Increased levels of serum urate in postmenopausal women are thought to be caused by a change in renal urate elimination associated with the loss of female hormones. In this study, we investigated the regulation of renal urate transporter expression by female hormones using ovariectomized mice with or without hormone replacement. Estradiol suppressed the protein levels of urate reabsorptive transporters urate transporter 1 and glucose transporter 9 (Urat1 and Glut9), and that of urate efflux transporter ATP-binding cassette sub-family G member 2 (Abcg2). Progesterone suppressed protein levels of sodium-coupled monocarboxylate transporter 1 (Smct1). However, neither estradiol nor progesterone influenced the respective levels of mRNA.

It is hypothesized that hyperuricemia in males is caused by androgen-induced urate reabsorptive transport system in the kidney. The expression of urate transporter 1 (Urat1), sodium-coupled monocarboxylate transporter 1 (Smct1) and glucose transporter 9 (Glut9) were investigated in orchiectomized mice with or without testosterone replacement. Testosterone enhanced mRNA and protein levels of Smct1 while those of Glut9 were attenuated. Although the mRNA level of Urat1 was enhanced by testosterone, the corresponding levels of Urat1 protein remained unaffected. Thus, the induction of Smct1 by testosterone is a candidate mechanism underlying hyperuricemia in males.

To elucidate the mechanism of obesity/metabolic syndrome-related hyperuricemia, this study aimed to determine the expression levels of transport systems for urate absorption (Urat1, Smct1, Glut9) and urate secretion (Abcg2). The kidneys of two obesity models in mice were used: 1) leptin-deficient mice (ob/ob mice) and 2) Quick fat diet model. 1) 8-week-old male ob/ob mice demonstrated the increased protein levels of Slc22a12 (Urat1), Slc2a9 (Glut9), and Abcg2 (Abcg2) and a decreased protein level of Slc5a8 (Smct1). However, no significant changes in the mRNA levels of these genes were observed. 2) C57BL/6 mice were fed with a Quick fat diet (crude fat content: 13.6%) from the age of 24 to 28 weeks (Quick fat diet group). The average body weights of the Quick fat diet group were heavier than those of the control group fed with a normal diet (crude fat content: 4.8%). The mRNA levels of Slc22a12, Slc2a9, Abcg2, or Slc5a8 did not change significantly in both groups. The protein levels of Slc22a12 (Urat1) and Abcg2 (Abcg2) increased significantly in the Quick fat diet group. Those of Slc2a9 (Glut9) and Slc5a8 (Smct1) were not changed significantly in the Quick fat diet group. In conclusion, the Quick fat diet enhanced the protein levels of Urat1 and Abcg2 without any changes in their mRNA transcription levels. The cause of obesity/metabolic syndrome-associated hyperuricemia appears to be associated with the urate reabsorption transporter Urat1 protein enhanced by fat.

In order to elucidate the mechanisms of post-exercise acute renal failure, one of the complications of hereditary renal hypouricemia, we have targeted the mouse Slc22a12 gene by the exchange of exons 1-4 with pMC1neo-polyA. The knockout mice revealed no gross anomalies. The concentration ratio of urinary urate/creatinine of the knockout mice was significantly higher than that of wildtype mice, indicating an attenuated renal reabsorption of urate. The plasma levels of urate were around 11 muM and were similar among the genotypes. Although the fractional excretion of urate of knockout mice was tend to higher than that of wildtype mice, the urate reabsorption ability remained in the kidney of knockout mice, indicating a urate reabsorptive transporter other than Urat1.

Abstract. Decreased expression levels of the glomerular slit membrane proteins, nephrin and podocin, have been reported after the onset of puromycin aminonucleoside (PA) nephrosis. We examined nephrin and podocin expressions prior to the onset of proteinuria of PA nephrosis to elucidate the proteinuria induction mechanism of PA. PA nephrosis was induced by a subcutaneous single injection of 120 mg kg -1 PA. The mRNA levels of nephrin and podocin in whole kidney total RNA were quantified by the TaqMan real time PCR quantification system. The localization and levels of nephrin and podocin molecules were analyzed by immunofluorescence and Western blotting, respectively. Albuminuria and proteinuria were significant on days 3 and 4 in PA nephrosis rats. The protein levels of nephrin and podocin decreased significantly at day 3. The protein localization of nephrin and podocin changed at day 2 and day 1, respectively. The mRNA level of nephrin increased at day 2 and subsequently decreased at day 4. The podocin mRNA level did not change significantly. In conclusions, the protein level of nephrin and podocin decreased at the onset of albuminuria in the PA nephrosis. However, the first change induced by PA was the change of podocin localization from a linear pattern to a dot-like one prior to the onset of albuminuria.