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1.  Geminin overexpression induces mammary tumors via suppressing cytokinesis 
Oncotarget  2011;2(12):1011-1027.
Aneuploidy plays an important role in the development of cancer. Here, we uncovered an oncogenic role for geminin in mitotic cells. In addition to chromatin, tyrosine phosphorylated geminin also localizes to centrosome, spindle, cleavage furrow and midbody during mitosis. Geminin binding to Aurora B prevents its binding to INCENP, and thus activation leading to lack of histone H3-(serine 10) phosphorylation, chromosome condensation failure, aborted cytokinesis and the formation of aneuploid, drug resistance cells. Geminin overexpressing human mammary epithelial cells form aneuploid, aggressive tumors in SCID mice. Geminin is overexpressed in more than half of all breast cancers analyzed. The current study reveals that geminin is a genuine oncogene that promotes cytokinesis failure and production of aneuploid, aggressive breast tumors when overexpressed and thus a worthy therapeutic target (oncotarget) for aggressive breast cancer.
PMCID: PMC3282064  PMID: 22184288
Geminin overexpression induces mammary tumors
2.  Expression of aromatase, androgen and estrogen receptors in peripheral target tissues in diabetes 
Steroids  2010;75(11):779-787.
Our previous studies have shown that diabetes in the male streptozotocin (STZ)-induced diabetic rat is characterized by a decrease in circulating testosterone and concomitant increase in estradiol levels. Interestingly, this increase in estradiol levels persists even after castration, suggesting extra-testicular origins of estradiol in diabetes. The aim of the present study was to examine whether other target organs of diabetes may be sources of estradiol. The study was performed in male Sprague-Dawley non-diabetic (ND), STZ-induced diabetic (D) and STZ-induced diabetic castrated (Dcas) rats (n=8-9/group). 14 weeks of diabetes was associated with decreased testicular (ND, 26.3±4.19; D, 18.4±1.54; P<0.05), but increased renal (ND, 1.83±0.92; D, 7.85±1.38; P<0.05) and ocular (D, 23.4±3.66; D, 87.1±28.1; P<0.05) aromatase activity. This increase in renal (Dcas, 6.30±1.25) and ocular (Dcas, 62.7±11.9) aromatase activity persisted after castration. The diabetic kidney also had increased levels of tissue estrogen (ND, 0.31 ±0.01; D, 0.51±0.11; Dcas, 0.45±0.08) as well as estrogen receptor alpha protein expression (ND, 0.63±0.09; D, 1.62±0.28; Dcas, 1.38±0.20). These data suggest that in male STZ-induced diabetic rats, tissues other than the testis may become sources of estradiol. In particular, the diabetic kidney appears to produce estradiol following castration, a state that is associated with a high degree or renal injury. Overall, our data provides evidence for the extra-testicular source of estradiol that in males, through an intracrine mechanism, may contribute to the development and/or progression of end-organ damage associated with diabetes.
PMCID: PMC2891268  PMID: 20064538
diabetes; aromatase; estrogen; testosterone; estrogen receptor; androgen receptor; testis; kidney; eye
3.  Association between testosterone, estradiol and sex hormone binding globulin levels in men with type 1 diabetes with nephropathy 
Steroids  2010;75(11):772-778.
Male sex is a risk factor for development and progression of diabetic nephropathy; however, the relationship between sex hormone levels and diabetic nephropathy in type 1 diabetic men is unknown. This was a prospective follow-up study as part of the nationwide Finnish Diabetic Nephropathy (FinnDiane) Study; 297 patients were followed for 5.9±1.5 years. Serum total testosterone (Tt) and estradiol (Te), calculated free testosterone (cFt) and estradiol (cFe) and sex hormone binding globulin were measured at baseline and correlated with urinary albumin excretion rate, estimated glomerular filtration rate and markers of metabolic syndrome. Diabetes without renal disease was associated with decreased Tt (p<0.001), Te (p<0.001) and cFt (p=0.001) levels compared with healthy non-diabetic men. With progression of renal disease from micro- to macroalbuminuria, this decrease in serum Tt was even more pronounced. Cox regression showed that cFt and cFe were independent predictors of the progression from macroalbuminuria to end-stage renal disease. Our study shows that men with type 1 diabetes exhibit dysregulated sex hormone levels, which is most pronounced in men with progressive renal disease, suggesting that sex hormones may play a role in the pathogenesis of diabetic nephropathy associated with type 1 diabetes.
