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Most of the available information on Leydig cells has been obtained using a rodent model system. With an objective to extend the observations made with rat Leydig cells (RLCs) to primates, a method has been developed to isolate Leydig cells from monkey (Macaca radiata) testis. Enzymatic dissociation of monkey testis followed by Percoll-gradient fractionation of the interstitial cells resulted in the recovery of Leydig cells at densities corresponding to 1.064-1.070 g/ml. Purified (90-94%) monkey Leydig cells (MLCs) stained positive for the Leydig cell marker 3beta-hydroxysteroid dehydrogenase. The cells responded to in vitro addition of human chorionic gonadotropin (hCG) and produced testosterone. Comparison of the in vitro testosterone-producing ability of MLCs with RLCs revealed that MLCs have much less steroidogenic capacity compared with the RLCs. Analysis revealed that limitation in substrate availability to mitochondrial P(450) side chain cleavage enzyme and low mitochondrial and smooth endoplasmic reticulum content in MLCs could be the possible reasons for the low steroidogenic capacity of the MLCs.
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Abstract
Abnormalities of GH secretion and clearance are well-documented in poorly controlled insulin-dependent diabetes mellitus (IDDM), but the contribution of the receptor (GHR) and the GH-binding protein (GHBP) to these abnormalities has not been defined. We studied the expression of the GHR/GHBP gene in the livers, hearts and kidneys in streptozocin-induced diabetes (STZ-D) in the rat. GHR and GHBP mRNA levels were measured by Northern blot and ribonuclease protection assays. Whereas levels of GHR and GHBP mRNA were significantly decreased in liver and heart of STZ-D rats when compared with the control group (P<0·01), GHR mRNA was significantly increased in the kidneys of STZ-D rats (P=0·03). Six days of insulin treatment did not significantly alter the levels of GHR/GHBP mRNA in the liver or heart of STZ-D rats, but significantly decreased GHBP mRNA (P=0·04) in the kidney. Circulating IGF-I was reduced, as was IGF-I mRNA in the liver and heart of STZ-D rats; only circulating IGF-I was restored by insulin treatment. Neither STZ-D nor insulin treatment affected IGF-I or IGF-I receptor mRNA concentrations in the kidney. We conclude that (1) STZ-D modulates the expression of the GHR/GHBP gene and (2) that these changes in GHR/GHBP mRNA concentrations are tissue-specific; STZ-D decreases GHR/GHBP mRNA in liver and heart tissue but increases GHR mRNA concentrations in the kidney. Our results indicate a role for decreased numbers of hepatic GHRs in the pathogenesis of resistance to GH's actions in terms of IGF-I generation and promotion of linear growth in IDDM. We postulate that increased GHR expression in the kidney may be involved in the renal complications of IDDM.
Journal of Endocrinology (1994) 142, 453–462
Isis Pharmaceuticals Inc., 1986 Rutherford Ave, Carlsbad, California 92008, USA
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
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Isis Pharmaceuticals Inc., 1986 Rutherford Ave, Carlsbad, California 92008, USA
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
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Isis Pharmaceuticals Inc., 1986 Rutherford Ave, Carlsbad, California 92008, USA
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
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Isis Pharmaceuticals Inc., 1986 Rutherford Ave, Carlsbad, California 92008, USA
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
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Isis Pharmaceuticals Inc., 1986 Rutherford Ave, Carlsbad, California 92008, USA
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
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Isis Pharmaceuticals Inc., 1986 Rutherford Ave, Carlsbad, California 92008, USA
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
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Isis Pharmaceuticals Inc., 1986 Rutherford Ave, Carlsbad, California 92008, USA
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
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Isis Pharmaceuticals Inc., 1986 Rutherford Ave, Carlsbad, California 92008, USA
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
Search for other papers by A M Rao in
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Isis Pharmaceuticals Inc., 1986 Rutherford Ave, Carlsbad, California 92008, USA
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
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Isis Pharmaceuticals Inc., 1986 Rutherford Ave, Carlsbad, California 92008, USA
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
Search for other papers by E M d’Aniello in
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Isis Pharmaceuticals Inc., 1986 Rutherford Ave, Carlsbad, California 92008, USA
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
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Diabetic retinopathy and acromegaly are diseases associated with excess action of GH and its effector IGF-I, and there is a need for improved therapies. We have designed an optimised 2′-O-(2-methoxyethyl)-modified phosphorothioate oligodeoxynucleotide, ATL 227446, and demonstrated its ability to suppress GH receptor mRNA in vitro. Subcutaneous injections of ATL 227446 reduced GH receptor mRNA levels, GH binding activity and serum IGF-I levels in mice after seven days of dosing. The reduction in serum IGF-I could be sustained for over ten weeks of dosing at therapeutically relevant levels, during which there was also a significant decrease in body weight gain in antisense-treated mice relative to saline and mismatch control-treated mice. The findings indicate that administration of an antisense oligonucleotide to the GH receptor may be applicable to human diseases in which suppression of GH action provides therapeutic benefit.
