Metallothioneins are cysteine-rich, small metal-binding proteins present in various mammalian tissues. Of the four common metallothioneins, MT-1 and MT-2 (MTs) are expressed in most tissues, MT-3 is predominantly present in brain, whereas MT-4 is restricted to the squamous epithelia. The expression of MT-1 and MT-2 in some organs exhibits sex, age, and strain differences, and inducibility with a variety of stimuli. In adult mammals, MTs have been localized largely in the cell cytoplasm, but also in lysosomes, mitochondria and nuclei. The major physiological functions of MTs include homeostasis of essential metals Zn and Cu, protection against cytotoxicity of Cd and other toxic metals, and scavenging free radicals generated in oxidative stress. The role of MTs in Cd-induced acute and chronic toxicity, particularly in liver and kidneys, is reviewed in more details. In acute toxicity, liver is the primary target, whereas in chronic toxicity, kidneys are major targets of Cd. The intracellular MTs bind Cd ions and form CdMT. In chronic intoxication, Cd stimulates de novo synthesis of MTs; it is assumed that toxicity in the cells starts when loading with Cd ions exceeds the buffering capacity of intracellular MTs. CdMT, released from the Cd-injured organs, or when applied parenterally for experimental purposes, reaches the kidneys via circulation, where it is filtered, endocytosed in the proximal tubule cells, and degraded in lysosomes. Liberated Cd can immediately affect the cell structures and functions. The resulting proteinuria and CdMT in the urine can be used as biomarkers of tubular injury.

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 ...

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