Pleiotropic effects of dihydrotestosterone in immortalized mouse proximal tubule cells Technical Note

Ouar, Zahia; Solé, Esther; Bens, Marcelle; Rafestin‐Oblin, Marie‐Edith; Meseguer, Anna; Vandewalle, Alain

doi:10.1046/j.1523-1755.1998.00721.x

Cited by 19 publications

(18 citation statements)

References 6 publications

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“…A decrease in 3␤-HSD4 expression could lead to an increase in dihydrotestosterone levels. Dihydrotestosterone has been demonstrated to cause an increase in cell proliferation in a proximal tubule cell line (25); thus decreased 3␤-HSD4 expression could result in increased proliferation of proximal tubule cells. Our results are consistent with this hypothesis as we found both a decrease in 3␤-HSD4 mRNA abundance and an increase in cell proliferation in kidneys from post-ovarian failure diabetic mice compared with cycling diabetic mice and control mice.…”

Section: Discussionmentioning

confidence: 99%

Hormonal status affects the progression of STZ-induced diabetes and diabetic renal damage in the VCD mouse model of menopause

Keck¹,

Romero-Aleshire²,

Cai³

et al. 2007

American Journal of Physiology-Renal Physiology

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Changes in the estrogen/testosterone balance at menopause may negatively influence the development of diabetic kidney disease. Furthermore, recent studies suggest that changes in hormone levels during perimenopause may influence disease development. Injection of 4-vinylcyclohexene diepoxide (VCD) in B 6C3F1 mice induces gradual ovarian failure, preserving both the perimenopausal (peri-ovarian failure) and menopausal (post-ovarian failure) periods. To address the impact of the transition into menopause on the development of diabetes and diabetic kidney damage, we used streptozotocin (STZ)-induced diabetes in the VCD model of menopause. After 6 wk of STZ-induced diabetes, blood glucose was significantly increased in post-ovarian failure (post-OF) diabetic mice compared with cycling diabetic mice. In peri-ovarian failure (peri-OF) diabetic mice, blood glucose levels trended higher but were not significantly different from cycling diabetic mice, suggesting a continuum of worsening blood glucose across the menopausal transition. Cell proliferation, an early marker of damage in the kidney, was increased in post-OF diabetic mice compared with cycling diabetic mice, as measured by PCNA immunohistochemistry. In post-OF diabetic mice, mRNA abundance of early growth response-1 (Egr-1), collagen-4␣1, and matrix metalloproteinase-9 were increased and 3␤-hydroxysteroid dehydrogenase 4 (3␤-HSD4) and transforming growth factor-␤2 (TGF-␤2) were decreased compared with cycling diabetic mice. In peri-OF diabetic mice, mRNA abundance of Egr-1 and 3␤-HSD4 were increased, and TGF-␤2 was decreased compared with cycling diabetic mice. This study highlights the importance and utility of the VCD model of menopause, as it provides a physiologically relevant system for determining the impact of the menopausal transition on diabetes and diabetic kidney damage. diabetes; 3␤-HSD4; perimenopause; real-time PCR; estrogen DIABETES IS ONE OF THE MOST prevalent and costly diseases afflicting developed countries, with estimates placing the current global cost of diabetes at $150 billion a year (1). Approximately one-third of all diabetics die of end-stage renal disease (33) due to progressive renal damage and hypertension.17␤-Estradiol is considered protective against the development and progression of many diseases, including cardiovascular (9) and renal disease (34). Premenopausal women have slower rates of progression of nondiabetic renal disease than age-matched men (23), a difference that seems to disappear after menopause (3). The impact of estrogen on diabetic renal disease is less clear, however. Several studies demonstrate a decreased incidence of diabetic renal disease in women, but others have found no difference between men and women (34).The 5-10 years preceding menopause is termed perimenopause, and during this time estrogen levels fluctuate, with periods of low estrogen interspersed with periods of very high estrogen (31). The periods of low estrogen become more frequent as a woman approaches menopause until circulating levels of 17␤...

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Section: Discussionmentioning

confidence: 99%

Hormonal status affects the progression of STZ-induced diabetes and diabetic renal damage in the VCD mouse model of menopause

Keck¹,

Romero-Aleshire²,

Cai³

et al. 2007

American Journal of Physiology-Renal Physiology

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“…Relative CAT\β-gal activity shows that maximal efficiency occurs at the 1 µM DHT dose for both constructs in both cultured cell types. This concentration of DHT was previously reported to be the most effective in the induction of domes formed by PKSV-PCT and PKSV-PR cells, corresponding to localized regions of the monolayer lifted from the Petri dishes, which are good indicators of vectorialized ionic transport processes and differentiation state [9]. This concentration of DHT was also reported to be the most effective for maximal androgendependent transactivation of the pCAT1430 promoter in human breast-cancer cells [22], which was also used as a control in the present study.…”

Section: Androgen-dependent Transactivation Of the Kap Promoter In Momentioning

confidence: 91%

“…Several studies have shown that these two proximal-tubule cell lines have conserved the main features of the parental cells from which they were derived [6][7][8]. We also showed that levels of the kidney androgen-regulated protein (KAP) and β-glucuronidase ( β-gluc) transcripts, differentially expressed in two cultured PKSV-PCT and PKSV-PR cell lines, decreased when cells were shifted from a serum-supplemented to a steroid-free medium, whereas DHT induced a slight increase in β-gluc and a more marked increase in KAP transcripts in both cell lines [9].…”