PMCID: PMC2891875  PMID: 20105436
type 1 diabetes; diabetic nephropathy; albuminuria; testosterone; SHBG; estradiol
4.  The TNF-α antagonist etanercept decreases blood pressure and protects the kidney in a mouse model of systemic lupus erythematosus 
Hypertension  2010;56(4):643-649.
Chronic inflammation has been implicated in the pathology of hypertension; however, the role for specific cytokines remains unclear. We tested whether TNF-α blockade with etanercept (Etan) reduces mean arterial pressure (MAP) in a female mouse model of systemic lupus erythematosus (SLE). SLE is a chronic inflammatory disorder with prevalent hypertension. Thirty week old SLE (NZBWF1) and control mice (NZW/LacJ) received Etan (0.8mg/kg SC weekly) for 4 weeks or vehicle. MAP (mmHg) was increased in SLE mice (150±5 vs. 113±5 in controls, p<0.05) and was lower in Etan treated SLE mice (132±3) but not controls (117±5). Albuminuria (µg/mg creatinine) was elevated in SLE mice (28742±9032 vs. 1075±883 p<0.05) and was lower in Etan treated SLE mice (8154±3899) but not control animals (783±226). Glomerulosclerosis (% of glomeruli) was evident in SLE mice (2.5±1.6 vs. 0.0±0.0 in controls, p<0.05) and was ameliorated in Etan treated SLE mice (0.1±0.1). Renal cortex CD68+ cell staining (% area) was elevated in SLE mice (4.75±0.80 vs. 0.79±0.12 in controls, p<0.05) and was lower in Etan treated SLE mice (2.28±0.32) but not controls (1.43±0.25). Renal cortex NADPH oxidase activity (RLU/mg of protein) was higher in SLE mice compared to controls (10718±1276 vs. 7584±229, p<0.05) and lowered in Etan treated SLE mice (6645±490). Renal cortex NFκB (phosphorylated and non-phosphorylated) was increased in SLE mice compared to controls and lower in Etan treated SLE mice. These data suggest that TNF-α mechanistically contributes to the development of hypertension in a chronic inflammatory disease through increased renal NFκB, oxidative stress and inflammation.
PMCID: PMC2989495  PMID: 20696988
Systemic Lupus Erythematosus; Hypertension; Inflammation; TNF-α-Oxidative Stress; cytokine
5.  Risk factors for cardiovascular disease in women with diabetes 
Gender medicine  2010;7(6):551-556.
