Estrogen receptor α-mediated events promote sex-specific diabetic glomerular hypertrophy

Lovegrove, Alecia S.; Sun, Jianhong; Gould, Karen A.; Lubahn, Dennis B.; Korach, Kenneth S.; Lane, Pascale H.

doi:10.1152/ajprenal.00414.2003

Cited by 35 publications

(38 citation statements)

References 43 publications

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“…31 These observations suggest that estradiol and progesterone in diabetic subjects may be of extratesticular origin, such as the adrenal gland 32 or even the kidney itself. 33 Despite the fact that previous studies from this and other laboratories demonstrated renoprotective effects of estradiol in female diabetic rats, 10,11,34,35 the present study does not support the concept of the beneficial effects of estradiol in the diabetic males, because estradiol levels were elevated with diabetes, coinciding with increases in albuminuria and renal pathology. What the present study demonstrates is that it is not the absolute level of sex hormones that correlates with the severity of the disease but rather the ratio of testosterone/estradiol and testosterone/progesterone.…”

Section: Discussioncontrasting

confidence: 95%

Imbalance in Sex Hormone Levels Exacerbates Diabetic Renal Disease

Wells

Garman

et al. 2008

Hypertension

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Abstract-Studies suggest that the presence of testosterone exacerbates, whereas the absence of testosterone attenuates, the development of nondiabetic renal disease. However, the effects of the absence of testosterone in diabetic renal disease have not been studied. The study was performed in male Sprague-Dawley nondiabetic, streptozotocin-induced diabetic, and streptozotocin-induced castrated rats (nϭ10 to 11 per group) for 14 weeks. Diabetes was associated with the following increases: 3.2-fold in urine albumin excretion, 6.3-fold in glomerulosclerosis, 6.0-fold in tubulointerstitial fibrosis, 1.6-fold in collagen type I, 1.2-fold in collagen type IV, 1.3-fold in transforming growth factor-␤ protein expression, and 32.7-fold in CD68-positive cell abundance. Diabetes was also associated with a 1.3-fold decrease in matrix metalloproteinase protein expression and activity. Castration further exacerbated all of these parameters. Diabetes was also associated with a 4.7-fold decrease in plasma testosterone, 2.9-fold increase in estradiol, and 2.1-fold decrease in plasma progesterone levels. Castration further decreased plasma testosterone levels but had no additional effects on plasma estradiol and progesterone. These data suggest that diabetes is associated with abnormal sex hormone levels that correlate with the progression of diabetic renal disease. Most importantly, our results suggest an important role for sex hormones in the pathophysiology of diabetic renal complications. (Hypertension. 2008;51:1218-1224.)Key Words: diabetes Ⅲ kidney Ⅲ sex hormones Ⅲ glomerulosclerosis Ⅲ tubulointerstitial fibrosis E pidemiological studies show that the incidence and the rate of progression of nondiabetic renal disease are greater in men compared with age-matched women. 1,2 These observations lead to the belief that the male sex is a risk factor and/or that the female sex is a protective factor against the development of renal disease. In the setting of diabetes, however, this relationship is not so clear. Although some studies indicate that the male sex is still a risk factor for the development of diabetic nephropathy and progression to end-stage renal disease, 3,4 other studies suggest either no difference 5,6 or that females progress at a faster rate. 7,8 The actual truth is that the existing data are inadequate for the precise determination of whether sex differences, which clearly exist in nondiabetic renal disease, exist or "disappear" in the setting of diabetes.Our previous studies have shown that diabetes is associated with reduced plasma levels of estradiol in the female streptozotocin (STZ)-induced diabetic rat. 9 Supplementation of estradiol in these animals either from the onset 10,11 or 2 months after the induction of diabetes 12 attenuates the development of renal disease. Clinical studies indicate that diabetes is associated with decreased testosterone levels in men with diabetes, 13,14 suggesting that testosterone deficiency may contribute or at least be associated with the development of diabetic renal disea...

