In vitro evidence of the promoting effect of testosterone in kidney stone disease: A proteomics approach and functional validation

Changtong, Channarong; Peerapen, Paleerath; Khamchun, Supaporn; Fong-ngern, Kedsarin; Thongboonkerd, Visith

doi:10.1016/j.jprot.2016.05.028

Cited by 25 publications

(16 citation statements)

References 52 publications

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“…annexin A1, α-enolase, heat shock protein 90 (HSP90)) on apical membranes of renal tubular epithelial cells as potential crystal receptors essential for COM crystal adhesion on apical surface of the cells, intratubular COM crystal retention, and subsequently, stone formation712131415. Interestingly, expression of these potential COM crystal receptors could be altered by stone modulators or risk factors.…”

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confidence: 99%

Caffeine prevents kidney stone formation by translocation of apical surface annexin A1 crystal-binding protein into cytoplasm: In vitro evidence

Peerapen

Thongboonkerd

2016

Sci Rep

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Recent large 3 cohorts have shown that caffeinated beverage consumption was associated with lower risk of kidney stone disease. However, its protective mechanisms remained unknown and had not been previously investigated. We thus evaluated protective effects of caffeine (1 μM–10 mM) on calcium oxalate monohydrate (COM) kidney stone formation, using crystallization, crystal growth, cell-crystal adhesion, Western blotting, and immunofluorescence assays. The results showed that caffeine reduced crystal number but, on the other hand, increased crystal size, resulting in unchanged crystal mass, consistent with crystal growth that was not affected by caffeine. However, caffeine significantly decreased crystal-binding capacity of MDCK renal tubular cells in a dose-dependent manner. Western blotting and immunofluorescence study of COM crystal-binding proteins revealed significantly decreased level of annexin A1 on apical surface and its translocation into cytoplasm of the caffeine-treated cells, but no significant changes in other COM crystal-binding proteins (annexin A2, α-enolase, HSP70, and HSP90) were observed. Moreover, caffeine decreased intracellular [Ca2+] but increased [Ca2+] secretory index. Taken together, our findings showed an in vitro evidence of the protective mechanism of caffeine against kidney stone formation via translocation of annexin A1 from apical surface into cytoplasm to reduce the crystal-binding capacity of renal tubular epithelial cells.

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confidence: 99%

Caffeine prevents kidney stone formation by translocation of apical surface annexin A1 crystal-binding protein into cytoplasm: In vitro evidence

Peerapen

Thongboonkerd

2016

Sci Rep

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“…Our previous expression proteomics study identified α-enolase as a COM crystal-binding protein on apical membranes of renal tubular epithelial cells by quadrupole time-of-flight (Q-TOF) tandem mass spectrometry (MS/MS)4. Additional supportive evidence has demonstrated that expression level of α-enolase was increased and decreased after renal tubular cells were treated with stone aggravators1213 and inhibitor14, respectively. However, its precise role as the potential COM crystal receptor remained unclear.…”

Section: Discussionmentioning

confidence: 96%

“…In kidney stone disease, increasing evidence has pointed out its significance in kidney stone formation. High oxalate and testosterone treatments, both of which are the stone aggravators, increase expression level of α-enolase in renal tubular cells1213, whereas epigallocatechin gallate (EGCG), a stone suppressor from both in vitro and in vivo studies, decreases α-enolase level in renal tubular cells14. Expression and additional data from these studies suggest that α-enolase may serve as a potential COM crystal receptor to mediate crystal binding on the cell surface.…”

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confidence: 99%

Alpha-enolase on apical surface of renal tubular epithelial cells serves as a calcium oxalate crystal receptor

Fong-ngern

Thongboonkerd

2016

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To search for a strategy to prevent kidney stone formation/recurrence, this study addressed the role of α-enolase on apical membrane of renal tubular cells in mediating calcium oxalate monohydrate (COM) crystal adhesion. Its presence on apical membrane and in COM crystal-bound fraction was confirmed by Western blotting and immunofluorescence staining. Pretreating MDCK cells with anti-α-enolase antibody, not isotype-controlled IgG, dramatically reduced cell-crystal adhesion. Immunofluorescence staining also confirmed the direct binding of purified α-enolase to COM crystals at {121} > {100} > {010} crystal faces. Coating COM crystals with urinary proteins diminished the crystal binding capacity to cells and purified α-enolase. Moreover, α-enolase selectively bound to COM, not other crystals. Chemico-protein interactions analysis revealed that α-enolase interacted directly with Ca2+ and Mg2+. Incubating the cells with Mg2+ prior to cell-crystal adhesion assay significantly reduced crystal binding on the cell surface, whereas preincubation with EDTA, a divalent cation chelator, completely abolished Mg2+ effect, indicating that COM and Mg2+ competitively bind to α-enolase. Taken together, we successfully confirmed the role of α-enolase as a COM crystal receptor to mediate COM crystal adhesion at apical membrane of renal tubular cells. It may also serve as a target for stone prevention by blocking cell-crystal adhesion and stone nidus formation.

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“…However, the underpinning mechanism is complicated and not fully elucidated. Testosterone may also increase the alpha-enolase expression on the surface of renal tubular cells, which involves a crystal cell adhesion process [23]. Therefore, androgen/testosterone may increase the risk of renal calculi via several different mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Decreased Risk of Renal Calculi in Patients Receiving Androgen Deprivation Therapy for Prostate Cancer

Lin

Liu

et al. 2020

IJERPH

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Renal calculi are common, with male predilection and androgen exposure potentially increasing the risk of renal calculi. Systemic effects of androgen deprivation therapy (ADT) have been observed but the influence of ADT on renal calculi in prostate cancer (PCa) patients is not fully understood. We conducted this population-based study to evaluate the impact of ADT on the subsequent risk of renal calculi. We used the National Health Insurance Research Database of Taiwan to analyze the incidences of renal calculi in ADT patients and non-ADT patients from 2001 to 2013. In total, 3309 patients with PCa were selected. After matching with 1:1 propensity-score analysis, 758 ADT patients with 758 matched non-ADT controls were enrolled in the final analysis. Demographic characteristics were analyzed and Cox regression analysis for calculating the hazard ratios (HR) was performed for the subsequent risk of renal calculi. Finally, 186 (186/1516, 12.3%) patients with diagnosed renal calculi were detected. ADT patients had a lower risk of subsequent renal calculi with an adjusted HR of 0.38 (7% vs. 17.5%, 95% confidence interval (CI) 0.28-0.53; p < 0.001) in comparison with the non-ADT group. The Kaplan-Meier curve showed significant differences of cumulative incidences of renal calculi. In conclusion, ADT patients had approximately one-third lower risk of subsequent renal calculi. Further studies are warranted to evaluate the clinical significance.

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In vitro evidence of the promoting effect of testosterone in kidney stone disease: A proteomics approach and functional validation

Cited by 25 publications

References 52 publications

Caffeine prevents kidney stone formation by translocation of apical surface annexin A1 crystal-binding protein into cytoplasm: In vitro evidence

Caffeine prevents kidney stone formation by translocation of apical surface annexin A1 crystal-binding protein into cytoplasm: In vitro evidence

Alpha-enolase on apical surface of renal tubular epithelial cells serves as a calcium oxalate crystal receptor

Decreased Risk of Renal Calculi in Patients Receiving Androgen Deprivation Therapy for Prostate Cancer

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