This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Molon-Noblot, S. Articles by Van Zwieten, M. J. Search for Related Content PubMed PubMed Citation Articles by Molon-Noblot, S. Articles by Van Zwieten, M. J. Social Bookmarking                         What's this?

Morphological Changes in the Kidney of Dogs Chronically Exposed to Exogenous Growth Hormone

Merck Sharp & Dohme-Chibret Laboratories, Research Center,Department of Safety Assessment, BP 134, Route de Marsat 63 203 Riom, France

Philippe Laroque

Merck Sharp & Dohme-Chibret Laboratories, Research Center,Department of Safety Assessment, BP 134, Route de Marsat 63 203 Riom, France

Srinivasa Prahalada

Merck Research Laboratories, Department of Safety Assessment, West Point, Pennsylvania 19486, USA

Lea G. Stabinski

Merck Research Laboratories, Department of Safety Assessment, West Point, Pennsylvania 19486, USA

Chennekatu P. Peter

Merck Research Laboratories, Department of Safety Assessment, West Point, Pennsylvania 19486, USA

Pierre Duprat

Merck Sharp & Dohme-Chibret Laboratories, Research Center,Department of Safety Assessment, BP 134, Route de Marsat 63 203 Riom, France

Matthew J. Van Zwieten

Merck Research Laboratories, Department of Safety Assessment, West Point, Pennsylvania 19486, USA

Porcine growth hormone was administered subcutaneously to beagle dogs at doses of 0.025,0.1, and 1 IU/kg/d for 14 weeks, markedly elevating serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels. This was accompanied by a significant increase in body weight gain and kidney weights in both male and female dogs. The increase in kidney weight (6 to 54%) was slightly greater than the increase in body weight (6 to 40%). By light microscopy, glomerular deposits, mesangial thickening, and very slight cellular infiltration in glomeruli were seen in mid- and high-dose groups. Based on morphometric evaluation, there was an increase in the renal glomerular area, which was statistically significant (p 0.05) in the mid- and high-dose males and in the high-dose females. This was associated with a statistically significant (p 0.05) increase in the number of total glomerular cells in the mid- and high-dose males. By transmission electron microscopy, thickening of the glomerular basal lamina and diffuse increase of the mesangial matrix were observed in both male and female dogs in the mid- and high-dose groups. Immunohistochemical reactions were negative for IgG, IgM, and C3. The morphological changes in the kidney of dogs resemble the diffuse glomerulosclerosis described in human diabetic nephropathy.

Key Words: Kidney • growth hormone • pharmacological effect • morphometry • electron microscopy • insulin-like growth factor-1