PMCID: PMC3179621  PMID: 21195355
Estrogens; hyperglycemia; dyslipidemia; obesity; hypertension; sex hormones; heart
6.  17β-estradiol attenuates diabetic kidney disease via regulating extracellular matrix and transforming growth factor-beta protein expression and signaling 
We have previously shown that supplementation with 17β-estradiol (E2) from the onset of diabetes attenuates the development of diabetic renal disease. The aim of this study was to examine if E2 can also attenuate the disease process once it has already developed. The study was performed in non-diabetic (ND) and streptozotocin (STZ)-induced diabetic (D) Sprague-Dawley rats. E2 supplementation began after 9 weeks of diabetes for further 8 weeks. Diabetes was associated with an increase in urine albumin excretion (UAE) (ND; 9.4±1.0; D, 56.2±8.9 mg/day; P<0.001), glomerulosclerosis (GSI; ND, 0.13±0.02; D, 1.38±0.09 AU; P<0.01), tubulointerstitial fibrosis (TIFI; ND, 0.17±0.04; D, 1.35±0.10 AU; P<0.01), renal cortical collagen type I (CI; ND, 1.02±0.05; D, 1.83±0.03 ROD; P<0.001), collagen type IV (CIV; ND, 0.97±0.05; D, 1.56±0.03 ROD, P<0.01), laminin (L; ND, 1.03±.0.03; D, 1.80±0.02 ROD; P<0.001), PAI-1 (ND, 0.34±0.08; D, 0.88±0.03 ROD; P<0.01), TIMP-1 (ND, 0.30±0.07; D, 0.93±0.14 ROD; P<0.01), TIMP-2 (ND, 0.40±0.09; D, 0.96±0.11 ROD; P<0.01), TGF-β (ND; 0.70±0.14; D, 1.63±0.08 ROD; P<0.001), TGF-βRI (ND, 0.69±0.23; D, 1.47±0.14 ROD; P<0.05), TGF-βRI (ND, 0.40±0.09; D, 1.07±0.10 ROD; P<0.001), Smad2/3 (ND, 0.68±0.08; D, 1.71±0.03 ROD; P<0.01), pSmad2/3 (ND, 0.28±0.07; D, 0.74±0.12 ROD, P<0.05) and Smad4 (ND, 0.82±.0.24; D, 1.77±0.03 ROD; P<0.05) protein expression and CD68-positive cells (ND, 5.0±0.8; D, 33.8±2.4 cells/mm2; P<0.001). Decreases in MMP-2 (ND, 1.35±0.06; D, 0.98±0.05 ROD; P<0.05) protein expression and activity (MMP-2 act; ND, 0.39±0.09; D, 0.22±0.01 ROD; P<0.05), Smad6 (ND, 0.85±0.10; D, 0.40±0.03 ROD; P<0.001) and Smad7 (ND, 1.41±0.06; D, 1.01±0.05 ROD; P<0.05) protein expression were also associated with D. E2 supplementation either completely or partially attenuated these changes. We conclude that E2 attenuates the progression of disease once it has already developed via regulating extracellular matrix, TGF-β and expression of its downstream regulatory proteins.
PMCID: PMC3179625  PMID: 17686959
diabetes; kidney; estrogen; extracellular matrix; fibrosis; glomerulosclerosis; transforming growth factor-beta; Smads
7.  Renoprotective effects of a selective estrogen receptor modulator, Raloxifene in an animal model of diabetic nephropathy 
American journal of nephrology  2007;27(2):120-128.
Our previous studies have shown that supplementation with 17-β estradiol (E2) from the onset of diabetes attenuates diabetic nephropathy. But, E2 is accompanied by feminizing effects as well as adverse side effects on other organs. The current study examined the renoprotective effects of a selective estrogen receptor modulator, raloxifene (RAL), in an experimental model of diabetic nephropathy. RAL activates estrogen receptors and estrogen receptor-mediated cellular events without the side effects of E2.
The study was performed in Sprague-Dawley non-diabetic (ND), streptozotocin (STZ)-induced diabetic (D) and STZ-induced diabetic+raloxifene (D+RAL) rats (n=6/group).
After 12 weeks of treatment, D was associated with increased albumin excretion (UAE; ND, 4.2±0.4; ND, 41.3±9.0 mg/day), glomerulosclerosis (GSI; ND, 0.26±0.04; D, 1.86±0.80 AU), tubulointerstitial fibrosis (TIFI; ND, 0.37±0.05; D, 2.12±0.50 AU), increased collagen type I (CI; ND, 1.31±0.07; D, 4.65±0.09 ROD), collagen type IV (CIV; ND, 0.64±0.03; D, 1.37±0.11 ROD) and transforming growth factor beta protein expression (TGF-β; ND, 0.65±0.08; D, 1.25±0.10 ROD), increased density of CD68-positive cells (CD68; ND, 1.37±3.02; D, 29.2±1.74 cells/mm2) and increased plasma levels of interleukin-6 (IL-6; ND, 14.8±5.0; D, 51.3±14.0 pg/ml). Treatment with RAL partially or fully attenuated these processes (UAE, 21.0±5.0 mg/day; GSI, 0.40±0.06 AU; TIFI, 0.20±0.04 AU; CI, 2.55±0.49 ROD; CIV, 0.70±0.09 ROD; TGF-β, 0.91±0.08 ROD; CD68, 6.03±2.38 cells/mm2; IL-6, 31.2±5.0 pg/ml).
