Rat renal glucose transporter SGLT1 exhibits zonal distribution and androgen-dependent gender differences

Abstract

Sabolić, Ivan, Mario Škarica, Valentin Gorboulev, Marija Ljubojević, Daniela Balen, Carol M. Herak-Kramberger, and Hermann Koepsell. Rat renal glucose transporter SGLT1 exhibits zonal distribution and androgen-dependent gender differences. Am J Physiol Renal Physiol 290: F913-F926, 2006. First published October 4, 2005 doi:10.1152/ajprenal.00270.2005.-SGLT1 (SLC5A1) mediates a part of glucose and galactose reabsorption in the mammalian proximal tubule (PT), but the detailed localization of the transporter along the tubule is still disputable. Here, we used several methods to localize rat SGLT1 (rSGLT1) in the kidneys of intact and variously treated male (M) and female (F) rats. In immunoblots of isolated cortical (C) and outer stripe (OS) brush-border membranes (BBM), a peptide-specific polyclonal antibody for rSGLT1 labeled a sharp inzone-, and genderdependent ϳ40-kDa protein and a broad ϳ75-kDa band that exhibited strong zonal (OS Ͼ C) and gender differences (F Ͼ M). In tissue cryosections, the antibody strongly stained BBM of the S3 PT segments in the OS and medullary rays (F Ͼ M) and smooth muscles of the blood vessels and renal capsule (F ϳ M) and weakly stained the apical domain of other PT segments in the C (F ϳ M). The phlorizinsensitive uptake of D-[ 3 H]galactose in BBM vesicles, as well as the tissue abundance of rSGLT1-specific mRNA, matched the immunoblotting data related to the 75-kDa protein and the immunostaining in S3, proving zonal and gender differences in the functional transporter. Ovariectomy had no effect, castration upregulated, whereas treatment of castrated rats with testosterone, but not with estradiol or progesterone, downregulated the 75-kDa protein and the immunostaining in S3. We conclude that in the rat kidney, the expression of SGLT1 is represented by a 75-kDa protein localized largely in the PT S3 segments, where it exhibits gender differences (F Ͼ M) at both the protein and mRNA levels that are caused by androgen inhibition. brush-border membrane; immunocytochemistry; kidney; sex differences; sodium-glucose cotransporters; steroid hormones THE EFFICIENT REABSORPTION of the filtered hexoses in the mammalian nephron is achieved by the concerted action of Na ϩ -dependent glucose cotransporters (SGLT1 and SGLT2), localized in the brush-border membranes (BBM), and Na ϩ -independent facilitated glucose transporters (GLUT1 and GLUT2), localized in the basolateral membranes (BLM) of proximal tubule cells (Refs. 11 and 34 and references therein). The two major brush-border glucose transporters in the proximal tubule, low-affinity/high-capacity SGLT2 and high-affinity/low-capacity SGLT1, differ in their affinity for glucose and Na ϩ (SGLT1 Ͼ SGLT2), their sensitivity to inhibitor phlorizin (SGLT1 Ͼ SGLT2), and their sugar selectivity (SGLT1 transports glucose and galactose equally well, whereas SGLT2 transports glucose at least 10 times better). At the protein level, both transporters have ϳ660 amino acid residues that share 59% homology and probably function as glycosylated monomers ...

The liver and kidney expression of sulfate anion transporter sat-1 in rats exhibits male-dominant gender differences

“…At the present, we cannot say if the female sex hormones inhibit the transporter synthesis and/or stimulate its degradation, or both, and whether these hormones act directly or via affecting the levels of some other hormones. The sex-hormone-driven mRNA-independent regulation of sat-1 protein expression is at odd with the recently described sex-hormone-driven regulation of numerous other renal transporters in rat and mouse kidneys via their mRNA expression [28,29,41,42]. Furthermore, in our microarray study of gender differences in various renal transporters in rats, the sat-1 mRNA expression was higher in males than in females [42].…”

“…Our previous studies in rats and mice indicated the presence of gender differences in the expression of Oat1 [28], Oat2 [29], Oat3 [28], and SGLT1 [41] in kidneys. We have also recently reported on higher sat-1 mRNA expression in kidneys of male rats, as studied by microarray technique [42].…”

Expression of Na+-d-glucose cotransporter SGLT2 in rodents is kidney-specific and exhibits sex and species differences

“…Patients with defect mutations of Sglt1 and SGLT1-deficient [Sglt1 Ϫ/Ϫ , knockout (KO)] mice suffer from the glucose-galactose malabsorption syndrome (16,33,52). In the rat kidney, SGLT1 protein is predominantly located in the BBM of proximal tubule S3 segment, showing higher expression and functional activity in females compared with males (5,38). Sglt1 KO mice lose ϳ3% of the filtered glucose in the urine (16).…”

“…This includes sex differences and changes of intracellular distribution during posttranscriptional regulations as has been described for SGLT1 (5,27,35,38,49). Localization of SGLT2 protein in rodents and humans is also required to anticipate potential side effects of selective SGLT2 inhibitors that are being developed by pharmaceutical companies for treating diabetic hyperglycemia (4,20,23).…”

Modulação do trocador NA+/H+ apical, NHE3, pelo transporte de glicose em túbulos renais in vivo.

“…A anidrase carbônica é uma enzima expressa de maneira quase ubíqua nas células do corpo, porém suas isoformas diferem dependendo do tecido em que são expressas. No rim há expressão das isoformas II, IV, XII, e XIV da anidrase carbônica (Kaunisto, et al, 2002 (Sabolic, et al, 2006e Splinter, et al, 2006.…”