The Role of Gender in the Progression of Renal Disease

Silbiger, Sharon; Neugarten, Joel

doi:10.1053/jarr.2003.50001

Cited by 123 publications

(116 citation statements)

References 108 publications

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“…The age-related changes in BP in this animal thus correlate with the changes in renal pathology, suggesting that the renoprotective effects of E 2 replacement may be mediated via its effects on BP. However, several studies suggest that estrogens exert a renoprotective effect independently of their BP-lowering effects (3,26) by reducing cell death by apoptosis and increasing ECM degradation. Studies in this laboratory have shown that, in a STZ model of diabetes, E 2 replacement reduces renal collagen type IV synthesis and tubulointerstitial fibrosis without an effect on BP (53).…”

Section: Discussionmentioning

confidence: 99%

“…However, numerous studies indicate that estrogen alone has cardiovascular protective effects. Estrogen improves serum lipid levels, increases endotheliumdependent vasodilation and markers of fibrinolysis and vascular inflammation, and protects against the development of atherosclerosis and hypertension (3,5,(7)(8)(9). Even though the estrogen-alone arm of the WHI trial has recently been terminated (10) (partly because estrogen did not appear to affect heart disease, which was the main question of the study), no renal effects have been evaluated in these trials.…”

mentioning

confidence: 99%

“…The rate of progression of cardiovascular and renal disease and hypertension increases with age and is lower in premenopausal women compared with age-matched men (1)(2)(3). Interestingly, a re-evaluation of the Modification of Diet in Renal Disease (MDRD) study showed that the differences in the rate of decline of renal function between men and women is reduced after age 52 yr (their dividing point) (4), suggesting that menopause may affect the progression of renal disease in women; however, no studies to date have clearly demonstrated this point, suggesting that our understanding of the contribution of ovarian hormones to the development of age-related disease processes remains unclear.…”

mentioning

confidence: 99%

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Glomerulosclerosis and Tubulointerstitial Fibrosis are Attenuated with 17β-Estradiol in the Aging Dahl Salt Sensitive Rat

