Induction of renal senescence marker protein-30 (SMP30) expression by testosterone and its contribution to urinary calcium absorption in male rats

Lin, Pyng-Jing; Jian, Cai-Yun; Chou, Jou-Chun; Chen, Chien‐Wei; Chen, Chih-Chieh; Soong, Christina; Hu, Sindy; Lieu, Fu-Kong; Wang, Paulus S.; Wang, Shyi-Wu

doi:10.1038/srep32085

Cited by 10 publications

(8 citation statements)

References 38 publications

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“…This metal-dependent enzyme promiscuity is responsible for a regulatory mechanism which allows a single enzyme to specifically control different metabolic pathways and produce different metabolites [21,26,27]. This study also supports the importance of HuSMP30 in the calcium homeostasis as it has shown significantly high binding affinity (Kd = 0.29 ± 0.13 μM, Table 1 ) with Ca 2+ [28–30].…”

Section: Discussionsupporting

confidence: 69%

Comparative analysis of the metal-dependent structural and functional properties of mouse and human SMP30

et al. 2019

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Senescence Marker Protein (SMP30) is a metalloenzyme that shows lactonase activity in the ascorbic acid (AA) biosynthesis pathway in non-primate mammals such as a mouse. However, AA biosynthesis does not occur in the primates including humans. Several studies have shown the role of SMP30 in maintaining calcium homeostasis in mammals. In addition, it is also reported to have promiscuous enzyme activity with an organophosphate (OP) substrate. Hence, this study aims to recombinantly express and purify the SMP30 proteins from both mouse and human, and to study their structural alterations and functional deviations in the presence of different divalent metals. For this, mouse SMP30 (MoSMP30) as well as human SMP30 (HuSMP30) were cloned in the bacterial expression vector. Proteins were overexpressed and purified from soluble fractions as well as from inclusion bodies as these proteins were expressed largely in insoluble fractions. The purified proteins were used to study the folding conformations in the presence of different divalent cations (Ca 2+ , Co 2+ , Mg 2+ , and Zn 2+ ) with the help of circular dichroism (CD) spectroscopy. It was observed that both MoSMP30 and HuSMP30 acquired native folding conformations. To study the metal-binding affinity, dissociation constant (Kd values) were calculated from UV-VIS titration curve, which showed the highest affinity of MoSMP30 with Zn 2+ . However, HuSMP30 showed the highest affinity with Ca 2+ , suggesting the importance of HuSMP30 in maintaining calcium homeostasis. Enzyme kinetics were performed with γ-Thiobutyrolactone and Demeton-S in the presence of different divalent cations. Interestingly, both the proteins showed lactonase activity in the presence of Ca 2+ . In addition, MoSMP30 and HuSMP30 also showed lactonase activity in the presence of Co 2+ and Zn 2+ respectively. Moreover, both the proteins showed OP hydrolase activities in the presence of Ca 2+ as well as Zn 2+ , suggesting the metal-dependent promiscuous nature of SMP30.

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Section: Discussionsupporting

confidence: 69%

Comparative analysis of the metal-dependent structural and functional properties of mouse and human SMP30

et al. 2019

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“…We speculated that this could have been due to the following reasons: (1) The affinity of testosterone for the AR in NRK52E cells may be comparatively lower than that in RMC cells; and (2) The main function of the AR in NRK52E cells may be biased toward being associated with other physiological roles. The literature demonstrates that NRK52E cells are directly associated with testosterone-induced senescence 28 , while expression of the renal senescence marker protein, SMP30, was upregulated by endogenous testosterone stimulation; the latter increases renal anti-aging klotho gene expression via an AR-mediated pathway 29 .…”

Section: Resultsmentioning

confidence: 99%

Renal Damaging Effect Elicited by Bicalutamide Therapy Uncovered Multiple Action Mechanisms As Evidenced by the Cell Model

Peng

Chen²,

Chen

et al. 2019

Sci Rep

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Bicalutamide (Bic) is frequently used in androgen deprivation therapy (ADT) for treating prostate cancer. ADT-induced hypogonadism was reported to have the potential to lead to acute kidney injury (AKI). ADT was also shown to induce bladder fibrosis via induction of the transforming growth factor (TGF)-β level. We hypothesized that Bic can likely induce renal fibrosis. To understand this, a cell model was used to explore expressions of relevant profibrotic proteins. Results indicated that Bic initiated multiple apoptotic and fibrotic pathways, including androgen deprivation, downregulation of the androgen receptor → phosphatidylinositol-3-kinase → Akt pathway, upregulation of the extrinsic apoptotic pathway- tumor necrosis factor α → nuclear factor κB → caspase-3, increased expressions of fibrosis-related proteins including platelet-derived growth factor β, fibronectin and collagen IV, and enhanced cell migration. The endoplasmic reticular stress pathway and smooth muscle actin were unaffected by Bic. Co-treatment with testosterone was shown to have an anti-apoptotic effect against Bic, suggesting a better outcome of Bic therapy if administered with an appropriate testosterone intervention. However, since Bic was found to inhibit the membrane transport and consumption rates of testosterone, a slightly larger dose of testosterone is recommended. In conclusion, these pathways can be considered to be pharmaceutically relevant targets for drug development in treating the adverse effects of Bic.

