (L-NAME, 3 to 4 mg/kg/day) for 2 weeks. Although there were no differences in basal renal hemodynamics between males and females, when factored for kidney weight, chronic L-NAME increased renal vascular resistance by 130% in males but by only 60% in females, and decreased renal plasma flow by 40% in males but had no effect in females. These data show that although the renal levels of eNOS mRNA and protein are higher in females than in males, the renal vasculature of males is more responsive to NO synthase inhibition. The data suggest that the renal vasculature of males may be more dependent on NO than is the renal vasculature in females.

Angiotensin II stimulates synthesis of endothelial nitric oxide synthase.

Previous studies have suggested that NO may play an important role in protecting the renal vessels from angiotensin II (ANGII)-mediated vasoconstriction. One possible mechanism for this interaction is that ANGII could stimulate NO production in the kidney by increasing endothelial NO synthase (NOS III). The present studies were performed in rats to determine whether acute or chronic elevations in ANGII are associated with enhanced renal NOS III mRNA or protein synthesis. In both acute and chronic studies captopril (20 microg/kg/min) was given I.V. to inhibit endogenous ANGII production. Acute suprarenal infusion of ANGII (8 ng/kg/min) for 110 minutes had no effect on arterial pressure but decreased GFR and renal plasma flow by 20% and 30%, respectively, and increased renal vascular resistance by 70%. Acute ANGII increased renal NOS III mRNA by 70% (as determined by ribonuclease protection assay), but had no effect on renal NOS III protein concentration (as detected by Western blot analyses). In contrast, chronic infusion of ANGII (5 ng/kg/min) for 10 days, increased arterial pressure by 30% and tended to reduce GFR and renal plasma flow. Chronic ANGII had no effect on renal NOS III mRNA levels, but increased NOS III protein by 90%. These data suggest that ANGII can stimulate NOS III synthesis and suggest that this may be one of the mechanisms whereby AngII may enhance NO production.

Testosterone exacerbates hypertension and reduces pressure-natriuresis in male spontaneously hypertensive rats.

Studies were performed in intact male and female, gonadectomized male and female, and gonadectomized female rats given testosterone for 5 weeks to investigate the role played by testosterone in altered blood pressure control and pressure-natriuresis in male SHR. Serum testosterone levels reached a peak at 12 weeks of age in intact male SHR. Systolic blood pressure, measured weekly from 5 to 20 weeks of age, was similar between groups until 12 weeks of age when blood pressure became higher in males (195+/-3 mm Hg) than in females (168+/-3 mm Hg) or males castrated at 4 weeks (173+/-4 mm Hg). At 17 to 19 weeks direct measurement of arterial pressure in anesthetized rats confirmed that mean arterial pressure was higher in male (182+/-1 mm Hg) than in female (159+/-2 mm Hg) and castrated male SHR (159+/-2 mm Hg). In addition, testosterone (5 mg in Silastic pellets, SC for 5 weeks) administered to ovariectomized (ovx+T) females caused arterial pressure to increase by mm 11% (175+/-2 mm Hg), which was significantly higher than in intact female, castrated male, or untreated ovariectomized (ovx) female SHR (158+/-2 mm Hg). Acute pressure-natriuresis was blunted in male SHR compared with females, castrated males, or ovx females, in which this relationship was similar. Pressure-natriuresis was also blunted in ovx+T females as found in intact male SHR. These data support the hypothesis that male sex hormones contribute to the exacerbation of hypertension in SHR by reducing pressure-natriuresis.

F2-isoprostanes and the kidney.

PGF(2)-like compounds are formed in abundance in vivo by the free radical-induced peroxidation of arachidonic acid, independent of the cyclooxygenase enzyme. These compounds are collectively referred to as F(2)-isoprostanes because of their structural similarity to cyclooxygenase-derived PGF(2alpha). Certain findings suggest a potential role for isoprostanes as mediators of some of the adverse sequelae of ischemia-reperfusion injury to kidney. Recent evidence also suggests a potentially important role for isoprostanes in the pathogenesis of hepatorenal syndrome. Cell culture studies suggest that cisplatin-induced LLC-PK1 cell injury may be attended by increased isoprostane production through a mechanism involving thiol depletion. Another area in which a role for free radical-induced lipid peroxidation and F(2)-isoprostanes has been suggested is in the pathogenesis of ciclosporin (CSA)-induced renal toxicity. A recent study also suggests that enhanced formation renal F(2)-isoprostanes may be relevant to the progressive reduction in renal blood flow demonstrable in aging kidneys. This emerging evidence suggests that further studies are warranted to determine the importance of F(2)-isoprostanes in human renal diseases characterized by renal vasoconstriction, such as renal ischemia, hepatorenal syndrome, renal senescence and toxic nephropathies.

Decline in renal hemodynamic function in aging SHR: role of androgens.

Although men and male rats are at increased risk for age-related renal and cardiovascular disease compared with women and female rats, the mechanisms are unknown. However, castration of male normotensive rats protects against age-related glomerular sclerosis, and castration of spontaneously hypertensive rats (SHR) attenuates the age-related progression of hypertension to levels found in female SHR. The present study was performed to determine whether there are differences between male and female renal function in SHR with aging, and if so, the role that androgens play in the age-related changes in renal function in SHR. Renal hemodynamics, glomerular filtration rate (GFR), and proteinuria were measured in anesthetized male and female SHR aged 7 to 8, 14 to 15, and 30 to 32 weeks (n=5 to 7 per sex per age group). Studies were also performed in male SHR that had been castrated at 4 weeks of age and allowed to age to 7 to 8, 14 to 15, and 30 to 32 months of age (n=5 to 9 per age group). At 7 to 8 weeks of age when blood pressures are similar between male, female, and castrated male SHR, there were no differences in renal hemodynamics between male and female SHR. As the rats aged, mean arterial blood pressure increased in all groups and was higher in the intact male SHR than in females. Blood pressure in aging castrated males was similar to the pressure in aging female SHR. With advancing age, GFR in intact male SHR decreased by 20% to 30% at 14 to 15 and 30 to 32 weeks of age, respectively. Renal plasma flow (RPF) also tended to decrease in male SHR but not statistically so. There was no age-related reduction in GFR or RPF in female or castrated male SHR. With advancing age, renal vascular resistance (RVR) increased in all rats. RVR increased by 40% and 60% at 14 to 15 and 30 to 32 weeks in male SHR. In comparison, RVR increased by 20% and 40% in female SHR at similar ages. RVR in castrated male SHR was similar to RVR in females. The levels of urinary protein excretion increased with aging to 14 weeks in the male SHR, but in females and castrated males urinary protein excretion reached a plateau at 6 to 8 weeks that was maintained until 14 weeks of age and was approximately sixfold lower than in male SHR. These data suggest that androgens may play an important role in mediating the hypertension and the age-related alterations in renal function in the male SHR.