Urinary Oxalate Excretion Decreased in Androgen Receptor-Knockout Mice by Suppressing Oxalate Synthesis in the Liver


The incidence of calcium oxalate stone in men is higher than that in women. We evaluated the association between the androgen receptor (AR) and urinary oxalate excretion using Crefloxed male androgen receptor-knockout (ARKO) mice (ARL-/Y) and floxed mice (ARL+/Y) as control. Four-teen-week-old ARL-/Y and ARL+/Y mice were fed distilled water. Drinking water was then swapped for 0.5% ethylene glycol (EG). Urinary oxalate was measured on days 0, 14, and 28. Urinary calcium, inorganic phosphorus, citrate, uric acid, and ion-actibity products of calcium oxalate (APCaOx) in mouse, AP (CaOx)-indexMOUSE, were evaluated on days 0 and 15. On day 28, livers were harvested to measure mRNA expression of enzymes. Urinary oxalate excretion was significantly higher in ARL+/Y than in ARL-/Y mice 14 and 28 days after EG treatment (p < 0.05). Since ARL-/Y mice exhibited atrophic testes and low serum testosterone, both ARKO and control mice were orchiectomized and implanted DHT pellets (ARL-/Y-ORX-DHT, and ARL+/Y-ORX-DHT), and the same experiments as above were performed. EG loading for 14 and 28 days resulted in significantly higher excretion in ARL+/Y-ORX-DHT mice than ARL-/Y-ORX-DHT mice (p < 0.005). AP(CaOx)-indexMOUSE was significantly higher in ARL+/Y-ORX-DHT mice than in ARL-1/Y-ORX-DHT mice. mRNA expression levels of glycolate oxidase (GO) in liver were lower in ARKO mice than in control ones. AR modulates the excretion of oxalate in urine after EG treatment, which may be associated with increased oxalate synthesis by activated GO in the liver via the AR pathway.

Share and Cite:

Takahashi, S. , Aruga, S. , Yamamoto, Y. and Matsumoto, T. (2015) Urinary Oxalate Excretion Decreased in Androgen Receptor-Knockout Mice by Suppressing Oxalate Synthesis in the Liver. Open Journal of Urology, 5, 123-132. doi: 10.4236/oju.2015.58020.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Robertson, W.G., Peacock, M., Heyburn, P.J. and Hanes, F.A. (1980) Epidemiological Risk Factors in Calcium Stone Disease. Scandinavian Journal of Urology and Nephrology. Supplementum, 53, 15-30.
[2] Soucie, J.M., Thun, M.J., Coates, R.J., McClellan, W. and Austin, H. (1994) Demographic and Geographic Variability of Kidney Stones in the United States. Kidney International, 46, 893-899.
[3] Parks, J.H. and Coe, F.L. (1986) A Urinary Calcium-Citrate Index for the Evaluation of Nephrolithiasis. Kidney International, 30, 85-90. http://dx.doi.org/10.1038/ki.1986.155
[4] Curhan, G.C., Willett, W.C., Speizer, F.E. and Stampfer, M.J. (2001) Twenty-Four-Hour Urine Chemistries and the Risk of Kidney Stones among Women and Men. Kidney International, 59, 2290-2298. http://dx.doi.org/10.1046/j.1523-1755.2001.00746.x
[5] Robertson, W.G. and Peacock, M. (1980) The Cause of Idiopathic Calcium Stone Disease: Hypercalciuria or Hyperoxaluria? Nephron, 26, 105-110. http://dx.doi.org/10.1159/000181963
[6] Robertson, W.G., Peacock, M., Heyburn, P.J., Marshall, D.H. and Clark, P.B. (1978) Risk Factors in Calcium Stone Disease of the Urinary Tract. British Journal of Urology, 50, 449-454.
[7] Holmes, R.P., Goodman, H.O. and Assimos, D.G. (2001) Contribution of Dietary Oxalate to Urinary Oxalate Excretion. Kidney International, 59, 270-276.
[8] Siener, R., Bade, D.J., Hesse, A. and Hoppe, B. (2013) Dietary Hyperoxaluria Is Not Reduced by Treatment with Lactic Acid Bacteria. Journal of Translational Medicine, 11, 306.
[9] Ushijima, Y. (1973) Identity of Aliphatic L-α-Hydroxyacid Oxidase and Glycolate Oxidase from Rat Livers. Archives of Biochemistry and Biophysics, 155, 361-367.
[10] Warren, W.A. (1970) Catalysis of Both Oxidation and Reduction of Glyoxylate by Pig Heart Lactate Dehydrogenase Isozyme 1. The Journal of Biological Chemistry, 245, 1675-1681.