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“…Radioimmunoassay (RIA) of testosterone. The concentrations of testosterone in the culture medium and plasma were determined by RIA as previously described 60 . Using an anti-testosterone serum (No.…”

Section: Preparation Of Rat Primary Leydig Cellsmentioning

confidence: 99%

“…Western blot, as described previously 60 . Briefly, quantitative amounts of samples (60 μg) were mixed with a sample buffer (0.125 M Tris-Cl pH 6.8, 20% glycerol, 4% sodium dodecyl sulfate (SDS), 10% 2-mercaptoethanol, 0.1% bromophenol blue) at a ratio of 1:1.…”

Section: Protein Preparation and Western Blot Analysis Total Cell Anmentioning

confidence: 99%

Downregulation of testosterone production through luteinizing hormone receptor regulation in male rats exposed to 17α-ethynylestradiol

Lin

Kuo²,

Chen

et al. 2020

Sci Rep

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The pharmaceutical 17α-ethynylestradiol (EE2) is considered as an endocrine-disrupting chemical that interferes with male reproduction and hormonal activation. In this study, we investigated the molecular mechanism underlying EE2-regulatory testosterone release in vitro and in vivo. The results show that EE2 treatment decreased testosterone release from rat Leydig cells. Treatment of rats with EE2 reduced plasma testosterone levels and decreased the sensitivity of human chorionic gonadotropin (hCG). EE2 reduced luteinizing hormone receptor (LHR) expression associated with decreased cAMP generation by downregulation of adenylyl cyclase activity and decreased intracellular calcium-mediated pathways. The expression levels of StAR and P450scc were decreased in Leydig cells by treatment of rats with EE2 for 7 days. The sperm motility in the vas deferens and epididymis was reduced, but the histopathological features of the testis and the total sperm number of the vas deferens were not affected. Moreover, the serum dihydrotestosterone (DHT) level was decreased by treatment with EE2. The prostate gland and seminal vesicle atrophied significantly, and their expression level of 5α-reductase type II was reduced after EE2 exposure. Taken together, these results demonstrate an underlying mechanism of EE2 to downregulate testosterone production in Leydig cells, explaining the damaging effects of EE2 on male reproduction.The endocrine system precisely mediates sexual development and reproductive ability through circulating sexual hormones, which act as signaling molecules to render adequate regulation. Endocrine-disrupting chemicals (EDCs) are natural or industrial chemicals that are released into the environment through industries, livestock activities, domestic wastewater, and hospital effluence 1,2 . Numerous studies have indicated that EDCs interfere with endogenous endocrine processes by mimicking hormonal action, leading to infertility, metabolic syndrome, and the rise of cancer incidence 3-5 . In humans, increasing studies have indicated that EDCs have detrimental effects on the reproductive system, resulting in poor sperm quality and testicular dysgenic occurrence in men 6,7 , and disorders of ovulation and the uterus as well as a rise in breast cancer incidences in women 8,9 . Hence, the risks of EDCs are a global health issue 10 .EE2 has been reported to exert a higher estrogenic activity than estradiol (E2), and is extremely stable against oxidation by metabolism or degradation in the human body due to the property of the ethynyl group in the C 17 position [11][12][13] . This characteristic potentially allows 17α-ethynylestradiol (EE2) to pass into the environment 14,15 . Therefore, it is reasonable to consider environmental EE2 to be an EDC and have deleterious effects on the health of both animals and human beings 15 . The pharmaceutical EE2 is a synthetic estrogen widely used as an oral contraceptive pill, but abundant animal studies have also reported that long-term exposure to EE2 interferes with the biological ...

show abstract

Induction of renal senescence marker protein-30 (SMP30) expression by testosterone and its contribution to urinary calcium absorption in male rats

Cited by 10 publications

References 38 publications

Comparative analysis of the metal-dependent structural and functional properties of mouse and human SMP30

Comparative analysis of the metal-dependent structural and functional properties of mouse and human SMP30

Renal Damaging Effect Elicited by Bicalutamide Therapy Uncovered Multiple Action Mechanisms As Evidenced by the Cell Model

Downregulation of testosterone production through luteinizing hormone receptor regulation in male rats exposed to 17α-ethynylestradiol

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