References

• Ascacio-Martinez JA, Barrera-Saldena HA (1994). A dog growth hormone cDNA codes for a mature protein identical to pig growth hormone. Gene 143: 277-280.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Baxter RC (1986). The somatomedines: Insulin-like growth factors. Adv Clin Chem 25: 49-115.[Web of Science][Medline] [Order article via Infotrieve]
• Bloodworth Jmb (1965). Experimental diabetic glomerulosclerosis. II. The dog. Arch Pathol 79: 113-125.[Web of Science][Medline] [Order article via Infotrieve]
• Bloodworth Jmb, Engerman RL, Powers KL (1969). Experimental diabetic microangiopathy. 1. Basement membrane statistics in the dog. Diabetes 18: 455-458.[Medline] [Order article via Infotrieve]
• Bondy CA, Chin E., Zhou J. ( 1994). Significant species differences in local IGF-1 and IGF-2 gene expression. In: Current Direction in Insulin-Like Growth Factor Research, Leroith D, Raisada M (eds). Raven Press, New York, pp 73-77.
• Campbell J., Rastogi KS (1966). Growth hormone-induced diabetes and high levels of serum insulin in dogs. Diabetes 15: 30-43.[Medline] [Order article via Infotrieve]
• Committee of Care and Use of Laboratory Animals (1985). Guide for the Care and Use of Laboratory Animals. NIH Publication 86-23, Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council, National Institutes of Health, Public Health Services, US Department of Health and Human Services, Washington, DC.
• Corvilain J., Abramow M. (1962). Some effects of human-growth hormone on renal hemodynamics and on tubular phosphate transport in man. J Clin Invest 41: 1230-1235.[Web of Science][Medline] [Order article via Infotrieve]
• Corvilain J., Abramow M. (1964). Effect of growth hormone on tubular transport of phosphate in normal and parathyroidectomized dogs. J Clin Invest 43: 1608-1612.[Web of Science][Medline] [Order article via Infotrieve]
• Daughaday WH (1972). Somatomedin: Proposed designation for sulphation factor. Nature 235: 107.[CrossRef][Medline] [Order article via Infotrieve]
• D'Ercole AJ (1987). Somatomedins/insulin-like growth factors and fetal growth. J Dev Physiol 9: 481-495.[Web of Science][Medline] [Order article via Infotrieve]
• Doi T., Striker LJ, Gibson CC, Agodoa LY, Brinster RL, Striker GE (1990). Glomerular lesions in mice transgenic for growth hormone and insulin like growth factor-1: Relationship between increased glomerular size and mesangial sclerosis. Am J Pathol 137: 541-552.[Abstract]
• Doi T., Striker LJ, Kimata K., Peten EP, Yamada Y., Striker GE (1991). Glomerulosclerosis in mice transgenic for growth hormone: Increased mesangial extracellular matrix is correlated with kidney mRNA levels. J Exp Med 173: 1287-1290.[Abstract/Free Full Text]
• Doi T., Striker LJ, Quaife C., Conti FG, Palmiter R., Behringer R., Brinster R., Striker GE (1988). 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 131: 398-403.[Abstract]
• Ebihara I., Suzuki S., Nakamura T., Fukui M., Yagucchi Y., Tomino Y., Koide H. (1993). Extracellular matrix component mRNA expression in glomeruli in experimental focal glomerulosclerosis. Am J Soc Nephrol 3: 1387-1397.[Abstract]
• Eigenmann JE (1981). Diagnosis and treatment of dwarfism in a german shepherd dog. J Am Anim Hosp Assoc 17: 798-804.[Web of Science]
• Eigenmann JE (1985). Growth hormone and insulin-like growth factor in the dog: Clinical and experimental investigations. Domest Anim Endocrinol 2(1): 1-16.[Medline] [Order article via Infotrieve]
• Fagin JA, Melmed S. (1987). Relative increase in insulin-like growth factor 1 messenger ribonucleic acid levels in compensatory renal hypertrophy. Endocrinology 120: 718-723.[Abstract/Free Full Text]
• Floege J., Alpers CE, Burns MW, Pritzl P., Gordon K., Couser WG, Johnson RJ (1992a). Glomerular cells, extracellular matrix accumulation, and the development of glomerulosclerosis in the remnant kidney model. Lab Invest 66: 485-497.[Web of Science][Medline] [Order article via Infotrieve]
• Floege J., Burns MW, Alpers CE, Yoshimura A., Pritzl P., Gordon K., Seifert RA, Bowen-Pope DF, Couser WG, Johnson RJ (1992b). Glomerular cell proliferation and PDGF expression precede glomerulosclerosis in the remnant kidney model. Kidney Int 41: 297-309.[Web of Science][Medline] [Order article via Infotrieve]
• Floege J., Johnson RJ, Couser WG (1992c). Mesangial cells in the pathogenesis of progressive glomerular disease in animal models. J Clin Invest 70: 857-864.
• Flyvbjerg A., Thorlacius-Ussing O., Naerra R., Ingerslev J., Orskov H. (1988). Kidney tissue somatomedin C and initial renal growth in diabetic and uninephrectomized rats. Diabetologica 31: 310-314.[Web of Science][Medline] [Order article via Infotrieve]
