Liver-derived IGF-I regulates kidney size, sodium reabsorption, and renal IGF-II expression

Svensson, Johan; Tivesten, Åsa; Sjögren, Klara; Isaksson, Olle; Bergström, Göran; Mohan, Subburaman; Mölne, Johan; Isgaard, Jörgen; Ohlsson, Claes

doi:10.1677/joe-07-0024

Cited by 18 publications

(13 citation statements)

References 37 publications

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“…Our studies suggest that hepatic-derived circulating IGF-I signaling is essential for normal kidney growth and normal bone density, which cannot be compensated by elevated GH alone, consistent with findings in the Laron mouse and human (19,25,26). Recently, it has been proposed that the combined effects of the GH-IGF-I system serve to augment the anabolic actions of GH, while concurrently counteracting its potential harmful effects in inducing insulin resistance and diabetes mellitus and limiting its lipolytic effects to prevent depletion of lipid stores (5).…”

Section: Discussionsupporting

confidence: 85%

“…A major difference between this model and ours, however, is that the availability of ALS at the bone environment may contribute to IGF activity in our model because the als gene itself was not disrupted. The kidneys of the GHRLD animals were significantly lighter than controls, documenting that unlike bone growth, hepaticderived IGF-I has an important role in kidney growth, as suggested previously (25,26).…”

Section: Discussionsupporting

confidence: 67%

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Liver-specific Deletion of the Growth Hormone Receptor Reveals Essential Role of Growth Hormone Signaling in Hepatic Lipid Metabolism

Fan

Menon

Cohen

et al. 2009

Journal of Biological Chemistry

239

209

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Growth hormone (GH) plays a pivotal role in growth and metabolism, with growth promotion mostly attributed to generation of insulin-like growth factor I (IGF-I) in liver or at local sites of GH action, whereas the metabolic effects of GH are considered to be intrinsic to GH itself. To distinguish the effects of GH from those of IGF-I, we developed a Cre-lox-mediated model of tissue-specific deletion of the growth hormone receptor (GHR). Near total deletion of the GHR in liver (GHRLD) had no effect on total body or bone linear growth despite a >90% suppression of circulating IGF-I; however, total bone density was significantly reduced. Circulating GH was increased 4-fold, and GHRLD displayed insulin resistance, glucose intolerance, and increased circulating free fatty acids. Livers displayed marked steatosis, the result of increased triglyceride synthesis and decreased efflux; reconstitution of hepatic GHR signaling via adenoviral expression of GHR restored triglyceride output to normal, whereas IGF-I infusion did not correct steatosis despite restoration of circulating GH to normal. Thus, with near total absence of circulating IGF-I, GH action at the growth plate, directly and via locally generated IGF-I, can regulate bone growth, but at the expense of diabetogenic, lipolytic, and hepatosteatotic consequences. Our results indicate that IGF-I is essential for bone mineral density, whereas hepatic GH signaling is essential to regulate intrahepatic lipid metabolism. We propose that circulating IGF-I serves to amplify the growth-promoting effects of GH, while simultaneously dampening the catabolic effects of GH.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 67%

Liver-specific Deletion of the Growth Hormone Receptor Reveals Essential Role of Growth Hormone Signaling in Hepatic Lipid Metabolism

Fan

Menon

Cohen

et al. 2009

Journal of Biological Chemistry

239

209

View full text Add to dashboard Cite

show abstract

“…26 Conversely, mice with liver-specific deletion of IGF1 have approximately 80% reduction in the circulating IGF1 and increased renal K ϩ excretion despite a normal filtered load of K ϩ . 27 Finally, inhibition of PI3K increases the density of native ROMK channels in mouse CCD, 28 providing further support for the physiologic role of PI3K in the inhibition of ROMK and renal K ϩ secretion. Insulin also activates PI3K and thus may be another upstream signal that uses the Akt1/SGK1-WNK1 pathway to inhibit renal K ϩ excretion.…”

Section: Discussionmentioning

confidence: 91%

Activation of PI3-Kinase Stimulates Endocytosis of ROMK via Akt1/SGK1-Dependent Phosphorylation of WNK1

