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

Blutke, Andreas; Schneider, Marlon R.; Wolf, Eckhard; Wanke, Rüdiger

doi:10.14814/phy2.12709

Cited by 29 publications

(38 citation statements)

References 56 publications

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“…GH transgenic mice displayed significant effacement in podocyte foot processes that resulted in impaired glomerular function [6]. In this study, we observed altered podocyte permeability to BSA as evidenced by paracellular influx assay performed with podocyte monolayers treated either with GH CM or TGF-β conditions.…”

Section: Former One Suggests Autocrine and Later Suggest Paracrine Acmentioning

confidence: 52%

“…Podocyte loss leaves GBM denuded and provokes neighboring podocytes to undergo compensatory hypertrophy.However, the molecular signals that initiate the podocyte or glomerular hypertrophy remains unclear.Elevated growth hormone (GH) levels in poorly controlled type 1 diabetes mellitus (DM) is implicated as a causative factor in the development of renal aberrations and proteinuria [2][3][4].GH transgenic animals developed significant renal hypertrophy and glomerulosclerosis [5].Albeit, part of the biological effects of GH are mediated by insulin-like growth factor 1 (IGF-1), the glomerular hypertrophy and significant renal manifestations are evidenced in GH transgenics with IGF-1 null background suggesting that GH, but not IGF-1 responsible for glomerular hypertrophy [6]. In GH transgenic animals, podocytes undergo hypertrophy while mesangial and endothelial cells undergo proliferation [6]. GH administration pronounced the usual renal hypertrophy and it was aggravated in streptozotocin (STZ)-induced diabetic rats [5].Mice with mutant GHR were protected from STZ-induced diabetic renal complications [7].…”

mentioning

confidence: 99%

“…Albeit, part of the biological effects of GH are mediated by insulin-like growth factor 1 (IGF-1), the glomerular hypertrophy and significant renal manifestations are evidenced in GH transgenics with IGF-1 null background suggesting that GH, but not IGF-1 responsible for glomerular hypertrophy [6]. In GH transgenic animals, podocytes undergo hypertrophy while mesangial and endothelial cells undergo proliferation [6]. GH administration pronounced the usual renal hypertrophy and it was aggravated in streptozotocin (STZ)-induced diabetic rats [5].…”

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confidence: 99%

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Growth hormone induces mitotic catastrophe of podocytes and contributes to proteinuria

Nishad

Mukhi

et al. 2019

Preprint

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24Growth hormone (GH) had direct effects on the glomerular podocyte. Increased levels of GH 25 are implicated in the pathogenesis of renal abnormalities in acromegaly and in diabetic 26 nephropathy in Type 1 diabetes mellitus. We investigated the role of Transforming growth 27 factor-β1 (TGF-β1) in GH's effects on the glomerular podocyte. Exposure of podocytes to GH 28 resulted in elevated expression of TGF-β1 and was concurrent with increased phosphorylation 29 of SMAD2/3 and nuclear accumulation of SMAD4. Conditioned media from podocytes exposed 30 to GH also triggered SMAD signaling. Podocytes treated with GH showed increased 31 permeability to albumin. Mice injected with GH demonstrated increased kidney size, glomerular 32 hypertrophy, and proteinuria. The renal manifestations in GH injected mice were associated with 33 increased TGF-β1 expression and activation of TGF-β1 signaling pathways. Concurrent 34 administration of TGF-β receptor antagonist (SB431542) with GH abrogated these renal effects 35 of GH administration. These results reveal the role of TGF-β1 in GH's actions on the glomerular 36 podocyte and provide a novel mechanistic basis for GH-induced glomerular dysfunction in 37 clinical conditions such as diabetes and acromegaly. 38 39 40 41 42 43

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Section: Former One Suggests Autocrine and Later Suggest Paracrine Acmentioning

confidence: 52%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Growth hormone induces mitotic catastrophe of podocytes and contributes to proteinuria

Nishad

Mukhi

et al. 2019

Preprint

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“…Even though the data we present are associative, it does not fully prove causality. However, we think that this study provides another evidence for the repeated clinical observations on the relative safety of chronic GH supplementation for children with CKD [3, 25], in spite of the theoretical concerns arising from the GH-transgenic mouse model [14, 15].…”

Section: Discussionmentioning

confidence: 99%

“…Medrano and Casellas [12] have described also a decreased life span for hg/hg mice, in 2 genetic backgrounds, in association with increased subcutaneous fibrosis and collagen deposition [13]. Since GH overexpression (in GH transgenic mice) causes glomerulosclerosis [14, 15], the goal of this study was to test the effects of SOCS2 silencing on kidney damage and body growth in a mouse model of CKD.…”