• Fukui M., Nakamura T., Ebihara I., Shirato I., Tomino Y., Koide H. (1992). ECM gene expression and its modulation by insulin in diabetic rats. Diabetes 41: 1520-1527.[Abstract]
• Groen JJ, Frenkel HS, Offerhans L. (1964). Observations on a case of spontaneous diabetes mellitus in a dog. Diabetes 13: 492-499.[Medline] [Order article via Infotrieve]
• Hammerman MR (1992). Action of growth hormone in the kidney. J Pediatr Endocrinol 5(1-2): 15-21.
• Hammerman MR, Karl IE, Hruska KA (1980). Regulation of canine renal vesicle Pi transport by growth hormone and parathyroid hormone. Biochim Biophys Acta 603: 322-335.[Medline] [Order article via Infotrieve]
• Hirschberg RR, Kopple JD (1988). Increase in renal plasma flow and glomerular filtration rate during growth hormone treatment may be mediated by insulin-like growth factor 1. Am J Nephrol 8: 249-253.[Web of Science][Medline] [Order article via Infotrieve]
• Hirschberg RR, Kopple JD (1989). Evidence that insulin-like growth factor 1 increases renal plasma flow and glomerular filtration rate in fasted rats. J Clin Invest 83: 326-330.[Web of Science][Medline] [Order article via Infotrieve]
• Hirschberg RR, Kopple JD, Blantz RC, Tucker BJ (1991). Effects of recombinant human insulin-like growth factor 1 of glomerular dynamics in the rat. J Clin Invest 87: 1200-1206.[Web of Science][Medline] [Order article via Infotrieve]
• Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM (1981). Hyperfiltration in remnant nephrons: A potentially adverse response to renal ablation. Am J Physiol 241: F85-F93.[Web of Science][Medline] [Order article via Infotrieve]
• Johnson V., Maack T. (1977). Renal extraction, filtration, absorption, and catabolism of growth hormone. Am J Physiol 233 (Renal Fluid Electrolyte Physiol 2): F185-F196.
• Karpf D., Braunstein GD (1986). Current concepts in acromegaly: Etiology, diagnosis, and treatment. Comprehen Ther 12: 22-30.
• Lajara R., Rotwein P., Bortz JD, Hansen VA, Sadow JL, Betts CR, Rogers SA, Hammerman MR (1989). Dual regulation of insulin-like growth factor 1 expression during renal hypertrophy. Am J Physiol 257 (Renal Fluid Electrolyte Physiol 26): F252-F261.
• Laroque P., Molon-Noblot S., Prahalada S., Stabinski LG, Hoe C-M., Peter CP, Duprat P., van Zwieten MJ (1998). Morphological changes in the pituitary gland of dogs chronically exposed to exogenous growth hormone. Toxicol Pathol 26: 201-206.[Abstract/Free Full Text]
• Mogensen CE, Andersen Mjf (1973). Increased kidney size and glomerular filtration rate in early juvenile diabetes. Diabetes 22: 706-712.[Web of Science][Medline] [Order article via Infotrieve]
• Mogensen CE, Andersen Mjf (1975). Increased kidney size and glomerular filtration rate in untreated juvenile diabetes: Normalization by insulin treatment. Diabetologia 11: 221-224.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Molon-Noblot S., Laroque P., Prahalada S., Stabinski LG, Hoe C-M., Peter CP, Duprat P., van Zwieten MJ (1998). Effect of chronic growth hormone administration on skeletal muscle in dogs. Toxicol Pathol 26: 207-212.[Abstract/Free Full Text]
• Mori H., Yamashita H., Nakanishi C., Koizumi K., Makino S., Kishimoto Y., Hayashi Y. (1986). Proteinuria induced by transplantable rat pituitary tumor MtT sA5: Model for homologous protein-overload proteinuria. Lab Invest 54: 636-644.[Web of Science][Medline] [Order article via Infotrieve]
• Nabaro JD (1987). Acromegaly. Clin Endocrinol 26: 481-512.[Medline] [Order article via Infotrieve]
• Orlowski CC, Chernausek SD (1988). Discordance of serum and tissue somatomedin levels in growth hormone-stimulated growth in the rat. Endocrinology 122: 44-49.
• Osterby R., Gundersen HJ (1975). Glomerular size and structure in diabetes mellitus. Diabetologia 11: 225-229.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Palmiter RD, Brinster RL, Hammer RE, Trumbauer ME, Rosenfeld MG, Birnberg NC, Evans RM (1982). Dramatic growth of mice that develop from eggs microinjected with metallothionein-growth hormone fusion genes. Nature 300: 611-615.[CrossRef][Medline] [Order article via Infotrieve]
• Palmiter RD, Norstedt G., Gelinas RE, Hammer RE, Brinster RL (1983). Metallothionein-human GH fusion genes stimulate growth of mice. Science 222(4625): 809-814.[Abstract/Free Full Text]
• Prahalada S., Stabinski LG, Chen HY, Morrissey RE, De Burlet G., Holder D., Patrick DH, Peter CP, van Zwieten MJ (1998). Pharmacological and toxicological effects of porcine growth hormone administration in dogs. Toxicol Pathol 26: 185-200.[Abstract/Free Full Text]
• Quaife CJ, Mathews LS, Pinkert CA, Hammer RE, Brinster RL, Palmiter RD (1989). Histopathology associated with elevated levels of growth hormone and insulin-like growth factor 1 in transgenic mice. Endocrinology 124: 40-48.[Abstract/Free Full Text]
