Estrogens and the diabetic kidney

Maric, Christine; Sullivan, Shannon D.

doi:10.1016/j.genm.2008.03.010

Cited by 74 publications

(75 citation statements)

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“…Several experimental studies have demonstrated a renoprotective role of exogenous oestrogens in models of type 1 diabetic retinopathy and nephropathy [36][37][38][39]. However, an experimental model of type 1 diabetes has also, however, shown that relative balance, rather than the absolute levels of sex hormones, correlates with conditions associated with diabetic complications [40].…”

Section: Discussionmentioning

confidence: 99%

Sex-related differences in the long-term risk of microvascular complications by age at onset of type 1 diabetes

et al. 2011

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Aims/hypothesis This study examined sex-related differences in the cumulative risk of proliferative retinopathy (PR) and end-stage renal disease (ESRD) over 40 years of duration of type 1 diabetes according to age at diabetes onset. Methods We assessed 4,416 patients from the Finnish Diabetic Nephropathy Study population. Kaplan-Meier analysis was used to provide cumulative incidence rates and Cox regression analyses for HRs. Results There were no sex-related differences in the cumulative incidence of ESRD in patients diagnosed with type 1 diabetes between 0 to 4 and 5 to 9 years. Thereafter the risk started to diverge. The cumulative incidence of ESRD in patients diagnosed between 10 to 14 and ≥15 years was 17.4% (95% CI 13.4-21.2) and 13.0% (9.6-16.2) respectively in women, while in men it was 32.2% (28.0-36.1) and 24.6% (20.8-28.1) respectively. The respective HRs were (onset at 10 to 14 years) 1.9 (p<0.0001) and (onset at ≥15 years) 1.8 (p<0.001), respectively. There was no difference in the risk of PR between men and women diagnosed between 0 and 4 years of age, but progressive sex-related differences in the cumulative incidence of PR were observed with increasing age at onset. The HRs for men in the age-at-onset groups 5 to 9, 10 to 14 and ≥15 years of age were 1.3 (95% CI 1.0-1.6), 1.3 (1.1-1.6) and 2.1 (1.6-2.6) compared with women in these groups, respectively. Conclusions/interpretation The difference between the sexes with regard to risk of diabetic microvascular complications is highly dependent on the age at onset of diabetes. The risk of ESRD and PR risk doubled in men compared with women when age at onset was ≥15 years.

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Section: Discussionmentioning

confidence: 99%

Sex-related differences in the long-term risk of microvascular complications by age at onset of type 1 diabetes

et al. 2011

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“…2 The loss of female "protection" in diabetes remains controversial. 3,4 Moreover, some risk factors for DN differ between men and women, 5 suggesting sex-specific mechanisms that may be related to differences in the hormonal profiles as estrogen exerts renoprotective effects in nondiabetic persons. 4 Furthermore, women with T1D have lower estradiol concentrations and a hormonal profile that more closely resembles that of men.…”

mentioning

confidence: 99%

“…4 Furthermore, women with T1D have lower estradiol concentrations and a hormonal profile that more closely resembles that of men. 3 Nevertheless, the role of estrogen in the progression of DN still remains ambiguous. 6 DN clusters in families, and the sibling risk ratio is conspicuously high for ESRD, suggesting that genetic variation influences the risk of ESRD.…”