Section: Introductionmentioning

confidence: 99%

Hormone-specific regulation of the kidney androgen-regulated gene promoter in cultured mouse renal proximal-tubule cells

Soler¹,

Tornavaca²,

Solé³

et al. 2002

Biochemical Journal

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The kidney androgen-regulated protein (KAP) is specifically expressed and differentially regulated by androgens and tri-iodothyronine (T3) in intact mouse early (PCT) and late (PR) proximal-tubule cells. Until now, detailed characterization of the molecular elements mediating androgen-responsive gene expression in the kidney has been hampered by the lack of appropriate cultured cell systems suitable for DNA transfection studies. In the present study we have analysed the hormone-dependent transactivation of the KAP gene promoter in immortalized differentiated PCT and PR proximal-tubule cells derived from L-PK/Tag1 transgenic mice. Transient transfection studies with different KAP promoter constructs indicated that a 224bp-truncated fragment was sufficient to mediate cell-specific expression of the KAP promoter. Dihydrotestosterone (DHT) stimulated in an androgen-dependent manner the transactivation of KAP in PCT and PR cells, while mutation of a putative androgen-response element (ARE) sequence located at −39bp from the transcription initiation site abolished the transactivation induced by DHT. Furthermore, insulin-like growth factor 1 (IGF-1), but not T3, enhanced the androgen-dependent transactivation of KAP in cultured PCT cells. These results demonstrate that the short 224bp fragment of the KAP promoter is sufficient to drive the proximal-tubule androgen-specific regulated expression of KAP and reveal synergistic interactions between IGF-1 and androgens for KAP regulation in PCT cells.

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“…After androgen stimulation, all three genes are expressed in epithelial cells of proximal convoluted tubules (segments S1 and S2) of cortical nephrons, but Kap is also expressed in the epithelial cells of proximal convoluted tubules in the juxtamedullary region (S3 segments). The differential effects of androgen action on ␤ -glucuronidase and Kap expression have been confirmed in immortalized proximal tubule cells (Ouar et al 1998).…”

Section: Discussionmentioning

confidence: 82%

“…Morphometric measurements indicated that the decreased expression of Kap in 1-month-old APRT-deficient male mice compared with wild-type controls was not the result of proximal tubule loss but may reflect the effects of hormonal changes in APRT deficiency. Androgens have a stimulating effect on cell growth through hypertrophy or hyperplasia (Preisig 1999), but in mouse kidney the primary effect appears to be hypertrophy (Ouar et al 1998). The growth stimulation seen in proximal tubules from APRT-deficient mice is due to hypertrophy rather than hyperplasia, and this effect may again be due to hormonal changes.…”

Section: Discussionmentioning

confidence: 99%

Gender- and Age-dependent Changes in Kidney Androgen Protein mRNA Expression in a Knockout Mouse Model for Nephrolithiasis

Tzortzaki

Glass

Yang

et al. 2002

J Histochem Cytochem.

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S U M M A R Y Kidney androgen-regulated protein (Kap) is the most abundant protein in the mouse kidney, but its function is unknown. We previously observed a significant decrease in Kap mRNA expression in whole kidney tissue from male mice with adenine phosphoribosyltransferase (APRT) deficiency and 2,8-dihydroxyadenine (DHA) nephrolithiasis. The disease phenotype is more severe in male mice and is age-dependent. To identify the cellular basis for differential Kap expression, we used in situ hybridization (ISH) and reverse transcription-polymerase chain reaction ISH (RT-PCR ISH) to identify the cell types expressing this mRNA in paraffin-embedded kidney sections. In 1-month-old wild-type male mice, Kap was detected primarily in S3 proximal tubule segments, but expression was very low in female mice. In 1-month-old APRT-deficient male mice, Kap expression was decreased significantly and was undetectable in female mice. Kap mRNA was not detected in 3-or 6-month-old mice using our standard ISH protocol, but we observed intense cytoplasmic staining in S3 proximal tubules in wild-type male mice of these age groups using an improved RT-PCR ISH procedure. Our studies demonstrate age-, gender-, and APRT genotypedependent changes in Kap mRNA expression in mouse kidney. Kap expression is under multihormonal control, and hormonal changes in DHA-induced nephrolithiasis may account for the decreased Kap expression in APRT-deficient mice.

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Pleiotropic effects of dihydrotestosterone in immortalized mouse proximal tubule cells Technical Note

Cited by 19 publications

References 6 publications

Hormonal status affects the progression of STZ-induced diabetes and diabetic renal damage in the VCD mouse model of menopause

Hormonal status affects the progression of STZ-induced diabetes and diabetic renal damage in the VCD mouse model of menopause

Hormone-specific regulation of the kidney androgen-regulated gene promoter in cultured mouse renal proximal-tubule cells

Gender- and Age-dependent Changes in Kidney Androgen Protein mRNA Expression in a Knockout Mouse Model for Nephrolithiasis

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