[11] Poore, R.E., Hurst, C.H., Assimos, D.G. and Holmes, R.P. (1997) Pathways of Hepatic Oxalate Synthesis and Their Regulation. American Journal of Physiology, 272, C289-C294.
[12] Bais, R., Rofe, A.M. and Conyers, R.A. (1991) Investigations into the Effect of Glyoxylate Deca-rboxylation and Transamination on Oxalate Formation in the Rat. Nephron, 57, 460-469.
[13] Lee, Y.H., Huang, W.C., Chiang, H., Chen, M.T., Huang, J.K. and Chang, L.S. (1992) Determinant Role of Testosterone in the Pathogenesis of Urolithiasis in Rats. The Journal of Urology, 147, 1134-1138.
[14] Lee, Y.H., Huang, W.C., Huang, J.K. and Chang, L.S. (1996) Testosterone Enhances Whereas Estrogen Inhibits Calcium Oxalate Stone Formation in Ethylene Glycol Treated Rats. The Journal of Urology, 156, 502-505. http://dx.doi.org/10.1016/S0022-5347(01)65914-7
[15] Yoshihara, H., Yamaguchi, S. and Yachiku, S. (1999) Effect of Sex Hormones on Oxalate-Synthesizing Enzymes in Male and Female Rat Livers. The Journal of Urology, 161, 668-673.
[16] Iguchi, M., Takamura, C., Umekawa, T., Kurita, T. and Kohri, K. (1999) Inhibitory Effects of Female Sex Hormones on Urinary Stone Formation in Rats. Kidney International, 56, 479-485.
[17] Fan, J., Chandhoke, P.S. and Grampsas, S.A. (1999) Role of Sex Hormones in Experimental Calcium Oxalate Nephrolithiasis. Journal of the American Society of Nephrology, 10, S376-S380.
[18] Yagisawa, T., Ito, F., Osaka, Y., Amano, H., Kobayashi, C. and Toma, H. (2001) The Influence of Sex Hormones on Renal Osteopontin Expression and Urinary Constituents in Experimental Urolithiasis. The Journal of Urology, 166, 1078-1082. http://dx.doi.org/10.1016/S0022-5347(05)65925-3
[19] Yoshioka, I., Tsujihata, M., Momohara, C., Akanae, W., Nonomura, N. and Okuyama, A. (2010) Effect of Sex Hormones on Crystal Formation in a Stone-Forming Rat Model. Urology, 75, 907-913.
[20] Li, J.Y., Zhou, T., Gao, X., Xu, C., Sun, Y., Peng, Y., et al. (2010) Testosterone and Androgen Receptor in Human Nephrolithiasis. The Journal of Urology, 184, 2360-2363.
[21] Matsumoto, T., Sakari, M., Okada, M., Yokoyama, A., Takahashi, S., Kouzmenko, A. and Kato, S. (2013) The Androgen Receptor in Health and Disease. Annual Review of Physiology, 75, 201-224.
[22] Dunn, J.F., Nisula, B.C. and Rodbard, D. (1981) Transport of Steroid Hormones: Binding of 21 Endogenous Steroids to Both Testosterone-Binding Globulin and Corticosteroid-Binding Globulin in Human Plasma. The Journal of Clinical Endocrinology & Metabolism, 53, 58-68.
[23] Sato, T., Matsumoto, T., Yamada, T., Watanabe, T., Kawano, H. and Kato, S. (2003) Late Onset of Obesity in Male Androgen Receptor-Deficient (AR KO) Mice. Biochemical and Biophysical Research Communications, 300, 167-171. http://dx.doi.org/10.1016/S0006-291X(02)02774-2
[24] Li, M., Indra, A.K., Warot, X., Brocard, J., Messaddeq, N., Kato, S., et al. (2000) Skin Abnormalities Generated by Temporally Controlled RXRα Mutations in Mouse Epidermis. Nature, 407, 633-636.
[25] Sekine, K., Ohuchi, H., Fujiwara, M., Yamasaki, M., Yoshizawa, T., Sato, T., et al. (1999) Fgf10 Is Essential for Limb and Lung Formation. Nature Genetics, 21, 138-141.
[26] Dupe, V., Davenne, M., Brocard, J., Dolle, P., Mark, M., Dierich, A., et al. (1997) In Vivo Functional Analysis of the Hoxa-1 3’ Retinoic Acid Response Element (3’RARE). Development, 124, 399-410.
[27] Gubbay, J., Collignon, J., Koopman, P., Capel, B., Economou, A., Münsterberg, A., et al. (1990) A Gene Mapping to the Sex-Determining Region of the Mouse Y Chromosome Is a Member of a Novel Family of Embryonically Expressed Genes. Nature, 346, 245-250. http://dx.doi.org/10.1038/346245a0
[28] Sato, T., Matsumoto, T., Kawano, H., Watanabe, T., Uematsu, Y., Sekine, K., et al. (2004) Brain Masculinization Requires Androgen Receptor Function. Proceedings of the National Academy of Sciences of the United States of America, 101, 1673-1678.