Our data indicate that treatment with RAL attenuates albuminuria and renal structural changes associated with diabetes.
PMCID: PMC3179626  PMID: 17308373
diabetes; kidney; raloxifene; glomerulosclerosis; tubulointerstitial fibrosis
8.  Estrogens and the Diabetic Kidney 
Gender medicine  2008;5(Suppl A):S103-S113.
Across all ages, the incidence and rate of progression of most nondiabetic renal diseases are markedly higher in men compared with age-matched women. These observations suggest that female sex may be renoprotective. In the setting of diabetes, however, this female protection against the development and progression of renal disease is diminished.
This review aimed to summarize our current understanding of sex differences in the development and progression of diabetic renal disease, and of the contribution of sex hormones, particularly estrogens, to the pathophysiology of this disease. We also attempted to answer why female sex does not protect the diabetic kidney.
The review employed PubMed as a search database using terms such as gender, sex, diabetes, diabetic nephropathy, estrogens, sex hormones, as well as targeted searches such as gender/sex differences in diabetic renal disease. Manuscripts identified from cited references were also used. Searches were restricted to English-language articles, while no restrictions were imposed on the publication dates.
Although the existing data regarding the sex differences in the incidence and progression of diabetic renal disease are inconclusive, the undisputed fact is that women with either type 1 or type 2 diabetes mellitus exhibit a much higher incidence of renal disease compared with nondiabetic women. It is conceivable that the loss of female sex as a renoprotective factor in diabetes may be related to the abnormal regulation of sex hormone concentrations. Both clinical and experimental data suggest that diabetes may be associated with an imbalance in estradiol concentrations. Supplementation with 17β-estradiol or administration of selective estrogen receptor modulators reduces the incidence of diabetes and attenuates the progression of diabetic renal disease.
Serum concentrations of ovarian hormones may provide a new means for predicting future risk of renal complications in diabetes. Exogenous steroid hormones may be an effective treatment for attenuating the progression of diabetic nephropathy.
PMCID: PMC3178838  PMID: 18395675
estrogen; diabetes; diabetic nephropathy; sex hormones
9.  Age-Related Renal Disease in Dahl Salt Sensitive Rats is Attenuated with 17β-Estradiol Supplementation by Modulating Nitric Oxide Synthase Expression 
Gender medicine  2008;5(2):147-159.
The incidence of chronic renal disease in women increases with aging especially after menopause suggesting that the loss of sex hormones contributes to the development and progression of renal disease. However, the mechanisms by which sex hormones, estrogens in particular, contribute to the disease process are unclear.
The present study examined the effects of ovariectomy (OVX) with or without 17β-estadiol (E2) supplementation (OVX+E2) on the expression of inducible (iNOS) and endothelial (eNOS) nitric oxide synthase in the kidney.
The study was performed in young (4 months, 4M) and aged (12 months, 12M) Dahl salt sensitive (DSS) rats fed a low salt (0.1% NaCl) diet.
OVX in the aged rats was associated with 35% and 25% decreases, respectively, in medullary iNOS (4M OVX, 1.81±0.14 vs. 12M OVX, 1.17±0.16, P<0.05) and eNOS (4M OVX, 1.91±0.09 vs. 12M OVX, 1.43±0.15, P<0.05) protein expression and a 25-fold increase in the abundance of CD68-positive cells indicating macrophage infiltration (4M OVX, 1.18±0.09 vs. 12M OVX, 30.0±0.74, P<0.001). E2 supplementation either partially or completely attenuated these changes in iNOS (4M OVX+E2, 2.26±0.08 vs. 12M OVX+E2, 1.70±0.09, P<0.05), eNOS (4M OVX+E2, 2.03±0.07 vs 12M OVX+E2, 1.77±0.11) and CD68 (4M OVX+E2, 1.46±0.07 vs. 12M OVX+E2, 6.87±1.6, P<0.01) associated with OVX in the aging kidney.
