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Gurevich E, Segev Y, Landau D. Growth Hormone and IGF1 Actions in Kidney Development and Function. Cells 2021; 10:cells10123371. [PMID: 34943879 PMCID: PMC8699155 DOI: 10.3390/cells10123371] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 11/16/2021] [Accepted: 11/24/2021] [Indexed: 01/17/2023] Open
Abstract
Growth hormone (GH) exerts multiple effects on different organs including the kidneys, either directly or via its main mediator, insulin-like-growth factor-1 (IGF-1). The GH/IGF1 system plays a key role in normal kidney development, glomerular hemodynamic regulation, as well as tubular water, sodium, phosphate, and calcium handling. Transgenic animal models demonstrated that GH excess (and not IGF1) may lead to hyperfiltration, albuminuria, and glomerulosclerosis. GH and IGF-1 play a significant role in the early development of diabetic nephropathy, as well as in compensatory kidney hypertrophy after unilateral nephrectomy. Chronic kidney disease (CKD) and its complications in children are associated with alterations in the GH/IGF1 axis, including growth retardation, related to a GH-resistant state, attributed to impaired kidney postreceptor GH-signaling and chronic inflammation. This may explain the safety of prolonged rhGH-treatment of short stature in CKD.
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Affiliation(s)
- Evgenia Gurevich
- Department of Nephrology, Schneider Children’s Medical Center of Israel, 14 Kaplan Street, Petach Tikva 4920235, Israel;
| | - Yael Segev
- Shraga Segal Department of Microbiology and Immunology, Ben Gurion University, Beer Sheva 8410501, Israel;
| | - Daniel Landau
- Department of Nephrology, Schneider Children’s Medical Center of Israel, 14 Kaplan Street, Petach Tikva 4920235, Israel;
- Sackler School of Medicine, Tel Aviv University, P.O. Box 39040, Tel Aviv 6997801, Israel
- Correspondence: ; Tel.: +972-3925-3651
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Brittain AL, Kopchick JJ. A review of renal GH/IGF1 family gene expression in chronic kidney diseases. Growth Horm IGF Res 2019; 48-49:1-4. [PMID: 31352157 DOI: 10.1016/j.ghir.2019.07.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 07/07/2019] [Accepted: 07/15/2019] [Indexed: 01/15/2023]
Abstract
Despite decades of study on the contribution of growth hormone (GH) to the development of kidney disease, there remains the question of the relative contribution of elevated levels of GH to kidney damage in humans, particularly in diabetic nephropathy occurring in type 1 patients. In this study, we reviewed several publicly available datasets to examine transcription of twelve genes associated with the GH/IGF1 axis in several types of human and rodent kidney diseases. Our analyses revealed downregulation of renal GHR and IGF1 gene expression in several different chronic human kidney diseases, including diabetic nephropathy, with general upregulation of IGFBP6 in the same tissues and diseases. These findings were generally supported by a review of studies in rodent models. In healthy and diseased human kidneys, increased GHR gene expression was associated with increases in glomerular filtration rate (GFR) and decreases in serum creatinine. IGFBP6 gene expression demonstrated the opposite clinical correlation. Our results suggest the kidney may exhibit GH insensitivity due to low GHR gene expression during most chronic kidney diseases.
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Affiliation(s)
- Alison L Brittain
- Edison Biotechnology Institute and Heritage College of Osteopathic Medicine, Ohio University, Konneker Research Center 206A, Athens, OH 45701, USA.
| | - John J Kopchick
- Edison Biotechnology Institute and Heritage College of Osteopathic Medicine, Ohio University, Konneker Research Center 206A, Athens, OH 45701, USA.
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Mendes-da-Cruz DA, Lemos JP, Passos GA, Savino W. Abnormal T-Cell Development in the Thymus of Non-obese Diabetic Mice: Possible Relationship With the Pathogenesis of Type 1 Autoimmune Diabetes. Front Endocrinol (Lausanne) 2018; 9:381. [PMID: 30050502 PMCID: PMC6052664 DOI: 10.3389/fendo.2018.00381] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 06/22/2018] [Indexed: 12/20/2022] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of insulin-producing cells in the pancreas, by direct interactions with autoreactive pancreas infiltrating T lymphocytes (PILs). One of the most important animal models for this disease is the non-obese diabetic (NOD) mouse. Alterations in the NOD mouse thymus during the pathogenesis of the disease have been reported. From the initial migratory disturbances to the accumulation of mature thymocytes, including regulatory Foxp3+ T cells, important mechanisms seem to regulate the repertoire of T cells that leave the thymus to settle in peripheral lymphoid organs. A significant modulation of the expression of extracellular matrix and soluble chemoattractant molecules, in addition to integrins and chemokine receptors, may contribute to the progressive accumulation of mature thymocytes and consequent formation of giant perivascular spaces (PVS) that are observed in the NOD mouse thymus. Comparative large-scale transcriptional expression and network analyses involving mRNAs and miRNAs of thymocytes, peripheral T CD3+ cells and PILs provided evidence that in PILs chemokine receptors and mRNAs are post-transcriptionally regulated by miR-202-3p resulting in decreased activity of these molecules during the onset of T1D in NOD mice. In this review, we discuss the abnormal T-cell development in NOD mice in the context of intrathymic expression of different migration-related molecules, peptides belonging to the family of insulin and insulin-like growth factors as well as the participation of miRNAs as post-transcriptional regulators and their possible influence on the onset of aggressive autoimmunity during the pathogenesis of T1D.