Cheng

Huang

2011

Journal of the American Society of Nephrology

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WNK kinases stimulate endocytosis of ROMK channels to regulate renal Kϩ handling. Phosphatidylinositol 3-kinase (PI3K)-activating hormones, such as insulin and IGF 1, phosphorylate WNK1, but how this affects the regulation of ROMK abundance is unknown. Here, serum starvation of ROMK-transfected HEK cells led to an increase of ROMK current density; subsequent addition of insulin or IGF1 inhibited ROMK currents in a PI3K-dependent manner. Serum and insulin also increased phosphorylation of the downstream kinases Akt1 and SGK1 as well as WNK1. A biotinylation assay suggested that insulin and IGF1 inhibit ROMK by enhancing its endocytosis, a process that WNK1 may mediate. Knockdown of WNK1 with siRNA or expression of a phospho-deficient WNK1 mutant (T58A) both prevented insulininduced inhibition of ROMK currents, suggesting that phosphorylation at Threonine-58 of WNK1 is important to mediate the inhibition of ROMK by PI3K-activating hormones or growth factors. In vitro and in vivo kinase assays supported the notion that Akt1 and SGK1 can phosphorylate WNK1 at this site, and we established that Akt1 and SGK1 synergistically inhibit ROMK through WNK1. We used dominantnegative intersectin and dynamin constructs to show that SGK1-mediated phosphorylation of WNK1 inhibits ROMK by promoting its endocytosis. Taken together, these results suggest that PI3K-activating hormones inhibit ROMK by enhancing its endocytosis via a mechanism that involves phosphorylation of WNK1 by Akt1 and SGK1.

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“…For this reason, the combination of IGF2 and BMP9 may be high risk in clinical applications. In contrast, IGF1 has shown a different phenotype, being constantly secreted in response to growth hormones in the liver, and released systemically after birth (25 , 26) . IGF1 functions as a major growth factor in adults and is well-known to have anabolic effects on a wide variety of tissues including muscle, cartilage, and bone (22 , 27 - 29) .…”

Section: Discussionmentioning

confidence: 99%

IGF1 potentiates BMP9-induced osteogenic differentiation in mesenchymal stem cells through the enhancement of BMP/Smad signaling

et al. 2016

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Engineered bone tissue is thought to be the ideal alternative for bone grafts in the treatment of related bone diseases. BMP9 has been demonstrated as one of the most osteogenic factors, and enhancement of BMP9-induced osteogenesis will greatly accelerate the development of bone tissue engineering. Here, we investigated the effect of insulin-like growth factor 1 (IGF1) on BMP9-induced osteogenic differentiation, and unveiled a possible molecular mechanism underling this process. We found that IGF1 and BMP9 are both detectable in mesenchymal stem cells (MSCs). Exogenous expression of IGF1 potentiates BMP9-induced alkaline phosphatase (ALP), matrix mineralization, and ectopic bone formation. Similarly, IGF1 enhances BMP9-induced endochondral ossification. Mechanistically, we found that IGF1 increases BMP9-induced activation of BMP/Smad signaling in MSCs. Our findings demonstrate that IGF1 can enhance BMP9-induced osteogenic differentiation in MSCs, and that this effect may be mediated by the enhancement of the BMP/Smad signaling transduction triggered by BMP9. [BMB Reports 2016; 49(2): 122-127]

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Liver-derived IGF-I regulates kidney size, sodium reabsorption, and renal IGF-II expression

Abstract: The GH/-IGF-I axis is important for kidney size and function and may also be involved in the development of renal failure. In this study, the role of liver-derived endocrine IGF-I for kidney size and function was investigated in mice with adult liver-specific IGF-I inactivation (LI-IGF-I

Cited by 18 publications

References 37 publications

Liver-specific Deletion of the Growth Hormone Receptor Reveals Essential Role of Growth Hormone Signaling in Hepatic Lipid Metabolism

Liver-specific Deletion of the Growth Hormone Receptor Reveals Essential Role of Growth Hormone Signaling in Hepatic Lipid Metabolism

Activation of PI3-Kinase Stimulates Endocytosis of ROMK via Akt1/SGK1-Dependent Phosphorylation of WNK1

IGF1 potentiates BMP9-induced osteogenic differentiation in mesenchymal stem cells through the enhancement of BMP/Smad signaling

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