Glomerular Dynamics and Morphology of Aged Spontaneously Hypertensive Rats

Komatsu, Kazutoshi; Fröhlich, Edward D.; Ono, Hitoshi; Ono, Yuko; Numabe, Atsushi; Willis, Gladden W.

doi:10.1161/01.hyp.25.2.207

Cited by 70 publications

(46 citation statements)

References 20 publications

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“…59 Although BP increases in female SHR after cessation of estrous cycling to levels not different or even higher than males, 60 females exhibit little glomerulosclerosis compared to males. 61 Whether P GC is increased in aged female SHR has not been determined.…”

Section: Hypertension and Sex Steroidsmentioning

confidence: 99%

Sex Steroids and Renal Disease

2008

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E pidemiological studies have shown that male sex is an independent risk factor for the development and progression of renal disease, and men progress to end stage renal disease (ESRD) faster than premenopausal women in such diseases as autoimmune glomerulonephritis, hypertensive glomerulosclerosis, and polycystic kidney disease. [1][2][3] Although the age-related decline in renal function is also faster in men, women become more susceptible to renal diseases after menopause. 4 Insight from in vitro studies and animal models suggest that sex steroids play pivotal roles in modifying the progression to ESRD. Because there is a paucity of data in humans showing the mechanisms by which sex steroids impact renal disease, most of the studies discussed this review will be in animals, mainly rats. Furthermore, determining the roles of sex steroids in various diseases has been done using gonedectomized animals; however, although gonadectomy removes more than sex steroids and most studies only replace the sex steroid of interest, these are still the best studies in which to evaluate mechanisms responsible for sex differences in renal disease. Studies in postmenopausal women will also be kept to a minimum in this review because it is likely that sex steroids change action with aging, as suggested by the Women's Health Initiative study. Estradiol and the KidneyEstrogen receptors (ER) are present in the kidney, although their localization in nephron segments has not been fully elucidated. Mesangial cells contain both ER␣ and ER␤, 5 as do endothelium and vascular smooth muscle cells. [5][6][7] Whether the newly described transmembrane estrogen receptor, GPR30, 8 is present in kidneys has not been determined. Ovariectomy (ovx) of Dahl salt sensitive rats (DS) caused decreases in ER␣ but increases in ER␤ expression in the renal cortex and medulla, 9 whereas ovx in salt resistant (DR) rats caused decreases in cortical and increases in medullary ER␣, and increases in ER␤. In addition, estradiol replacement returned ER␤ expression to preovx levels in both DS and DR, but had no effect on ER␣. In contrast, in internal mammary arteries from humans, ER␤ mRNA expression was 10-fold higher than ER␣ or GPR30, and 17␤-estradiol downregulated ER␣, ER␤, and GPR30. 10 Estradiol is usually thought to be renoprotective. For example, in cultured mesangial cells, 17␤-estradiol inhibits apoptosis and transforming growth factor (TGF)-␤ activity and expression. 11 In addition, estradiol is antiinflammatory. 12-14 However, with low nitric oxide (NO) and high angiotensin (Ang) II, estradiol exacerbated renal injury via upregulation of renal AT 1 receptor expression. 15 In addition, in women, oral contraceptives increase in BP and albumin excretion, 16 and occasionally result in hypertension 17 and biopsy-proven renal damage in the absence of primary renal disease. 18 The roles of the ER subtypes in renal function or injury have been studied mainly by using ER␣ and ER␤ knockout (KO) mice. ER␣ is mainly responsible for gene regulation because 10 000 ge...

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Section: Hypertension and Sex Steroidsmentioning

confidence: 99%

Sex Steroids and Renal Disease

2008

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“…73 These findings included elevated arterial pressure; reduced total renal blood flow and increased renal vascular resistance; increased afferent and efferent glomerular arteriolar resistance, elevated glomerular hydrostatic pressure, and a diminished renal filtration coefficient; reduced glomerular filtration rate; massive proteinuria; and the classical histopathological glomerular and renal arteriolar injury lesions of severe nephrosclerosis. Moreover, when these rats were treated for only 3 weeks with an ACE inhibitor, each of these pathophysiological alterations was significantly reversed or normalized.…”

Section: End-stage Renal Diseasementioning

confidence: 99%

Local Hemodynamic Changes in Hypertension

Fröhlich

2001

Hypertension

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Abstract-As a result of antihypertensive therapy, there has been a remarkable decrease in morbidity and mortality from such cardiovascular endpoints as stroke, coronary heart disease, and major hypertensive emergencies. In contrast, there has been no relenting in the increasing prevalence of cardiac failure and end-stage renal disease (ESRD) associated with hypertensive cardiovascular disease. Recent experience in our laboratories that involved the natural development of the cardiac and renal hemodynamic alterations in spontaneously hypertensive rats demonstrated that the natural history and pathophysiological lesions associated with cardiac failure and ESRD may be vastly different from the heretofore more pressure-dependent brain and other cardiac endpoints reported in earlier years. These initial antihypertensive agents (eg, diuretics, ␤-adrenergic receptor inhibitors) had minimal anti-ischemic and antifibrotic effects on heart and kidney and did not exert the cardiac and nephroprotective hemodynamic effects of the newer classes of agents. The cardiac and renal endpoints resulting in organ failure today are more related to ischemia, intraorgan fibrosis, and aging. Our experimental studies summarized herein strongly suggest that the newer classes of antihypertensive drugs (ie, ACE inhibitors, angiotensin II type 1 receptor antagonists, certain calcium antagonists, and perhaps L-arginine) may reverse these pathophysiological lesions through improving blood flow and flow reserve, their antifibrotic and other actions.

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“…Furthermore, the glomerular and arteriolar injury indices were likewise significantly reduced. 63 Earlier studies involving much younger SHRs (23 weeks), failed to demonstrate impaired renal flow and function or the intrarenal micropuncture indices of flow and function. 64,65 We set out to reproduce the pathophysiological indices of nephrosclerosis of the older SHRs by treating these younger rats with the nitric oxide synthetase inhibitor L-NAME for a three week period.…”

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confidence: 97%

“…After this treatment, all the pathophysiological alterations associated with nephrosclerosis in the older 72-week old SHRs, except for the increased glomerular hydrostatic pressure, were reproduced. 63 Glomerular hydrostatic pressure was not increased because of the more severe afferent arteriolar resistance associated with a reduced glomerular flow. 63 Pharmacological therapy was initiated to assess impact on prevention or reversal of accelerated SHR/L-NAME induced nephrosclerosis.…”

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confidence: 99%

“…63 Glomerular hydrostatic pressure was not increased because of the more severe afferent arteriolar resistance associated with a reduced glomerular flow. 63 Pharmacological therapy was initiated to assess impact on prevention or reversal of accelerated SHR/L-NAME induced nephrosclerosis. When an ACE-I was co-administered with L-NAME, it prevented the development of the pathophysiological structural and functional lesions, but this was reversed when the ACE-I was administered for three weeks following L-NAME administration.…”

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confidence: 99%

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