Renal effects of growth hormone in health and in kidney disease

Haffner, Dieter; Grund, Andrea; Leifheit-Nestler, Maren

doi:10.1007/s00467-021-05097-6

Cited by 40 publications

(42 citation statements)

References 240 publications

(287 reference statements)

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“…Elevated GH levels in humans (acromegaly) presented with signi cant structural hitherto functional changes in the renal system. Studies of the GH transgenic mice 31 , GH antagonist transgenic mice 32 , and pharmacological blockade of the GHR 33 revealed a more direct involvement of GH/GHR axis in the pathogenesis of DN [13][14][15][16]34 . An immediate action(s) of GH on the kidney was more evident upon the discovery of GHR and activation of canonical GH signaling cascade in podocytes 17 .…”

Section: Discussionmentioning

confidence: 99%

Growth hormone induces TNF-α in podocytes and contributes to monocyte-to-macrophage differentiation: Implications in Diabetic kidney disease

Pasupulati

Nishad

Mukhi

et al. 2022

Preprint

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Diabetes shortens the life expectancy by more than a decade, and the excess mortality in diabetes is correlated with the incidence of kidney disease. Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. In human biopsies and experimental models of DKD, macrophage accumulation predicts the severity of kidney damage. The mechanism of macrophage accumulation in diabetic glomeruli, however, is unknown. Increased growth hormone (GH) levels in type 1 diabetes and acromegalic patients had deleterious effects on glomerular biology. GH-treated mice had significant podocyte injury, glomerulosclerosis as well as increased macrophages. This study investigated if human podocytes injured by a GH stimulus contributed to macrophage accumulation. Following GH treatment, TNF-α signaling was increased in podocytes, as determined by RNA-seq analysis. Conditioned media from GH-treated human podocytes induced differentiation of THP1 monocytes to macrophages. Depleting the TNF-α in conditioned media with neutralizing antibodies diminished the effect of conditioned media from GH-treated podocytes on monocytes. Conditioned media from GH-treated primary podocytes with depleted TNF-α levels fail to elicit monocyte-to-macrophage differentiation. Mice administered with GH displayed glomerular accumulation of macrophages, podocyte injury, and proteinuria. Renal biopsies from DKD patients demonstrated activated TNF-α signaling, macrophage accumulation, and fibrosis. Together, this study suggests TNF-α secreted by podocytes under the influence of GH could contribute to macrophage accumulation, thus eliciting adverse renal inflammation and impaired function. Our study suggests targeting GH and/or TNF-α signaling could be a therapeutic approach to combat DKD.

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Section: Discussionmentioning

confidence: 99%

Growth hormone induces TNF-α in podocytes and contributes to monocyte-to-macrophage differentiation: Implications in Diabetic kidney disease

Pasupulati

Nishad

Mukhi

et al. 2022

Preprint

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“…Previous studies demonstrated that podocytes express IGF1 and its receptor IGF1R in control human glomeruli and that IGF1 protects podocytes from apoptosis in vitro [ 16 , 21 ] suggesting that an autocrine IGF1/IGF1R signaling may play a role in podocyte survival. Notably, dysregulation of the IGF1 system has been described in several kidney diseases, including diabetic nephropathy, polycystic kidneys and proteinuric kidney diseases [ 22 , 23 ]. According to our data, analysis of the glomerular transcriptomic dataset available on Nephroseq showed that IGF1 was downregulated in focal segmental glomerulosclerosis patients compared to healthy controls ( ; accessed on 24 Sempember 2021).…”

Section: Discussionmentioning

confidence: 99%

Unravelling the Role of PAX2 Mutation in Human Focal Segmental Glomerulosclerosis

et al. 2021

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No effective treatments are available for familial steroid-resistant Focal Segmental Glomerulosclerosis (FSGS), characterized by proteinuria due to ultrastructural abnormalities in glomerular podocytes. Here, we studied a private PAX2 mutation identified in a patient who developed FSGS in adulthood. By generating adult podocytes using patient-specific induced pluripotent stem cells (iPSC), we developed an in vitro model to dissect the role of this mutation in the onset of FSGS. Despite the PAX2 mutation, patient iPSC properly differentiated into podocytes that exhibited a normal structure and function when compared to control podocytes. However, when exposed to an environmental trigger, patient podocytes were less viable and more susceptible to cell injury. Fixing the mutation improved their phenotype and functionality. Using a branching morphogenesis assay, we documented developmental defects in patient-derived ureteric bud-like tubules that were totally rescued by fixing the mutation. These data strongly support the hypothesis that the PAX2 mutation has a dual effect, first in renal organogenesis, which could account for a suboptimal nephron number at birth, and second in adult podocytes, which are more susceptible to cell death caused by environmental triggers. These abnormalities might translate into the development of proteinuria in vivo, with a progressive decline in renal function, leading to FSGS.

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“… Physiological (main figure) and pathophysiological actions of GH (upper left insert) and IGF-1 on the kidneys. The original figure has been published by Hafner et al [ 107 ] and published here with permission. The figure is licensed under a Creative Commons Attribution 4.0 International License.…”

Section: Figurementioning

confidence: 99%

Growth Hormone and IGF1 Actions in Kidney Development and Function

Gurevich

Segev

Landau

2021

Cells

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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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Renal effects of growth hormone in health and in kidney disease

Cited by 40 publications

References 240 publications

Growth hormone induces TNF-α in podocytes and contributes to monocyte-to-macrophage differentiation: Implications in Diabetic kidney disease

Growth hormone induces TNF-α in podocytes and contributes to monocyte-to-macrophage differentiation: Implications in Diabetic kidney disease

Unravelling the Role of PAX2 Mutation in Human Focal Segmental Glomerulosclerosis

Growth Hormone and IGF1 Actions in Kidney Development and Function

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