These data suggest that ovarian E2 loss with aging may contribute to the development of age-related renal disease through downregulation of iNOS and eNOS protein abundance and increased renal inflammation. Furthermore, E2 supplementation may be protective in the aging kidney by attenuating these changes.
PMCID: PMC3177159  PMID: 18573482
kidney; aging; estradiol; hypertension; nitric oxide; nitric oxide synthase
10.  Obesity, metabolic syndrome and diabetic nephropathy 
Contributions to nephrology  2011;170:28-35.
Diabetic nephropathy is becoming an increasingly important cause of morbidity and mortality worldwide owing to the increasing prevalence of type 2 diabetes, largely driven by increasing obesity. There is considerable evidence that obesity, hypertension and other elements of the metabolic syndrome also contribute to the progression of renal disease independent of diabetes. How they interact and contribute to diabetic nephropathy, however, is not completely understood. Clinical diabetic nephropathy is preceded by an increase in glomerular filtration rate (GFR), microalbuminuria and glomerular hypertrophy. Poor glycemic control and elevated systolic blood pressure exacerbate proteinuria and renal injury that may culminate in end-stage renal disease. A similar sequence of events may lead to obesity-related renal disease even in the absence of diabetes. This article compares and contrasts factors involved in the development of glomerular hemodynamic and kidney pathological processes associated with diabetes and obesity.
PMCID: PMC3177237  PMID: 21659755
11.  Role of renal microcirculation in experimental renovascular disease 
Nephrology Dialysis Transplantation  2009;25(4):1079-1087.
Background. Renal artery stenosis (RAS) causes renal injury partly via microvascular (MV) endothelial dysfunction and damage. Vascular endothelial growth factor (VEGF) is crucial for preservation of microvasculature and promotes vascular proliferation and endothelial repair. We have previously shown that MV rarefaction is associated with decreased VEGF in the kidney exposed to chronic RAS, accompanied by deteriorated renal function and fibrosis. We hypothesized that preserving the renal microcirculation in the stenotic kidney will halt the progression of renal damage.
Methods. Unilateral RAS was induced in 16 pigs. In eight, VEGF (0.05 micrograms/kg) was infused intra-renally at the onset of RAS. After 6 weeks, single-kidney haemodynamics and function were assessed using in vivo multi-detector computed tomography (CT). Renal microvessels, angiogenic pathways and morphology were investigated ex vivo using micro-CT, real-time PCR and histology.
Results. Blood pressure and degree of RAS was similar in RAS and RAS + VEGF pigs. Single-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were reduced in RAS compared to Normal (221.1 ± 46.5 and 29.9 ± 3.8 vs. 522.5 ± 60.9 and 49.3 ± 3.4 mL/min, respectively, P < 0.05), accompanied by decreased cortical MV density and increased renal fibrosis. Pre-emptive administration of VEGF preserved MV architecture, attenuated fibrosis and normalized RBF and GFR (510.8 ± 50.9 and 39.9.1 ± 4.1 mL/min, P = not significant vs. Normal).
Conclusions. This study underscores the importance of the renal microcirculation in renovascular disease. Intra-renal administration of VEGF preserved renal MV architecture and function of the stenotic kidney, which in turn preserved renal haemodynamics and function and decreased renal fibrosis. These observations suggest that preventing renal MV loss may be a potential target for therapeutic approaches for patients with chronic renovascular disease.
PMCID: PMC2902859  PMID: 19934087
computerized tomography; microcirculation; renal artery stenosis; renal haemodynamics; VEGF
12.  Imbalance in Sex Hormone Levels Exacerbates Diabetic Renal Disease 
Hypertension  2008;51(4):1218-1224.