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Affiliation(s)
- Daniella A. Mendes-da-Cruz
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- National Institute of Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Julia P. Lemos
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- National Institute of Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Geraldo A. Passos
- Department of Morphology, Physiology and Basic Pathology, Ribeirão Preto Medical School, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Wilson Savino
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- National Institute of Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
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Bach LA, Hale LJ. Insulin-like growth factors and kidney disease. Am J Kidney Dis 2014; 65:327-36. [PMID: 25151409 DOI: 10.1053/j.ajkd.2014.05.024] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Accepted: 05/03/2014] [Indexed: 11/11/2022]
Abstract
Insulin-like growth factors (IGF-1 and IGF-2) are necessary for normal growth and development. They are related structurally to proinsulin and promote cell proliferation, differentiation, and survival, as well as insulin-like metabolic effects, in most cell types and tissues. In particular, IGFs are important for normal pre- and postnatal kidney development. IGF-1 mediates many growth hormone actions, and both growth hormone excess and deficiency are associated with perturbed kidney function. IGFs affect renal hemodynamics both directly and indirectly by interacting with the renin-angiotensin system. In addition to the IGF ligands, the IGF system includes receptors for IGF-1, IGF-2/mannose-6-phosphate, and insulin, and a family of 6 high-affinity IGF-binding proteins that modulate IGF action. Disordered regulation of the IGF system has been implicated in a number of kidney diseases. IGF activity is enhanced in early diabetic nephropathy and polycystic kidneys, whereas IGF resistance is found in chronic kidney failure. IGFs have a potential role in enhancing stem cell repair of kidney injury. Most IGF actions are mediated by the tyrosine kinase IGF-1 receptor, and inhibitors recently have been developed. Further studies are needed to determine the optimal role of IGF-based therapies in kidney disease.
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Affiliation(s)
- Leon A Bach
- Department of Endocrinology and Diabetes, Alfred Hospital, Melbourne, Victoria, Australia; Department of Medicine (Alfred), Monash University, Melbourne, Victoria, Australia.
| | - Lorna J Hale
- Baker-IDI Research Institute, Melbourne, Victoria, Australia
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Kamenický P, Mazziotti G, Lombès M, Giustina A, Chanson P. Growth hormone, insulin-like growth factor-1, and the kidney: pathophysiological and clinical implications. Endocr Rev 2014; 35:234-81. [PMID: 24423979 DOI: 10.1210/er.2013-1071] [Citation(s) in RCA: 142] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Besides their growth-promoting properties, GH and IGF-1 regulate a broad spectrum of biological functions in several organs, including the kidney. This review focuses on the renal actions of GH and IGF-1, taking into account major advances in renal physiology and hormone biology made over the last 20 years, allowing us to move our understanding of GH/IGF-1 regulation of renal functions from a cellular to a molecular level. The main purpose of this review was to analyze how GH and IGF-1 regulate renal development, glomerular functions, and tubular handling of sodium, calcium, phosphate, and glucose. Whenever possible, the relative contributions, the nephronic topology, and the underlying molecular mechanisms of GH and IGF-1 actions were addressed. Beyond the physiological aspects of GH/IGF-1 action on the kidney, the review describes the impact of GH excess and deficiency on renal architecture and functions. It reports in particular new insights into the pathophysiological mechanism of body fluid retention and of changes in phospho-calcium metabolism in acromegaly as well as of the reciprocal changes in sodium, calcium, and phosphate homeostasis observed in GH deficiency. The second aim of this review was to analyze how the GH/IGF-1 axis contributes to major renal diseases such as diabetic nephropathy, renal failure, renal carcinoma, and polycystic renal disease. It summarizes the consequences of chronic renal failure and glucocorticoid therapy after renal transplantation on GH secretion and action and questions the interest of GH therapy in these conditions.
