Numerous renal abnormalities accompany thyroid disease, most of which have been ascribed to the effects of thyroid hormone on renal metabolism. In the present report, we investigate the renal expression of the nominally thyroid-specific proteins, thyroid-stimulating hormone (TSH) receptor (TSHR) and thyroglobulin (Tg), as potential links between renal and thyroid function. The expression of TSHR has been identified in several extrathyroidal tissues, but its presence in the kidney remains controversial. We have used reverse-transcriptase polymerase chain reaction and DNA sequencing to demonstrate the presence of TSHR transcript in human and mouse kidney, in a primary culture of human kidney, and in a green monkey kidney epithelioid cell line. Furthermore, human kidney cells responded to TSH with a 2.5- fold increase in intracellular cyclic adenosine monophosphate, suggesting the presence of functional TSHR protein. Comparison of renal expression of TSHR in a bovine growth hormone transgenic mouse model of progressive glomerulosclerosis with control mice suggested increased TSHR transcript in the renal cortex of transgenic animals. TSHR transcript was also detected in mouse mesangial cells in vitro which responded to TSH with significant increases in the formation of three-dimensional hillhocks. Polymerase chain reaction also confirmed the presence of Tg transcript in human and mouse kidneys and in mouse mesangial cells, but no effect of either TSH or cyclic adenosine monophosphate on Tg transcript levels could be discerned. Immunofluorescent staining with a monoclonal anti-Tg antibody identified positive staining in the cytoplasm of mesangial cells. These data suggest that the kidney is capable of expressing the thyroid-specific genes, TSHR and Tg, which could conceivably mediate effects of thyroid disease in the kidney.

Keywords:
Thyrotropin receptor, Thyroglobulin, Mesangial cells, Thyroid
1.
Katz AI, Emmanouel DS, Lindheimer MD: Thyroid hormone and the kidney. Nephron 1975;15:223–249.
2.
Nagayama Y, Kaufman KD, Seto P, Rapoport B: Molecular cloning, sequence and functional expression of the cDNA for the human thyrotropin receptor. Biochem Biophys Res Commun 1989;165:1184–1190.
3.
Akamizu T, Ikuyama S, Saji M, Kosugi S, Kozak C, McBride OW, Kohn LD: Cloning, chromosomal assignment, and regulation of the rat thyrotropin receptor: Expression of the gene is regulated by thyrotropin, agents that increase cAMP levels, and thyroid autoantibodies. Proc Natl Acad Sci USA 1990;87:5677–5681.
4.
Davies TF: The thyrotropin receptors spread themselves around. J Clin Endocrinol Metab 1994;79:1232–1233.
5.
Drvota V, Janson A, Norman C, Sylven C, Haggblad J, Bronnegard M, Marcus C: Evidence for the presence of functional thyrotropin receptor in cardiac muscle. Biochem Biophys Res Commun 1995;211:426–431.
6.
Feliciello A, Porcellini A, Ciullo I, Bonavolonta G, Avvedimento EV, Fenzi G: Expression of thyrotropin-receptor mRNA in healthy and Graves’ disease retro-orbital tissue. Lancet 1993;342:337–338.
7.
Endo T, Ohta K, Haraguchi K, Onaya T: Cloning and functional expression of a thyrotropin receptor cDNA from rat fat cells. J Biol Chem 1995;270:10833–10837.
8.
Koshiyama H, Sellitti DF, Akamizu T, Doi SQ, Takeuchi Y, Inoue D, Sakaguchi H, Takemura G, Sato Y, Takatsu Y, Nakao K: Cardiomyopathy associated with Graves’ disease. Clin Endocrinol (Oxf) 1996;45:111–116.
9.
Sellitti DF, Hill R, Doi SQ, Akamizu T, Czaja J, Tao S, Koshiyama H: Differential expression of thyrotropin receptor mRNA in the porcine heart. Thyroid 1997;7:641–646.
10.
Paschke R, Vassart G, Ludgate M: Current evidence for and against the TSH receptor being the common antigen in Graves’ disease and thyroid associated ophthalmopathy. Clin Endocrinol (Oxf) 1995;42:565–569.
11.
Jordan SC, Buckingham B, Sakai R, Olson D: Studies of immune-complex glomerulonephritis mediated by human thyroglobulin. N Engl J Med 1981;304:1212–1215.
12.