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confidence: 99%

Chromosome 2q31.1 Associates with ESRD in Women with Type 1 Diabetes

Sandholm

McKnight

Salem

et al. 2013

Journal of the American Society of Nephrology

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Sex and genetic variation influence the risk of developing diabetic nephropathy and ESRD in patients with type 1 diabetes. We performed a genome-wide association study in a cohort of 3652 patients from the Finnish Diabetic Nephropathy (FinnDiane) Study with type 1 diabetes to determine whether sex-specific genetic risk factors for ESRD exist. A common variant, rs4972593 on chromosome 2q31.1, was associated with ESRD in women (P,5310 28 ) but not in men (P=0.77). This association was replicated in the meta-analysis of three independent type 1 diabetes cohorts (P=0.02) and remained significant for women (P,5310 28 ; odds ratio, 1.81 [95% confidence interval, 1.47 to 2.24]) upon combined meta-analysis of the discovery and replication cohorts. rs4972593 is located between the genes that code for the Sp3 transcription factor, which interacts directly with estrogen receptor a and regulates the expression of genes linked to glomerular function and the pathogenesis of nephropathy, and the CDCA7 transcription factor, which regulates cell proliferation. Further examination revealed potential transcription factor-binding sites within rs4972593 and predicted eight estrogen-responsive elements within 5 kb of this locus. Moreover, we found sex-specific differences in the glomerular expression levels of SP3 (P=0.004). Overall, these results suggest that rs4972593 is a sex-specific genetic variant associated with ESRD in patients with type 1 diabetes and may underlie the sex-specific protection against ESRD. 24: 153724: -154324: , 201324: . doi: 10.1681 In the non-diabetic population, ESRD is more common in men than in women, and women seem protected from ESRD until menopause. 1 Similarly, diabetic nephropathy (DN) and ESRD are more common in diabetic men than in diabetic women. 2 However, the female "protection" from ESRD appears attenuated in diabetic women because women who were younger than age 15 years at onset of type 1 diabetes (T1D) do not differ from diabetic men regarding their incidence of ESRD. 2 The loss of female "protection" in diabetes remains controversial. 3,4 Moreover, some risk factors for DN differ between men and women, 5 suggesting sex-specific mechanisms that may be related to differences in the hormonal profiles as estrogen exerts renoprotective effects in nondiabetic persons. 4 Furthermore, women with T1D have lower estradiol concentrations and a hormonal profile that more closely resembles that of men. 3 Nevertheless, the role of estrogen in the progression of DN still remains ambiguous. 6 DN clusters in families, and the sibling risk ratio is conspicuously high for ESRD, suggesting that genetic variation influences the risk of ESRD. 7 We previously identified two genetic loci that are associated with ESRD in patients with T1D, namely AFF3 and RGMA-MCTP2. 8 However, no genetic variants have so far been robustly associated with ESRD in a sex-specific manner. Therefore, we studied common genetic variation affecting the risk of ESRD in men and women separately, using a genomewide association ...

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“…The influence of estrogens on the development and progression of diabetic kidney damage, although a subject of intense translational research effort, remains a matter of controversy [1][2][3][4][5]. The aim of this review will be to summarize the clinical and experimental data regarding the effects of estrogens on the development and progression of diabetes-induced kidney damage, with special regards to the most recent data concerning podocyte injury and dysfunction.…”

mentioning

confidence: 99%

“…The uncertainty of the contribution of gender to the progression of renal disease is even greater when we consider diabetes-induced kidney damage, in the setting of either type 1 or type 2 diabetes [2,3]. Several clinical studies indicate that diabetic kidney damage progresses faster in males than in females [16][17][18][19][20][21][22].…”

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confidence: 99%

Estrogens and Progression of Diabetic Kidney Damage

Doublier¹,

Lupia²,

Catanuto³

et al. 2011

CDR

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It is generally accepted that estrogens affect and modulate the development and progression of chronic kidney diseases (CKD) not related to diabetes. Clinical studies have indeed demonstrated that the severity and rate of progression of renal damage tends to be greater among men, compared with women. Experimental studies also support the notion that female sex is protective and male sex permissive, for the development of CKD in non-diabetics, through the opposing actions of estrogens and testosterone. However, when we consider diabetes-induced kidney damage, in the setting of either type 1 or type 2 diabetes, the contribution of gender to the progression of renal disease is somewhat uncertain. Previous studies on the effects of estrogens in the pathogenesis of progressive kidney damage have primarily focused on mesangial cells. More recently, data on the effects of estrogens on podocytes, the cell type whose role may include initiation of progressive diabetic renal disease, became available.The aim of this review will be to summarize the main clinical and experimental data on the effects of estrogens on the progression of diabetes-induced kidney injury. In particular, we will highlight the possible biological effects of estrogens on podocytes, especially considering those critical for the pathogenesis of diabetic kidney damage.

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Estrogens and the diabetic kidney

Cited by 74 publications

References 84 publications

Sex-related differences in the long-term risk of microvascular complications by age at onset of type 1 diabetes

Sex-related differences in the long-term risk of microvascular complications by age at onset of type 1 diabetes

Chromosome 2q31.1 Associates with ESRD in Women with Type 1 Diabetes

Estrogens and Progression of Diabetic Kidney Damage

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