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Affiliation(s)
- Peter Kamenický
- Assistance Publique-Hôpitaux de Paris (P.K., M.L., P.C.), Hôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Le Kremlin Bicêtre F-94275, France; Univ Paris-Sud (P.K., M.L., P.C.), Faculté de Médecine Paris-Sud, Le Kremlin Bicêtre F-94276, France; Inserm Unité 693 (P.K., M.L., P.C.), Le Kremlin Bicêtre F-94276, France; and Department of Clinical and Experimental Sciences (A.G., G.M.), Chair of Endocrinology, University of Brescia, 25125 Brescia, Italy
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Kumar PA, Brosius FC, Menon RK. The glomerular podocyte as a target of growth hormone action: implications for the pathogenesis of diabetic nephropathy. Curr Diabetes Rev 2011; 7:50-5. [PMID: 21067510 PMCID: PMC4007067 DOI: 10.2174/157339911794273900] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2010] [Accepted: 09/10/2010] [Indexed: 01/28/2023]
Abstract
Involvement of the growth hormone (GH) / insulin-like growth factor 1 (IGF-I) axis in the pathogenesis of diabetic nephropathy (DN) is strongly suggested by studies investigating the impact of GH excess and deficiency on renal structure and function. GH excess in both the human (acromegaly) and in transgenic animal models is characterized by significant structural and functional changes in the kidney. In the human a direct relationship has been noted between the activity of the GH/IGF-1 axis and renal hypertrophy, microalbuminuria, and glomerulosclerosis. Conversely, states of GH deficiency or deficiency or inhibition of GH receptor (GHR) activity confer a protective effect against DN. The glomerular podocyte plays a central and critical role in the structural and functional integrity of the glomerular filtration barrier and maintenance of normal renal function. Recent studies have revealed that the glomerular podocyte is a target of GH action and that GH's actions on the podocyte could be detrimental to the structure and function of the podocyte. These results provide a novel mechanism for GH's role in the pathogenesis of DN and offer the possibility of targeting the GH/IGF-1 axis for the prevention and treatment of DN.
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Affiliation(s)
- P Anil Kumar
- Pediatrics & Communicable Diseases, University of Michigan, Ann Arbor, MI 48109-0718, USA
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Landau D, Eshet R, Troib A, Gurman Y, Chen Y, Rabkin R, Segev Y. Increased renal Akt/mTOR and MAPK signaling in type I diabetes in the absence of IGF type 1 receptor activation. Endocrine 2009; 36:126-34. [PMID: 19387875 DOI: 10.1007/s12020-009-9190-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2009] [Revised: 03/24/2009] [Accepted: 03/26/2009] [Indexed: 10/20/2022]
Abstract
Growth hormone (GH) and IGF-I have been implicated in the pathogenesis of type I diabetic (DM) nephropathy. We investigated renal GH receptor (GHR) and IGF-type 1 receptor (IGF1R) signaling in an animal model of type I DM. Kidney tissue was examined for GHR and IGF1R key signaling molecules. GHR levels were unchanged and IGF-I mRNA levels were decreased in the diabetic group (D). Basal and GH stimulated phosphorylated (p-) JAK2 and STAT5 levels were similar in controls (C) and D. The levels of p-IGF1R were similar in the two groups at baseline, while pAkt, pGSK3, p-mTOR, p-rpS6, p-erk1/2 (Mapk), and pSTAT-3 were increased in D. Following IGF-I administration p-Akt, p-rpS6, p-Mapk, and p-GSK levels increased more pronouncedly in D versus C. In conclusion, the lack of JAK2-STAT5 activation and the decrease in kidney IGF-I mRNA levels in D argue against a role for the GH activated JAK2-STAT5 pathway in the pathogenesis of diabetic nephropathy. On the other hand while IGF1R phosphorylation was unchanged, Akt/mTOR and MAPK signaling were hyperactivate in DM, suggesting their involvement. The increase in baseline activated Akt, mTOR, rpS6, and MAPK cannot be explained by activation of the IGF1R, but may be triggered by other growth factors and nutrients.
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Affiliation(s)
- Daniel Landau
- Department of Pediatrics, Soroka Medical Center, Ben Gurion University of the Negev, Beer Sheva, 84101, Israel.