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Section: Discussioncontrasting

confidence: 95%

Imbalance in Sex Hormone Levels Exacerbates Diabetic Renal Disease

Wells

Garman

et al. 2008

Hypertension

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“…Similar observations were made in experimental models of type 1 DM. 40,41 Further supporting the link between sex hormones and diabetes are the observations that women with type 1 DM have impaired ovarian function, delayed age at menarche, are at a higher risk for having menstrual irregularities, and have a higher risk of adverse pregnancy outcomes (eg, spontaneous abortions, stillbirths, and congenital anomalies) than age-matched nondiabetic women. 37,42,43 These observations suggest that type 1 DM is associated with dysregulation of sex hormones, and it is conceivable that reduced estradiol concentrations may be responsible for the loss of female sex as a protective factor, at least in type 1 DM.…”

Section: Nephropathy Sex Hormones and Diabetesmentioning

confidence: 99%

“…Similar to humans, treatment with raloxifene in experimental models attenuated albuminuria and the renal structural damage associated with diabetes. 62,63 Experimental studies also indicate that estrogen receptor α is abnormally regulated in the diabetic kidney 40,41 and, coupled with the abnormal regulation of its ligand, 40,41 contributes to the progression of diabetic renal disease. Indeed, a recent study reported an association between introns 1 and 2 of the estrogen receptor-α gene and diabetic nephropathy in African-American and European-American populations, 64 further stressing the potential importance of sex hormones and their receptors in the pathophysiology of diabetic nephropathy.…”

Section: Estrogens and Diabetic Nephropathymentioning

confidence: 99%

Estrogens and the diabetic kidney

Maric

Sullivan

2008

Gender Medicine

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“…We have recently reported that female mice lacking estrogen receptor-␣ (ERKO) are protected from diabetic glomerular hypertrophy, although not from overall diabetic kidney growth (19). Differences in kidney weight were noted in nondiabetic mice, suggesting that this genotype also altered normal kidney development.…”

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confidence: 99%

Compensatory kidney growth in estrogen receptor-α null mice

Sun¹,

Langer²,

Devish³

et al. 2006

American Journal of Physiology-Renal Physiology

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Females are relatively protected in many progressive kidney diseases. Processes of kidney scarring and growth are intricately linked, and female kidneys are smaller than male kidneys. To better understand links between sex, growth, and the kidney, we examined compensatory kidney growth (CKG) after uninephrectomy (Unx) in wild-type and estrogen receptor-α null mice (ERKO). Mice (10 wk old) underwent Unx or sham procedure, with removal of all remaining kidney(s) 48 h later. Studies included kidney weight, renal content of protein, DNA, and insulin-like growth factor-I (IGF-I), serum IGF-I, mean glomerular area, and immunostaining for proliferating cell nuclear antigen (PCNA). Sham Unx produced no differences between left and right kidneys. Unx altered kidney weight, glomerular area, DNA content, IGF-I content, and PCNA regardless of sex or genotype. Females showed greater increases in kidney weight (26 vs. 19%) and glomerular area (73 vs. 51%) than males. Differences in kidney weight were restricted to wild-type females (32% increase); ERKO females showed an increase in kidney weight similar to males (19%). Genotype did not influence glomerular growth in this model. Both male and female mice exhibit hyperplastic growth 48 h after Unx, with more pronounced enlargement in females. Lack of estrogen receptor-α is associated with reduced CKG in females, probably via suppression of proliferation. ERKO mice did not demonstrate any alterations in compensatory glomerular enlargement. Kidney IGF-I content doubled after Unx, regardless of sex or genotype, implicating other mechanisms with regard to these findings.

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Estrogen receptor α-mediated events promote sex-specific diabetic glomerular hypertrophy

Cited by 35 publications

References 43 publications

Imbalance in Sex Hormone Levels Exacerbates Diabetic Renal Disease

Imbalance in Sex Hormone Levels Exacerbates Diabetic Renal Disease

Estrogens and the diabetic kidney

Compensatory kidney growth in estrogen receptor-α null mice

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