Horvath F, Teague P, Gaffney EF, Mars DR, Fuller TJ: Thyroid antigen associated immune complex glomerulonephritis in Graves’ disease. Am J Med 1979;67:901–904.
13.
Zannini M, Francis-Lang H, Plachov D, Di Lauro R: Pax-8, a paired domain containing protein, binds to a sequence overlapping the recognition site of a homeodomain and activates transcription from two thyroid-specific promoters. Mol Cell Biol 1992;12:4230–4241.
14.
Plachov D, Chowdhory K, Walther C, Simon D, Guenet J-L, Gruss P: Pax 8, a murine paired box gene expressed in the developing excretory system and thyroid gland. Development 1990;110:643–651.
15.
Poleev A, Wendler F, Fickenscher H, Zannini M, Yaginuma K, Abbott C, Plachov D: Distinct functional properties of three human paired-box-protein, Pax 8, isoforms generated by alternative splicing in thyroid, kidney and Wilms’ tumors. Eur J Biochem 1995;228:899–911.
16.
Doi T, Striker LJ, Quaife C, Conti FG, Palmiter R, Behringer R, Brinster R, Striker GE: Progressive glomerulosclerosis develops in transgenic mice chronically expressing growth hormone and growth hormone releasing factor but not in those expressing insulin-like growth factor-1. Am J Pathol 1988;131:398–403.
17.
Jacot TA, Striker GE, Stetler-Stevenson M, Striker LJ: Mesangial cells from transgenic mice with progressive glomerulosclerosis exhibit stable, phenotypic changes including undetectable MMP-9 and increased type IV collagen. Lab Invest 1996;75:791–799.
18.
Stein SA, Oates EL, Hall CR, Grumbles RM, Fernandez LM, Taylor NA, Puett D, Jin S: Identification of a point mutation in the thyrotropin receptor of the hyt/hyt hypothyroid mouse. Mol Endocrinol 1994;8:129–138.
19.
Di Lauro R, Obici S, Condliffe D, Ursini VM, Musti A, Moscatelli C, Avvedimento VE: The sequence of 967 amino acids at the carboxyl-end of rat thyroglobulin: Location and surroundings of two thyroxine-forming sites. Eur J Biochem 1985;148:7–11.
20.
Dutton CM, Joba W, Spitzweg C, Heufelder AE, Bahn RS: Thyrotropin receptor expression in adrenal, kidney, and thymus. Thyroid 1997;7:879–884.
21.
Haraguchi K, Shimura H, Lin L, Endo T, Onaya T: Differentiation of rat preadipocytes is accompanied by expression of thyrotropin receptors. Endocrinology 1996;137:3200–3205.
22.
Glass WF, Teng P, Haney LB: Extracellular matrix distribution and hillock formation in human mesangial cells in culture without serum. J Am Soc Nephrol 1996;7:2230–2243.
23.
Matsuura M, Kikkawa Y, Akashi K, Kitagawa T, Inage Z, Iwamori M, Takimoto T, Iidaka K, Serisawa T: Thyroid antigen-antibody nephritis: Possible involvement of fucosyl-GM1 as the antigen. Endocrinol Jpn 1987;34:587–593.
24.
Dunn JT: Thyroglobulin: Chemistry and biosynthesis; in Braverman LE, Utiger RD (eds): Werner and Ingbar’s The Thyroid. Philadelphia, Lippincott-Raven, 1996, pp 85–95.
25.
Alvino CG, Acquaviva AM, Catanzano A, Tassi V: Evidence that thyroglobulin has an associated protein kinase activity correlated with the presence of an adenosine triphosphate binding site. Endocrinology 1995;136:3179–3185.
26.
Kohn LD: Thyroglobulin – a new cyclic adenosine monophosphate-dependent protein kinase? Endocrinology 1995;136:3177–3188.
27.
Jordan SC, Johnston WH, Bergstein JM: Immune complex glomerulonephritis mediated by thyroid antigens. Arch Pathol Lab Med 1978;102:530–533.
28.
Chelly J, Concordet J-P, Kaplan J-C, Kahn A: Illegitimate transcription: Transcription of any gene in any cell type. Proc Natl Acad Sci USA 1989;86:2617–2621.
29.
Miazaki T, Kanou Y, Kambe F, Niwa T, Maeda K, Seo H: Human mesangial cells express Pax 8 gene (abstract). J Am Soc Nephrol 1995;6:802.
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2000
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