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Luque RM, Park S, Kineman RD. Role of endogenous somatostatin in regulating GH output under basal conditions and in response to metabolic extremes. Mol Cell Endocrinol 2008; 286:155-68. [PMID: 18258353 DOI: 10.1016/j.mce.2007.12.005] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2007] [Revised: 11/28/2007] [Accepted: 12/05/2007] [Indexed: 01/26/2023]
Abstract
Somatostatin (SST) was first described over 30 years ago as a hypothalamic neuropeptide which inhibits GH release. Since that time a large body of literature has accumulated describing how endogenous SST mediates its effects on GH-axis function under normal conditions and in response to metabolic extremes. This review serves to summarize the key findings in this field with a focus on recent progress, much of which has been made possible by the availability of genetically engineered mouse models and SST receptor-specific agonists.
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Affiliation(s)
- Raul M Luque
- Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
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Zhao C, Wang Z, Robertson MW, Davies JD. Cachexia in the non-obese diabetic mouse is associated with CD4+ T-cell lymphopenia. Immunology 2008; 125:48-58. [PMID: 18397274 DOI: 10.1111/j.1365-2567.2008.02819.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
One of the long-term consequences of Type I diabetes is weight loss with muscle atrophy, the hallmark phenotype of cachexia. A number of disorders that result in cachexia are associated with immune deficiency. However, whether immune deficiency is a cause or an effect of cachexia is not known. This study examines the non-obese diabetic mouse, the mouse model for spontaneous Type I diabetes, as a potential model to study lymphopenia in cachexia, and to determine whether lymphopenia plays a role in the development of cachexia. The muscle atrophy seen in patients with Type I diabetes involves active protein degradation by activation of the ubiquitin-proteasome pathway, indicating cachexia. Evidence of cachexia in the non-obese diabetic mouse was determined by measuring skeletal muscle atrophy, activation of the ubiquitin-proteasome pathway, and apoptosis, a state also described in some models of cachexia. CD4+ T-cell subset lymphopenia was measured in wasting and non-wasting diabetic mice. Our data show that the mechanism of wasting in diabetic mice involves muscle atrophy, a significant increase in ubiquitin conjugation, and upregulation of the ubiquitin ligases, muscle RING finger 1 (MuRF1) and muscle atrophy F box/atrogin-1 (MAFbx), indicating cachexia. Moreover, fragmentation of DNA isolated from atrophied muscle tissue indicates apoptosis. While CD4+ T-cell lymphopenia is evident in all diabetic mice, CD4+ T cells that express a very low density of CD44 were significantly lost in wasting, but not non-wasting, diabetic mice. These data suggest that CD4+ T-cell subsets are not equally susceptible to cachexia-associated lymphopenia in diabetic mice.
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Affiliation(s)
- Chunfang Zhao
- Torrey Pines Institute for Molecular Studies, General Atomics Court, San Diego, CA 92121, USA
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Landau D, Segev Y. Role of IGF-I in Type 2 diabetes: a focus on the mouse model. Expert Rev Endocrinol Metab 2008; 3:43-49. [PMID: 30743784 DOI: 10.1586/17446651.3.1.43] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Insulin resistance, the key mechanism in Type 2 diabetes mellitus (T2DM) is also associated with the deregulation of other glucose homeostasis pathways, such as the growth hormone (GH)-IGF-I system. In this review, we summarize the endocrine and renal GH-IGF axis changes in db/db mice, a model of T2DM, and compare it with the nonobese diabetic mouse model of T1DM. In the latter, elevated circulating GH levels (associated with kidney disease) could be ameliorated with the use of GH antagonists. Contrary to that, in the obese db/db mice, serum GH and IGF-I levels are decreased and tissue levels of IGF-binding protein 1 (Igfbp1) are increased. The latter hinted again for the known inverse correlation between insulin and Igfbp1 and was mediated by changes in the transcription factor phosphorylated forkhead box O1 in obese animals. In addition, the decrease in circulating IGF-I and GH levels causes a state of low free and active IGF-I, which may further impair tissue viability (including pancreatic β-cells). Thus, further GH inhibition to modulate complications in T2DM is not indicated, but the therapeutic role of IGF-1 in this disease remains to be determined.
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Affiliation(s)
- Daniel Landau
- a Department of Pediatrics A, Faculty of Health Sciences, Ben Gurion University of the Negev, Soroka University Medical Center, PO Box 151, Beer Sheva 84101, Israel.
| | - Yael Segev
- b Department of Microbiology and Immunology, Faculty of Health Sciences, Ben Gurion University of the Negev, Soroka University Medical Center, PO Box 151, Beer Sheva 84101, Israel.