[29] Kataoka, K., Takada, M., Kato, Y., Iguchi, M., Kohri, K. and Kurita, T. (1990) Determination of Urinary Oxalate by High-Performance Liquid Chromatography Monitoring with an Ultraviolet Detector. Urological Research, 18, 25-28. http://dx.doi.org/10.1007/BF00294577
[30] Sarkar, B.C. and Chauhan, U.P. (1967) A New Method for Determining Micro Quantities of Calcium in Biological Materials. Analytical Biochemistry, 20, 155-166.
[31] Tiselius, H.G., Ferraz, R.R. and Heilberg, I.P. (2012) Simplified Estimates of Ion-Activity Products of Calcium Oxalate and Calcium Phosphate in Mouse Urine. Urological Research, 40, 285-291.
[32] Christian, G.D. (1969) Medicine, Trace Elements, and Atomic Absorption Spectroscopy. Analytical Chemistry, 41, 24A-40A. http://dx.doi.org/10.1021/ac60270a719
[33] Ambuhl, P., Amemiya, M., Preisig, P.A., Moe, O.W. and Alpern, R.J. (1998) Chronic Hyperosmolality Increases NHE3 Activity in OKP Cells. Journal of Clinical Investigation, 101, 170-177.
[34] Zisoulis, D.G., Kai, Z.S., Chang, R.K. and Pasquinelli, A.E. (2012) Autoregulation of MicroRNA Biogenesis by Let-7 and Argonaute. Nature, 486, 541-544. http://dx.doi.org/10.1038/nature11134
[35] Kawano, H., Sato, T., Yamada, T., Matsumoto, T., Sekine, K., Watanabe, T., et al. (2003) Suppressive Function of Androgen Receptor in Bone Resorption. Proceedings of the National Academy of Sciences of the United States of America, 100, 9416-9421.
[36] De Gendt, K., Atanassova, N., Tan, K.A., de Franca, L.R., Parreira, G.G., McKinnell, C., et al. (2005) Development and Function of the Adult Generation of Leydig Cells in Mice with Sertoli Cell-Selective or Total Ablation of the Androgen Receptor. Endocrinology, 146, 4117-4126.
[37] Liang, L., Li, L., Tian, J., Lee, S.O., Dang, Q., Huang, C.-K., et al. (2014) Androgen Receptor Enhances Kidney Stone-CaOx Crystal Formation via Modulation of Oxalate Biosynthesis & Oxidative Stress. Molecular Endocrinology, 28, 1291-1303. http://dx.doi.org/10.1210/me.2014-1047
[38] Wesson, J.A., Johnson, R.J., Mazzali, M., Beshensky, A.M., Stietz, S., Giachelli, C., et al. (2003) Osteopontin Is a Cri- tical Inhibitor of Calcium Oxalate Crystal Formation and Retention in Renal Tubules. Journal of the American Society of Nephrology, 14, 139-147.
[39] Mo, L., Huang, H.Y., Zhu, X.H., Shapiro, E., Hasty, D.L. and Wu, X.-R. (2004) Tamm-Horsfall Protein Is a Critical Renal Defense Factor Protecting against Calcium Oxalate Crystal Formation. Kidney International, 66, 1159-1166. http://dx.doi.org/10.1111/j.1523-1755.2004.00867.x
[40] Okada, A., Nomura, S., Higashibata, Y., Hirose, M., Gao, B., Yoshimura, M., et al. (2007) Successful Formation of Calcium Oxalate Crystal Deposition in Mouse Kidney by Intraabdominal Glyoxylate Injection. Urological Research, 35, 89-99. http://dx.doi.org/10.1007/s00240-007-0082-8
[41] Davis, R.H., Morgan, D.B. and Rivlin, R.S. (1970) The Excretion of Calcium in the Urine and Its Relation to Calcium Intake, Sex and Age. Clinical Science, 39, 1-12.
[42] Morgan, B. and Robertson, W.G. (1974) The Urinary Excretion of Calcium. An Analysis of the Distribution of Values in Relation to Sex, Age and Calcium Deprivation. Clinical Orthopaedics & Related Research, 101, 254-267.
[43] Hsu, Y.J., Dimke, H., Schoeber, J.P., Hsu, S.C., Lin, S.H., Chu, P., et al. (2010) Testosterone Increases Urinary Calcium Excretion and Inhibits Expression of Renal Calcium Transport Proteins. Kidney International, 77, 601-608. http://dx.doi.org/10.1038/ki.2009.522

Copyright © 2022 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.