Section: Introductionmentioning

confidence: 99%

SOCS2 Silencing Improves Somatic Growth without Worsening Kidney Function in CKD

et al. 2020

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Background: Growth hormone (GH) resistance in CKD is partly due to increased expression of SOCS2, a GH signaling negative regulator. In SOCS2 absence, body growth is exaggerated. However, GH overexpression in mice causes glomerulosclerosis. Accordingly, we tested whether lack of SOCS2 improves body growth, but accelerates kidney damage in CKD. Methods: Eight-week-old mutant SOCS2-deficient high growth (HG) and normal wild-type mice (N) underwent 5/6 nephrectomy (CKD) or sham operation (C) and were sacrificed after 12 weeks, generating 4 groups: C-N, C-HG, CKD-N, CKD-HG. Results: Somatic growth, inhibited in CKD-N, increased significantly in CKD-HG. Liver p-STAT5, a key intracellular signal of GH receptor (GHR) activation, was decreased in CKD-N but not in CKD-HG. Serum Cr as well as histopathological scores of renal fibrosis were similar in both CKD groups. Kidney fibrogenic (TGF-β and collagen type IV mRNA) and inflammatory precursors (IL6, STAT3, and SOCS3 mRNA) were similarly increased in C-HG, CKD-HG, and CKD-N versus C-N. Renal GHR mRNA was decreased in C-HG, CKD-HG, and CKD-N versus C-N. Kidney p-STAT5 was decreased in CKD-N but not elevated in CKD-HG. Conclusions: CKD-related growth retardation is overcome by SOCS2 silencing, in association with increased hepatic STAT5 phosphorylation. Renal insufficiency is not worsened by SOCS2 absence, as kidney GHR and STAT5 are not upregulated. This may be due to elevated kidney proinflammatory cytokines and their mediators, phospho-STAT3 and SOCS3, which may counteract for the absence in SOCS2 and explain the renal safety of prolonged GH therapy in CKD.

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Three‐dimensional morphometry of kidney in New Zealand rabbit using unbiased design‐based stereology

Sadeghinezhad,

Lazzarini,

Bojarzadeh

et al. 2024

Microscopy Res & Technique

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The rabbit is widely used as a laboratory animal in experimental models of kidney diseases. This species is also important from a veterinary perspective as a companion animal. Stereology has been accepted as an accurate approach to kidney morphometry. The objective of the present project was to provide normal quantitative stereological parameters for adult rabbit kidneys. The left kidneys of five adult male New Zealand rabbits were used. Isotropic sections were obtained using the orientation method. Total kidney volume was calculated by the Cavalieri principle. The volume fraction of the renal structures was estimated using the point counting system. The lengths of the proximal convoluted tubule (PCT) and distal convoluted tubule (DCT) were calculated using counting frames. The total glomerular number was accounted for using the physical/fractionator technique. The mean glomerular volume was obtained by dividing the total volume of glomeruli by their total number. The total volume of rabbit kidneys calculated was 10.39 ± 1.98 cm3. The fractional volume of the kidney cortex and medulla accounted for 57.79 ± 0.65% and 42.2 ± 0.65%, respectively. The total glomerular volume was 2.18 ± 0.32% of the whole kidney. The total number of glomeruli in the rabbit kidney was estimated as 204.68 ± 12 × 103. The mean glomerular volume measured 1.07 ± 0.12 × 106 μm3. The total length of PCT and DCT was 2.96 ± 0.29 km and 1.38 ± 0.24 km, respectively. These findings can be used as a reference in experimental nephrology research and may help to expand the knowledge of nephrology in mammals by comparing with available data on humans and other species.Research Highlights Three‐dimensional morphometry of adult rabbit kidney structures was analyzed using quantitative stereology. Total volume of kidney, fractional volume of cortex and medulla, length of renal tubules and number of nephrons were estimated. These three‐dimensional morphometrical data can be used as a reference in experimental nephrology research and may help to expand the knowledge of nephrology in mammals.

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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

Cited by 29 publications

References 56 publications

Growth hormone induces mitotic catastrophe of podocytes and contributes to proteinuria

Growth hormone induces mitotic catastrophe of podocytes and contributes to proteinuria

SOCS2 Silencing Improves Somatic Growth without Worsening Kidney Function in CKD

Three‐dimensional morphometry of kidney in New Zealand rabbit using unbiased design‐based stereology

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