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Segev Y, Eshet R, Yakir O, Haim N, Phillip M, Landau D. Systemic and renal growth hormone-IGF1 axis involvement in a mouse model of type 2 diabetes. Diabetologia 2007; 50:1327-34. [PMID: 17443310 DOI: 10.1007/s00125-007-0663-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2007] [Accepted: 02/23/2007] [Indexed: 10/23/2022]
Abstract
AIMS/HYPOTHESIS In previous studies we have shown a significant involvement of the growth hormone (GH)-IGF axis in animal models of type 1 diabetes mellitus, but the role of this endocrine system in type 2 diabetes mellitus is less well characterised. We therefore examined the endocrine and renal GH-IGF axis changes in db/db mice, a model of type 2 diabetes mellitus and nephropathy. MATERIALS AND METHODS Obese and lean animals were followed, beginning at hyperglycaemia onset, for 4 weeks. Albuminuria and creatinine clearance, as well as kidney and glomerular morphology were assessed. Tissue protein levels were determined by western blotting and mRNA levels by RT-PCR. RESULTS Serum GH and IGF1 levels immediately prior to killing were decreased and liver mRNA levels of insulin-like growth factor binding protein 1 (Igfbp1) were increased in obese animals. Kidney weight was increased in obese animals, associated with hyperfiltration, albuminuria and glomerular hypertrophy. Administration of a somatostatin analogue (PTR-313) did not improve any of these parameters of diabetic renal involvement. Renal Igf1 mRNA was decreased and renal Igfbp1 mRNA and protein were significantly increased in obese animals. Renal insulin-driven levels of phosphorylated forkhead box O1 (FOXO1) were decreased in obese animals. CONCLUSIONS/INTERPRETATION Diabetic db/db mice show significant renal changes (and IGFBP1 renal accumulation), similar to the findings in models of type 1 diabetes mellitus. A decreased signalling through the insulin receptor and decreased FOXO1 phosphorylation may allow Igfbp1 gene transcription. These renal changes are associated with low circulating IGF1 and GH levels and unchanged hepatic growth hormone receptor expression, unlike the condition in type 1 diabetes mellitus. This suggests that further GH inhibition to modulate renal complications in type 2 diabetes mellitus is not indicated.
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Affiliation(s)
- Y Segev
- Department of Microbiology and Immunology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
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Luque RM, Park S, Kineman RD. Severity of the catabolic condition differentially modulates hypothalamic expression of growth hormone-releasing hormone in the fasted mouse: potential role of neuropeptide Y and corticotropin-releasing hormone. Endocrinology 2007; 148:300-9. [PMID: 17038558 DOI: 10.1210/en.2006-0592] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
To determine whether the severity of the catabolic condition differentially regulates the GH axis, male mice were either fed ad libitum or fasted for 12, 24, and 48 h. Hypothalami, pituitaries, and stomachs were collected for assessment of mRNA levels by quantitative real-time RT-PCR, and blood collected for measurement of plasma hormone and metabolite levels by commercial assay kits. Overnight (12 h) fasting resulted in a significant suppression of circulating glucose, insulin, IGF-I, and leptin levels and an increase in corticosterone, free fatty acids, and n-octanoyl ghrelin levels, and these directional changes were maintained at the 24- and 48-h time points. Fasting (24 h) also increased circulating GH levels, which was associated with an increase in pituitary mRNA levels for GHRH receptor and ghrelin receptor and a decrease in mRNA levels for somatostatin (SST) receptor (SSTR) subtypes, SSTR2, SSTR3, and SSTR5, where the changes in ghrelin receptor and SSTR expression persisted after 48 h fasting. Hypothalamic SST mRNA levels were not altered by fasting, whereas there was a transient rise in stomach SST mRNA levels 24 h after food withdrawal. In contrast, there was a biphasic effect of fasting on GHRH expression. GHRH mRNA levels were significantly elevated at 12 and 24 h but fell to approximately 50% of fed controls 48 h after food withdrawal. A sequential rise in hypothalamic neuropeptide Y (NPY) and CRH mRNA levels preceded the fall in GHRH expression, where fasting-induced changes in CRH and GHRH mRNA levels were not observed in 48-h-fasted NPY knockout mice. These observations, in light of previous reports showing both NPY and CRH can inhibit GHRH expression and GH release, suggest that these neuronal systems may work in concert to control the ultimate impact of fasting on GH axis function.