• Quigley R., Baum M. ( 1991). Effects of growth hormone and insulin-like growth hormone factor 1 on rabbit proximal convoluted tubule transport. J Clin Invest 88: 368-374.[Web of Science][Medline] [Order article via Infotrieve]
• Rhodin JA (1974). Histology: A Text and Atlas. Oxford University Press, New York, pp 648-664.
• Rogers SA, Hammerman MR (1989). Growth hormone activates phospholipase C in proximal tubular basolateral membranes from canine kidney. Proc Natl Acad Sci USA 86: 6363-6366.[Abstract/Free Full Text]
• Rogers SA, Hammerman MR (1989). Growth hormone directly stimulates gluconeogenesis in canine renal proximal tubule. Am J Physiol 257: E751-E756.[Web of Science][Medline] [Order article via Infotrieve]
• Rogers SA, Hammerman MR (1989). Mannose 6-phosphate potentiates insulin-like growth factor 2-stimulated inositol triphosphate production in proximal tubular basolateral membranes. J Biol Chem 264:4273-4276.[Abstract/Free Full Text]
• Rogers SA, Miller SB, Hammerman MR (1990). Growth hormone stimulates IGF 1 gene expression in isolated rat renal collecting duct. Am J Physiol 259: F474-F479.[Web of Science][Medline] [Order article via Infotrieve]
• Rosenfeld RG, Wilson DM, Dollar LA, Bennett A., Hintz RL (1982). Both human pituitary growth hormone and recombinant DNA-derived human growth hormone cause insulin resistance at a postreceptor site. J Clin Endocrinol Metab 54: 1033-1038.[Abstract/Free Full Text]
• Schoenle E., Zapf J., Froesch ER (1978). Effects of insulin on glucose metabolism and glucose transport in fat cells of hormone-treated hypophysectomized rats: Evidence that growth hormone restricts glucose transport. Endocrinology 105(5): 1237-1242.[Web of Science]
• Schoenle E., Zapf J., Froesch ER (1982). Glucose transport in adipocytes and its control by growth hormone in vivo. Am J Physiol 22 (Endocrinol Metab 5): E368-E372.
• Seyer-Hansen K. (1987). Renal hypertrophy in experimental diabetes: Some functional aspects. J Diabet Complicat 1: 7-10.[CrossRef]
• Seyer-Hansen K., Hansen J., Gundersen Hjg (1980). Renal hypertrophy in experimental diabetes: A morphometric study. Diabetologia 18: 501-505.[Web of Science][Medline] [Order article via Infotrieve]
• Siperstein MD, Unger RL, Madison LL (1968). Studies of muscle capillary basement membrane in normal subjects, diabetic and pre-diabetic patients. J Clin Invest 47: 1973-1999.[Web of Science][Medline] [Order article via Infotrieve]
• Sloan JM, Oliver IM (1975). Progestagen-induced diabetes in the dog. Diabetes 24: 337-344.[Medline] [Order article via Infotrieve]
• Stiles AD, Sosenko Irs, D'Ercole J., Smith BT (1985). Relation of kidney tissue somatomedin-C/insulin-like growth factor 1 to post-nephrectomy renal growth in the rat. Endocrinology 117: 2397-2401.[Abstract/Free Full Text]
• Takahashi Y., Ebihara S., Nakamura Y., Takahashi K. (1981). A model of human sleep-related growth hormone secretion in dogs: Effects of 3, 6, and 12 hours of forced wakefulness on plasma growth hormone, cortisol, and sleep stages. Endocrinology 109: 262-272.[Abstract/Free Full Text]
• Tannembaum GS (1993). Genesis of episodic growth hormone secretion. J Pediatr Endocrinol 6: 273-282.
• Yang CW, Striker LJ, Pesce C., Chen WY, Peten EP, Elliot S. Doi T., Kopchick JJ, Striker GE (1993). Glomerulosclerosis and body growth are mediated by different portions of bovine growth hormone: Studies in transgenic mice. Lab Invest 68: 62-70.[Web of Science][Medline] [Order article via Infotrieve]
• Yang CW, Wlassara H., Peten EP. He CJ, Striker GE, Striker LJ (1994). Advanced glycosylation endproducts up-regulate gene expression found in diabetic glomerular disease. Proc Natl Acad Sci USA 91:9436-9440.[Abstract/Free Full Text]
• Yoshida H., Mitarai T., Kitamira M., Szuki T., Ishikawa H., Fogo A., Sakai O. (1994). The effect of selective growth hormone defect in the progression of glomerulosclerosis. Am J Kidney Dis 23: 302-312.[Web of Science][Medline] [Order article via Infotrieve]

Toxicologic Pathology, Vol. 28, No. 4, 510-517 (2000)
DOI: 10.1177/019262330002800402


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				S. Molon-Noblot, M.-F. Hubert, C.-M. Hoe, K. Keenan, and P. Laroque The Effects of Ad Libitum Feeding and Marked Dietary Restriction on Spontaneous Skeletal Muscle Pathology in Sprague-Dawley Rats Toxicol Pathol, August 1, 2005; 33(5): 600 - 608. [Abstract] [Full Text] [PDF]

This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Molon-Noblot, S. Articles by Van Zwieten, M. J. Search for Related Content PubMed PubMed Citation Articles by Molon-Noblot, S. Articles by Van Zwieten, M. J. Social Bookmarking                         What's this?