Maric¹,

Sandberg²,

Hinojosa‐Laborde³

2004

Journal of the American Society of Nephrology

192

136

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Abstract. This study examined the effects of estrogen deficiency by ovariectomy (OVX) and 17␤-estradiol (E 2 ) replacement (OVXϩE 2 ) on glomerulosclerosis and tubulointerstitial fibrosis and the mechanisms contributing to these changes, including expression of collagen type IV and laminin, transforming growth factor-␤ (TGF-␤), and activity of matrix metalloproteinases (MMP) in the kidneys of young (4 mo [4M]) and aged (12 mo [12M]) Dahl salt-sensitive (DSS) rats maintained on a low-salt (0.1% NaCl) diet. While normal renal morphology was observed in the 4M rats in all treatment groups, moderate to severe glomerulosclerosis (glomerulosclerotic index [GSI]: 4M, 0.22 Ϯ 0.09 versus 12M, 1.43 Ϯ 0.17; P Ͻ 0.001) and cortical tubulointerstitial fibrosis (CTIFI: 4M, 0 versus 12M, 57.1 Ϯ 4.9; P Ͻ 0.01) was observed in the 12M rats. The severity of glomerulosclerosis and cortical tubulointerstitial fibrosis in the 12M group was augmented with OVX (GSI, 3.27 Ϯ 0.34; CTIFI, 74.4 Ϯ 9.2; P Ͻ 0.01 versus Intact at 12M) and attenuated with E 2 replacement ([GSI], 1.09 Ϯ 0.09; CTIFI, 49.2 Ϯ 6.8). In the 12M animals, OVX was also associated with increased deposition and expression of laminin (Intact, 228.1 Ϯ 6.7; OVX, 277.4 Ϯ 9.6 AU; P Ͻ 0.01), increased expression of TGF-␤ (Intact, 85.0 Ϯ 23.0; OVX, 178.0 Ϯ 20.5 AU; P Ͻ 0.001), and decreased activity of cortical MMP-9 (Intact, 3.8 Ϯ 0.8; OVX, 2.4 Ϯ 0.6 AUC; P Ͻ 0.01). E 2 replacement opposed these effects (laminin, 229.9 Ϯ 6.2 AU; TGF-␤, 101.3 Ϯ 25.2 AU; MMP-9, 5.2 Ϯ 0.2 AUC). The severity of the disease in the 12M rats correlated with a modest decrease in creatinine clearance (Intact, 0.26 Ϯ 0.01; OVX, 0.22 Ϯ 0.01; OVXϩE 2 , 0.28 Ϯ 0.01 mg/min per 100 g) and increase in BUN (Intact, 20.3 Ϯ 2.1; OVX, 32.6 Ϯ 5.1; OVXϩE 2 , 24.3 Ϯ 2.4 mg/dl). The authors conclude that E 2 is renoprotective in the aging DSS rat by attenuating glomerulosclerosis and tubulointerstitial fibrosis.The rate of progression of cardiovascular and renal disease and hypertension increases with age and is lower in premenopausal women compared with age-matched men (1-3). Interestingly, a re-evaluation of the Modification of Diet in Renal Disease (MDRD) study showed that the differences in the rate of decline of renal function between men and women is reduced after age 52 yr (their dividing point) (4), suggesting that menopause may affect the progression of renal disease in women; however, no studies to date have clearly demonstrated this point, suggesting that our understanding of the contribution of ovarian hormones to the development of age-related disease processes remains unclear. The Women's Health Initiative (WHI) reported that hormone replacement therapy with the estrogen-progesterone combination Prempro (conjugated equine estrogen and progestin) causes a slight increase in the risk of cardiovascular disease in a large population of postmenopausal women (5,6). However, numerous studies indicate that estrogen alone has cardiovascular protective effects. Estrogen improves serum lipid levels, increases end...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Glomerulosclerosis and Tubulointerstitial Fibrosis are Attenuated with 17β-Estradiol in the Aging Dahl Salt Sensitive Rat

Maric¹,

Sandberg²,

Hinojosa‐Laborde³

2004

Journal of the American Society of Nephrology

192

136

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“…These data confirm and extend previous studies that reported that female patients with GS show milder symptoms than do male patients (40), which could be explained by a positive effect of estrogens. Several lines of evidence have shown that estrogens affect a variety of mediators in renal tissues (e.g., by stimulating the transcription and/or activity of nitric oxide synthase isoforms, interacting with components of the renin-angiotensin system [41]). In turn, such estrogen-mediated mechanisms could play a role in the association of male gender with faster progression in various types of renal disease (42).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional and Functional Analyses of SLC12A3 Mutations

Riveira-Muñoz¹,

Chang²,

Godefroid³

et al. 2007

Journal of the American Society of Nephrology

144

125

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Gitelman syndrome (GS) is a recessive salt-losing tubulopathy that is caused by mutations in the SLC12A3 gene that encodes the sodium-chloride co-transporter (NCC). GS is characterized by significant inter-and intrafamilial phenotype variability, with early onset and/or severe clinical manifestations in some patients. No correlations between the disease variability and the position/nature of SLC12A3 mutations have been investigated thus far. In this study, extensive mutational analyses of SLC12A3 were performed in 27 patients with GS, including genomic DNA sequencing, multiplex ligation-dependent probe amplification, cDNA analysis, and quantification of allele-specific transcripts, in parallel with functional analyses in Xenopus laevis oocytes and detailed phenotyping. Twenty-six SLC12A3 mutations were identified in 25 patients with GS, including eight novel (detection rate 80%). Transcript analysis demonstrated that splicing mutations of SLC12A3 lead to frameshifted mRNA subject to degradation by nonsense-mediated decay. Heterologous expression documented a novel class of NCC mutants with defective intrinsic transport activity. A subgroup of patients presented with early onset, growth retardation, and/or detrimental manifestations, confirming the potential severity of GS. The mutations that were associated with a severe presentation were the combination at least for one allele of a missplicing resulting in a truncated transcript that was downregulated by nonsense-mediated decay or a nonfunctional, cell surface-absent mutant. The most recurrent mutation on the second allele was a newly described NCC mutant that affected the functional properties of the co-transporter. These data suggest that the nature/position of SLC12A3 mutation, combined with male gender, is a determinant factor in the severity of GS and provide new insights in the underlying pathogenic mechanisms of the disease.