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Affiliation(s)
- Raul M Luque
- Department of Medicine, University of Illinois, Chicago, USA
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Abstract
There is an increasing number of patients with diabetes mellitus in many countries. Diabetic kidney disease, one of its microvascular complications, is also increasing markedly and has become a major cause of end stage renal disease worldwide. Intervention for preventing and delaying the development and progression of diabetic kidney disease is not only a medical concern, but also a social issue. Despite extensive efforts, however, medical interventions thus far are not effective enough to prevent the progression of the disease and the development of end stage renal disease. This justifies attempts to develop novel therapeutic approaches for diabetic nephropathy. Recent insights on its pathogenesis and progression have suggested new targets for the specific treatment of this disease. They include aldosterone, aldose reductase, arachidonic acid metabolites, growth factors, advanced glycosylation end-products, peroxisome proliferator-activated receptors and endothelin. Several other biochemical mediators have been targeted in experimental animal models with the goal to prevent diabetic nephropathy progression, but translation to clinics of these experimental achievements are still limited or lacking.
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Affiliation(s)
- Simona Bruno
- Mario Negri Institute for Pharmacological Research, Department of Medicine and Transplantation, Ospedali Riuniti di Bergamo, Via Gavazzeni 11, 24125 Bergamo, Italy
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Cingel-Ristić V, Flyvbjerg A, Drop SLS. The physiological and pathophysiological roles of the GH/IGF-axis in the kidney: lessons from experimental rodent models. Growth Horm IGF Res 2004; 14:418-430. [PMID: 15519249 DOI: 10.1016/j.ghir.2004.06.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The growth hormone (GH)/insulin-like growth factor (IGF) system plays an important role in renal development, growth, function and pathophysiology. IGF-I has been associated with renal/glomerular hypertrophy and compensatory renal growth. Potential effects on glomerular size are of interest, since an increase in glomerular size may be permissive for the development of glomerulosclerosis. In an effort to abolish the decline of renal function and possibly to restore the renal structure, different approaches have been tested in experimental models of nephropathy, focusing mainly on early renal changes. The involvement of the GH/IGF system in renal pathophysiology has been studied in much detail in the rat. In view of the growing interest in murine physiology, occurring in large part by genetically modified animals, this review examines those aspects of GH, IGFs, their receptors and binding proteins that relate both to mouse kidney physiology and to a number of conditions characterized by pathophysiological renal changes. A deeper understanding of the role of the GH/IGF system in renal dysfunction may stimulate the development of novel therapeutic approaches aiming at preventing or retarding various kidney diseases.
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Affiliation(s)
- Vesna Cingel-Ristić
- Laboratory of Pediatrics, Subdivision of Molecular Endocrinology, P.O. Box 1738, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands.
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Segev Y, Eshet R, Rivkis I, Hayat C, Kachko L, Phillip M, Landau D. Comparison between somatostatin analogues and ACE inhibitor in the NOD mouse model of diabetic kidney disease. Nephrol Dial Transplant 2004; 19:3021-8. [PMID: 15494355 DOI: 10.1093/ndt/gfh528] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND The growth hormone (GH)-insulin-like growth factor (IGF)-SST (SST) axis is involved in diabetic nephropathy (DN). We have recently shown a beneficial effect on diabetic kidney disease markers by the use of a novel somatostatin (SST) analogue (PTR-3173) (S). The purpose of this study is to compare the effects of S with a previously used SST analogue (octreotide) and an ACE inhibitor (ACEi), a standard of care in DN. METHODS Non-obese diabetic mice (a model of type I diabetes) were treated with either S (DS), octreotide (DO), enalapril (DA), or PTR-3173 and enalapril (DAS group) for 3 weeks. RESULTS Diabetic renal hypertrophy was blunted in the DS and DO groups only. Serum GH and IGF-I were markedly increased and decreased, respectively, in the D group, a change significantly blunted in DO and DS. Diabetic hyperfitration and albuminuria were blunted in all the four treated diabetic groups. The marked deposition of type IV collagen and PAS material were mildly decreased in DA, but more markedly reduced in DS as well as DO. Diabetic renal laminin accumulation was suppressed in all treated animal groups. No synergistic effect was observed for any parameter in the combination group DAS. CONCLUSION SST analogues exert beneficial effects in most parameters of diabetic kidney disease to the same extent as the ACEi. Enalapril treatment had no effect on renal hypertrophy and did not cause a significant decrease in mesangial type IV collagen deposition. A synergistic effect of combined SST-ACEi therapy could not be shown in this study.
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Affiliation(s)
- Yael Segev
- Department of Micrbiology and Immunology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
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Li JB, Wang CY, Chen JW, Feng ZQ, Ma HT. Expression of liver insulin-like growth factor 1 gene and its serum level in rats with diabetes. World J Gastroenterol 2004; 10:255-9. [PMID: 14716834 PMCID: PMC4717015 DOI: 10.3748/wjg.v10.i2.255] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To explore the effect of diabetic duration and blood glucose level on insulin like growth factor 1 (IGF-1) gene expression and serum IGF-1 level.
