Systemic overexpression of growth hormone (GH) in transgenic FVB/N inbred mice: an optimized model for holistic studies of molecular mechanisms underlying GH-induced kidney pathology

Waldthausen, Dagmar C. von; Schneider, Marlon R.; Renner‐Müller, Ingrid; Rauleder, Dirk N.; Herbach, Nadja; Aigner, Bernhard; Wanke, Rüdiger; Wolf, Eckhard

doi:10.1007/s11248-007-9163-2

Cited by 6 publications

(4 citation statements)

References 43 publications

(41 reference statements)

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“…In contrast, short‐living animals that exhibit very high levels of circulating GH lived 50% longer (from 12 to 18 months) when fed 80% less MET throughout their life . These GH transgenic mice exhibit significant disease burden including a high incidence of hepatic and mammary cancers and succumb to glomerulosclerosis and glomerulonephritis . We observed significant reductions in tumor incidence and enlarged bladders, two findings identified by necropsy, in the accelerated aging GH Tg mice consuming 0.16% MET from 8 weeks of age to death .…”

Section: Discussionmentioning

confidence: 68%

“…These high levels of polyamines reflect known stimulatory effects of GH on ornithine decarboxylase activity and represent systemic indicators of malignancy, especially hepatic . Overall, MTA is a key player in the balance between cell death and survival in hepatocytes and the high levels in GH Tg mice may contribute to the increased incidence of neoplastic disease observed and ultimately, shortened life spans …”

Section: Discussionmentioning

confidence: 99%

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Metabolic adaptation of short‐living growth hormone transgenic mice to methionine restriction and supplementation

Brown‐Borg

Rakoczy

Wonderlich

et al. 2018

Annals of the New York Academy of Sciences

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Extension of mammalian health and life span has been achieved using various dietary interventions. We previously reported that restricting dietary methionine (MET) content extends life span only when growth hormone signaling is intact (no life span increase in GH deficiency or GH resistance). To understand the metabolic responses of altered dietary MET in the context of accelerated aging (high GH), the current study evaluated MET and related pathways in short-living GH transgenic (GH Tg) and wild-type mice following 8 weeks of restricted (0.16%), low (0.43%), or enriched (1.3%) MET consumption. Liver MET metabolic enzymes were suppressed in GH Tg compared to diet-matched wild-type mice. MET metabolite levels were differentially affected by GH status and diet. SAM:SAH ratios were markedly higher in GH Tg mice. Glutathione levels were lower in both genotypes consuming 0.16% MET but reduced in GH Tg mice when compared to wild type. Tissue thioredoxin and glutaredoxin were impacted by diet and GH status. The responsiveness to the different MET diets is reflected across many metabolic pathways indicating the importance of GH signaling in the ability to discriminate dietary amino acid levels and alter metabolism and life span.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Metabolic adaptation of short‐living growth hormone transgenic mice to methionine restriction and supplementation

Brown‐Borg

Rakoczy

Wonderlich

et al. 2018

Annals of the New York Academy of Sciences

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“…A lifetime of excess plasma GH leads to significant disease burden and premature death (von Waldthausen et al ., 2008). Dietary MET levels significantly impacted the presence of tumors as well as enlarged bladders in GH transgenic mice.…”

Section: Discussionmentioning

confidence: 99%

Growth hormone signaling is necessary for lifespan extension by dietary methionine

et al. 2014

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Summary Growth hormone significantly impacts lifespan in mammals. Mouse longevity is extended when growth hormone (GH) signaling is interrupted but markedly shortened with high plasma hormone levels. Methionine metabolism is enhanced in growth hormone deficiency, e.g. Ames dwarf, but suppressed in GH transgenic mice. Methionine intake affects also lifespan, thus, GH mutant mice and respective wild type littermates were fed 0.16%, 0.43% or 1.3% methionine to evaluate the interaction between hormone status and methionine. All wild type and GH transgenic mice lived longer when fed 0.16% methionine but not when fed higher levels. In contrast, animals without growth hormone signaling due to hormone deficiency or resistance, did not respond to altered levels of methionine in terms of lifespan, body weight or food consumption. Taken together, our results suggest that the presence of growth hormone is necessary to sense dietary methionine changes thus, strongly linking growth and lifespan to amino acid availability.

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“…; von Waldthausen et al. ). GH‐transgenic mice exhibit permanently elevated systemic concentrations of GH and IGF1.…”

Section: Introductionmentioning

confidence: 98%

Growth hormone (GH)-transgenic insulin-like growth factor 1 (IGF1)-deficient mice allow dissociation of excess GH and IGF1 effects on glomerular and tubular growth

Blutke¹,

Schneider

Wolf

et al. 2016

Physiol Rep

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Growth hormone (GH)‐transgenic mice with permanently elevated systemic levels of GH and insulin‐like growth factor 1 (IGF1) reproducibly develop renal and glomerular hypertrophy and subsequent progressive glomerulosclerosis, finally leading to terminal renal failure. To dissociate IGF1‐dependent and ‐independent effects of GH excess on renal growth and lesion development in vivo, the kidneys of 75 days old IGF1‐deficient (I −/−) and of IGF1‐deficient GH‐transgenic mice (I −/− /G), as well as of GH‐transgenic (G) and nontransgenic wild‐type control mice (I +/+) were examined by quantitative stereological and functional analyses. Both G and I −/− /G mice developed glomerular hypertrophy, hyperplasia of glomerular mesangial and endothelial cells, podocyte hypertrophy and foot process effacement, albuminuria, and glomerulosclerosis. However, I −/− /G mice exhibited less severe glomerular alterations, as compared to G mice. Compared to I +/+ mice, G mice exhibited renal hypertrophy with a significant increase in the number without a change in the size of proximal tubular epithelial (PTE) cells. In contrast, I −/− /G mice did not display significant PTE cell hyperplasia, as compared to I −/− mice. These findings indicate that GH excess stimulates glomerular growth and induces lesions progressing to glomerulosclerosis in the absence of IGF1. In contrast, IGF1 represents an important mediator of GH‐dependent proximal tubular growth in GH‐transgenic mice.

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Systemic overexpression of growth hormone (GH) in transgenic FVB/N inbred mice: an optimized model for holistic studies of molecular mechanisms underlying GH-induced kidney pathology

Cited by 6 publications

References 43 publications

Metabolic adaptation of short‐living growth hormone transgenic mice to methionine restriction and supplementation

Metabolic adaptation of short‐living growth hormone transgenic mice to methionine restriction and supplementation

Growth hormone signaling is necessary for lifespan extension by dietary methionine

Growth hormone (GH)-transgenic insulin-like growth factor 1 (IGF1)-deficient mice allow dissociation of excess GH and IGF1 effects on glomerular and tubular growth

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