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 (n=10 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-β 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.
PMCID: PMC2858393  PMID: 18259041
diabetes; kidney; sex hormones; glomerulosclerosis; tubulointerstitial fibrosis
13.  Association between lipid profile and circulating concentrations of estrogens in young men 
Atherosclerosis  2008;203(1):257-262.
Men show higher rates of cardiovascular morbidity and mortality than pre-menopausal women and this sexual dimorphism may be related to sex-specific effects of sex steroids on cardiovascular risk factors. Unlike androgens, estrogens were not extensively investigated in relation to cardiovascular phenotypes in men.
We examined associations of estradiol and estrone and their precursors (total testosterone and androstenedione) with traditional cardiovascular risk factors (lipids, blood pressure, body mass) in 933 young (median age – 19 years), apparently healthy Polish men.
Total estradiol was associated with total cholesterol (p=0.006) and HDL-cholesterol (p<0.001) and estrone showed the strongest associations with both total cholesterol (p<0.001) and LDL-cholesterol (p<0.001) in the unadjusted ANOVA analysis. In the multivariable adjusted models in which other independent variables were held as constant one standard deviation increase in estradiol level was associated with 6%-standard deviation increase in total cholesterol (standardized B=0.06, p=0.038) and 6%-standard deviation decrease in HDL-cholesterol (standardized B=-0.06, p=0.036). An increase in estrone levels by one standard deviation was associated with respective 12%- and 13%-standard deviation increases in total cholesterol (standardized B=0.12, p<0.001) and LDL-cholesterol levels (standardized B=0.12, p<0.001) after controlling for other predictors of lipids. Estrone correlated linearly with androstenedione (r=0.28, p<0.001) but there was no correlation between estradiol and testosterone. Estrogens retained their independent associations with lipids after adjustment for their biochemical precursors in the multivariable analysis.
Increased levels of estrogens are associated with unfavourable lipid profile in men and that this association is apparent early in life, before cardiovascular disease manifestations.
PMCID: PMC2693280  PMID: 18639879
lipids; estrogens; sex steroids; association; risk factors
14.  Inverse Associations Between Androgens and Renal Function: The Young Men Cardiovascular Association (YMCA) Study 
American journal of hypertension  2008;22(1):100-105.
Men exhibit higher risk of nondiabetic renal diseases than women. This male susceptibility to renal disease may be mediated by gender-specific factors such as sex hormones.
We have undertaken a cross-sectional examination of associations between renal function (creatinine clearance estimated based on Cockcroft–Gault equation) and circulating levels of sex steroids (total testosterone, total estradiol, estrone, androstenedione, dehydroepiandrosterone sulfate (DHEA-S), and dihydrotestosterone) in 928 young (mean age: 18.5 ± 1.2 years) men.
Both androstenedione and DHEA-S showed inverse linear associations with renal function in the crude analysis of lean men (those with body mass index (BMI) less than median). However, only DHEA-S retained its association with renal function in lean subjects after adjustment—assuming no changes in other independent variables 1 s.d. increase in DHEA-S was associated with 13%-s.d. decrease in creatinine clearance (P = 0.004). Testosterone decreased across tertiles of creatinine clearance only in the crude analysis of nonlean (BMI greater than median) subjects (P < 0.001). The adjusted regression analysis that assumed no changes in other independent variables showed that 1 s.d. increase in total testosterone was associated with 11%-s.d. decrease in creatinine clearance of nonlean men (P = 0.006). Factor analysis confirmed an inverse association of renal function with both sex steroids and a different pattern of their loadings on glomerular filtration–related factors in lean (DHEA-S) and nonlean (testosterone) subjects.
Our data may suggest that androgens are inversely associated with estimated renal function in apparently healthy men without history of cardiovascular disease.
PMCID: PMC2808108  PMID: 19096379

Results 1-14 (14)