METHODS: Diabetes was induced into Sprague Dawley rats by alloxan and then the rats were subdivided into different groups with varying blood glucose level and diabetic duration. The parameters were measured as follows: IGF-1 mRNA by reverse transcriptase- polymerase chain reaction (RT-PCR), IGF-1 peptide and serum IGF-1 concentration by enzyme-linked immunosorbent assay (ELISA).
RESULTS: During early diabetic stage (week 2), in comparison with normal control group (NC), IGF-1 mRNA (1.17 ± 0.069 vs 0.79 ± 0.048, P < 0.001; 1.17 ± 0.069 vs 0.53 ± 0.023, P < 0.0005, respectively), IGF-1 peptide contents [(196.66 ± 14.9) ng·mg-1vs (128.2 ± 11.25) ng·mg-1, P < 0.0005; (196.66 ± 14.9) ng·mg-1vs (74.43 ± 5.33) ng·mg-1, P < 0.0001, respectively] were reduced in liver tissues of diabetic rats. The IGF-1 gene downregulation varied with glucose control level of the diabetic state, and deteriorated gradually further with duration of diabetes. By month 6, hepatic tissue IGF-1mRNA was 0.71 ± 0.024 vs 1.12 ± 0.056, P < 0.001; 0.47 ± 0.021 vs 1.12 ± 0.056, P < 0.0005, respectively. IGF-1 peptide was (114.35 ± 8.09) ng·mg-1vs (202.05 ± 15.73) ng·mg-1, P < 0.0005; (64.58 ± 3.89) ng·mg-1vs (202.05 ± 15.73) ng·mg-1, P < 0.0001 respectively. Serum IGF-1 was also lowered in diabetic group with poor control of blood glucose. On week 2, serum IGF-1 concentrations were (371.0 ± 12.5) ng·mg-1vs (511.2 ± 24.7) ng·mg-1, P < 0.0005, (223.2 ± 9.39) ng·mg-1vs (511.2 ± 24.7) ng·mg-1, P < 0.0001 respectively. By month 6, (349.6 ± 18.62) ng·mg-1vs (520.7 ± 26.32) ng·mg-1, P < 0.0005, (188.5 ± 17.35 vs 520.7 ± 26.32) ng·mg-1, P < 0.0001, respectively. Serum IGF-1 peptide change was significantly correlated with that in liver tissue (r = 0.99, P < 0.001). Furthermore, No difference was found in the above parameters between diabetic rats with euglycemia and non-diabetic control group.
CONCLUSION: The influence of diabetic status on IGF-1 gene expression in liver tissues is started from early diabetic stage, causing down regulation of IGF-1 expression, and progresses with the severity and duration of diabetic state. Accordingly serum IGF-1 level decreases. This might indicate that liver tissue IGF-1 gene expression is greatly affected in diabetes, thus contributing to reduction of serum IGF-1 level.
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Affiliation(s)
- Jian-Bo Li
- Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
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Schmidt RE, Dorsey DA, Beaudet LN, Peterson RG. Analysis of the Zucker Diabetic Fatty (ZDF) type 2 diabetic rat model suggests a neurotrophic role for insulin/IGF-I in diabetic autonomic neuropathy. THE AMERICAN JOURNAL OF PATHOLOGY 2003; 163:21-8. [PMID: 12819007 PMCID: PMC1868158 DOI: 10.1016/s0002-9440(10)63626-7] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 04/02/2003] [Indexed: 11/18/2022]
Abstract
Dysfunction of the autonomic nervous system is a recognized complication of diabetes. Neuroaxonal dystrophy (NAD), a distinctive axonopathy involving distal axons and synapses, represents the neuropathologic hallmark of diabetic sympathetic autonomic neuropathy in human and several insulinopenic experimental rodent models. Recent studies have suggested that loss of the neurotrophic effects of insulin and/or IGF-I on sympathetic neurons and not hyperglycemia per se, may underlie the development of sympathetic NAD. The streptozotocin (STZ)-diabetic and BB/W rat, the most commonly used experimental rodent models, develop marked hyperglycemia and concomitant deficiency in both circulating insulin and IGF-I. These animals reproducibly develop NAD in nerve terminals in the prevertebral sympathetic ganglia and the distal portions of noradrenergic ileal mesenteric nerves. The Zucker Diabetic Fatty (ZDF) rat, an animal model of type 2 diabetes, also develops severe hyperglycemia comparable to that in the STZ- and BB/W-diabetic rat models, although in the presence of hyperinsulinemia. In our study, ZDF rats maintained for 6 to 7 months in a severely diabetic state, as assessed by plasma glucose and glycated hemoglobin levels, maintained significant hyperinsulinemia and normal levels of plasma IGF-I at sacrifice. NAD did not develop in diabetic ZDF rat sympathetic ganglia and ileal mesenteric nerves as assessed by quantitative ultrastructural techniques, which is in dramatic contrast to neuropathologic findings in comparably hyperglycemic 6-month STZ-diabetic insulinopenic rats. These data combined with our previous results argue very strongly that hyperglycemia is not the critical and sufficient element in the pathogenesis of diabetes-induced NAD, rather that it is the loss of trophic support, most likely of IGF-I or insulin, that causes NAD.