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“…Gender differences in disease susceptibility have been well characterized in many cardiovascular diseases (1)(2)(3). The increased risk for cardiovascular diseases in men and postmenopausal women (4) has been attributed primarily to lack of estrogen-mediated protection (5-7).…”

mentioning

confidence: 99%

Orchiectomy Attenuates Post-ischemic Oxidative Stress and Ischemia/Reperfusion Injury in Mice

Kim

Kil

Seok

et al. 2006

Journal of Biological Chemistry

115

116

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Males are much more susceptible to ischemia/reperfusion (I/R)-induced kidney injury when compared with females. Recently we reported that the presence of testosterone, rather than the absence of estrogen, plays a critical role in gender differences in kidney susceptibility to I/R injury in mice. Although reactive oxygen species and antioxidant defenses have been implicated in I/R injury, their roles remain to be defined. Here we report that the orchiectomized animal had significantly less lipid peroxidation and lower hydrogen peroxide levels in the kidney 4 and 24 h after 30 min of bilateral renal ischemia when compared with intact or dihydrotestosterone-treated orchiectomized males. The post-ischemic kidney expression and activity of manganese superoxide dismutase (MnSOD) in orchiectomized mice was much greater than in intact or dihydrotestosterone-administered orchiectomized mice. Four hours after 30 min of bilateral ischemia, superoxide formation was significantly lower in orchiectomized mice than in intact mice. In Madin-Darby canine kidney cells, a kidney epithelial cell line, 1 mM H 2 O 2 decreased MnSOD activity, an effect that was potentiated by pretreatment with dihydrotestosterone. Orchiectomy prevented the post-ischemic decrease of catalase activity. Treatment of male mice with manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP), a SOD mimetic, reduced the post-ischemic increase of plasma creatinine, lipid peroxidation, and tissue hydrogen peroxide. These results suggest that orchiectomy accelerates the post-ischemic activation of MnSOD and reduces reactive oxygen species and lipid peroxidation, resulting in reduced kidney susceptibility to I/R injury.Gender differences in disease susceptibility have been well characterized in many cardiovascular diseases (1-3). The increased risk for cardiovascular diseases in men and postmenopausal women (4) has been attributed primarily to lack of estrogen-mediated protection (5-7). Recently we demonstrated that male mice are much more susceptible to kidney ischemia/reperfusion (I/R) 5 injury when compared with female mice (8), and that orchiectomy decreases kidney susceptibility to I/R injury (9), whereas ovariectomy has no effect on kidney susceptibility to I/R injury (8). Testosterone administration to orchiectomized male or female mice reverses the protective phenotype, increasing susceptibility to kidney I/R injury. We concluded that the presence of testosterone, rather than the absence of estrogen, plays a critical role in the gender differences in kidney susceptibility to I/R injury. The detailed molecular mechanisms responsible for this testosterone effect remain to be defined.Ischemia/reperfusion markedly increases the production of reactive oxygen species (ROS) including superoxide anions, hydroxyl radicals, hypochlorous acid, hydrogen peroxide, and peroxynitrite (10). The abnormal excessive production of ROS results in lipid peroxidation, leukocyte activation, endothelial cell damage, and cytokine production, all of which contribute to tissue ...

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The Role of Gender in the Progression of Renal Disease

Cited by 123 publications

References 108 publications

Glomerulosclerosis and Tubulointerstitial Fibrosis are Attenuated with 17β-Estradiol in the Aging Dahl Salt Sensitive Rat

Glomerulosclerosis and Tubulointerstitial Fibrosis are Attenuated with 17β-Estradiol in the Aging Dahl Salt Sensitive Rat

Transcriptional and Functional Analyses of SLC12A3 Mutations

Orchiectomy Attenuates Post-ischemic Oxidative Stress and Ischemia/Reperfusion Injury in Mice

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