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Affiliation(s)
- Robert E Schmidt
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
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Landau D, Israel E, Rivkis I, Kachko L, Schrijvers BF, Flyvbjerg A, Phillip M, Segev Y. The effect of growth hormone on the development of diabetic kidney disease in rats. Nephrol Dial Transplant 2003; 18:694-702. [PMID: 12637637 DOI: 10.1093/ndt/gfg142] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Nephropathy is the most severe complication of diabetes mellitus. We investigated the effect of exogenous growth hormone (GH) administration on renal function and matrix deposition in the streptozotocin (STZ) model of type I-diabetic rat. METHODS Adult female STZ-diabetic rats (D), non-diabetic control rats injected with saline (C) and control and diabetic rats injected with bovine GH for 3 months (CGH and DGH, respectively) were used. RESULTS The usual renal hypertrophy seen in D animals was more pronounced in the DGH group. Creatinine clearance increased only in the D rats, but not in the other groups, including DGH. Albuminuria was observed in the D animals but was significantly elevated in the DGH group. Glomeruli from DGH animals showed more extensive matrix accumulation (manifested as an increase in mesangial/glomerular area ratio). Renal extractable insulin-like growth factor (IGF-I) mRNA was decreased in the D and DGH groups, but renal IGF-I protein was not significantly increased. Renal IGF binding protein-1 was increased in the D groups and further increased in the DGH group, at both the mRNA and protein levels. CONCLUSIONS GH-treated diabetic rats had less hyperfiltration and more albuminuria, concomitant with more glomerular matrix deposition, when compared with regular diabetic animals. This was associated with a significant increase in renal IGFBP-1, and dissociated from IGF-I changes. Thus, in this model, GH exacerbates the course of diabetic kidney disease.
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Affiliation(s)
- Daniel Landau
- Department of Pediatrics, Soroka University Medical Center, Ben Gurion University of the Negev, Beer Sheva, Israel.
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Landau D, Segev Y, Afargan M, Silbergeld A, Katchko L, Podshyvalov A, Phillip M. A novel somatostatin analogue prevents early renal complications in the nonobese diabetic mouse. Kidney Int 2001; 60:505-12. [PMID: 11473633 DOI: 10.1046/j.1523-1755.2001.060002505.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND PTR-3173 (S) is a novel somatostatin analogue that has been found to exert a prolonged inhibitory action on the growth hormone (GH)-insulin-like growth factor (IGF)-I axis, but not on insulin secretion. We investigated the potential effect of this agent on the development of markers of diabetic nephropathy in the nonobese diabetic (NOD) mouse model of insulin-dependent diabetes. METHODS Female diabetic NOD mice treated with PTR-3173 (DS group) or saline (D) and their control groups of nonhyperglycemic age-matched littermates (C) and C mice treated with PTR-3173 (CS) were sacrificed three weeks after onset of diabetes. RESULTS Serum GH was elevated in the D group, decreased in the DS group, and unchanged in the CS group. Serum IGF-I was significantly decreased in both the D and DS groups. Kidney weight, glomerular volume, albuminuria, and creatinine clearance were increased in the D animals and showed a trend toward normalization in the DS animals. Renal extractable IGF-I protein and IGFBP1 mRNA were increased in the D group and normalized in the DS group. CONCLUSIONS GH antagonism by PTR-3173 has a blunting effect on renal/glomerular hypertrophy, albuminuria, and glomerular filtration rate (GFR) in diabetic NOD mice. This phenomenon is apparently associated with the prevention of renal IGF-I accumulation. Thus, modulation of GH effects may have beneficial therapeutic implications in diabetic nephropathy.
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Affiliation(s)
- D Landau
- Department of Pediatrics, Soroka Medical Center, Ben Gurion University of the Negev, Beer Sheva, Israel.
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