Impaired JAK-STAT signal transduction contributes to growth hormone resistance in chronic uremia

Schaefer, Franz; Chen, Yu; Tsao, Tanny; Nouri, Pouneh; Rabkin, Ralph

doi:10.1172/jci200111895

Cited by 50 publications

(48 citation statements)

References 47 publications

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“…An important recently described cause of GH resistance in uremia is a defect in the GHR-JAK2-STAT signal transduction pathway [48,49]. In CRF rats, resistance to GH was evident from the diminished response to treatment with supramaximal doses of recombinant GH with respect to body growth, and both hepatic and skeletal muscle IGF-I gene expression, compared with control animals ingesting the same quantity of food [48,49]. This attenuated response could not be attributed to a defect at the level of the GHR, as GHR binding, GHR protein levels, and the distribution of the receptor between the cytoplasmic and plasma membrane compartments were unaltered in liver, as were the GHR protein levels in skeletal and cardiac muscle.…”

Section: Gh-igf-i Insensitivity and Growth Failure In Ckdmentioning

confidence: 99%

“…Serum IGFBP-1, -2, -4, and -6 levels are elevated, as are immunoreactive IGFBP-3 levels, although the latter is largely the result of the accumulation of immunoreactive fragments with reduced IGF-I affinity; intact IGFBP-3 levels are not elevated [52][53][54][55]. The bioavailability of IGF-I in CKD is compromised because of increased levels of IGFBP-1, -2, -4, and -6 [48][49][50]. Furthermore, as a result of an increased proteolysis of IGFBP-3, less IGF-I circulates as the 150-kDa ternary complex.…”

Section: Gh-igf-i Insensitivity and Growth Failure In Ckdmentioning

confidence: 99%

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The growth hormone–insulin-like growth factor-I axis in chronic kidney disease

Mak

Cheung

Roberts

2008

Growth Hormone & IGF Research

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Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are important physiologic regulators of growth, body composition, and kidney function. Perturbations in the GH-IGF-I axis are responsible for many important complications seen in chronic kidney disease (CKD), such as growth retardation and cachectic wasting, as well as disease progression. Recent evidence suggests that CKD is characterized by abnormalities in GH and IGF-I signal transduction and the interaction of these pathways with those that involve other molecules such as ghrelin, myostatin, and the suppressor of cytokine signaling (SOCS) family. Further understanding of GH/IGF pathophysiology in CKD may lead to the development of therapeutic strategies for these devastating complications, which are associated with high rates of mortality and morbidity.

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Section: Gh-igf-i Insensitivity and Growth Failure In Ckdmentioning

confidence: 99%

Section: Gh-igf-i Insensitivity and Growth Failure In Ckdmentioning

confidence: 99%

The growth hormone–insulin-like growth factor-I axis in chronic kidney disease

Mak

Cheung

Roberts

2008

Growth Hormone & IGF Research

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“…The rationale for this hypothesis was that intact JAK2-STAT5-mediated signaling is regarded as a prerequisite for GH-mediated body growth, because mice that lack the genes for STAT5a and 5b are growth retarded (20), as are humans with a STAT5b mutation (21). In rats with chronic renal failure, a condition of acquired growth failure associated with GH resistance, we recently demonstrated that hepatic GH-dependent JAK-STAT signaling is impaired (22). In this condition, phosphorylation of JAK2 and STAT5, STAT3, and STAT1 is depressed as is nuclear translocation of the phosphorylated STAT.…”

Section: Discussionmentioning

confidence: 99%

Growth Hormone–Mediated Janus Associated Kinase–Signal Transducers and Activators of Transcription Signaling in the Growth Hormone–Resistant Potassium-Deficient Rat

Schaefer¹,

Yoon

Nouri

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Potassium deficiency (KD) is associated with severe growth failure, in part caused by growth hormone (GH) resistance. This study set out to determine whether the resistance could be caused by a defect in GH-mediated janus associated kinasesignal transducers and activators of transcription (STAT) signaling as occurs in uremia. To this end, rats were fed a K-deficient diet for 8 d and pair-fed controls received a K-replete diet. Animals from each group received GH or vehicle, and during this period, KD rats were GH resistant; GH induced body and liver weight gain and linear body growth were severely attenuated in these rats. In addition, signal transduction was studied in the liver of rats that were killed 10 or 15 min after an intravenous GH bolus or vehicle. When the rats were killed, GH receptor mRNA and protein levels were similar in the two groups. The abundance of STAT5, STAT3, and STAT1, proteins that mediate GH signaling, was significantly increased by 40 to 130% in KD. Furthermore, GH induced a far greater increase in STAT5 and STAT3 phosphorylation in this group. STAT5 phosphorylation was enhanced fourfold even when normalized for total STAT5 content. Phosphorylated STAT5 and STAT3 proteins were also increased in nuclear extracts, suggesting normal nuclear translocation of the activated signaling proteins. DNA binding of nuclear STAT5 was unaltered. Thus, in KD, there is resistance to the growth-promoting action of GH despite hyperactivation of the janus associated kinase-STAT signaling pathway. This suggests the presence of a defect distal to the nuclear binding of STAT or, alternatively, a defect in a STAT-independent GH-activated signaling pathway.

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“…CRF was created by a two-step five-sixths nephrectomy procedure with ketamine (80 mg/kg) and xylazine (10 mg/kg) anesthesia as described previously. 25 Sham nephrectomy operations were performed on other animals. Free access to food and water was allowed.…”

Section: Experimental Animals and Protocolsmentioning

confidence: 99%

“…In animals, we established that GH resistance arises, in part, because of a defect in GH-mediated JAK-STAT5 signaling. 23,25,26 This pathway is used by GH to increase production of IGF-1 that in turn mediates most but not all of GH's actions. 27,28 It is thus difficult to separate the actions of these two hormones on cardiac structure and function, although it seems that the hemodynamic response to GH is largely mediated through IGF1.…”

mentioning

confidence: 99%

Low-Dose Growth Hormone is Cardioprotective in Uremia

Rabkin

Awwad

Chen

et al. 2008

Journal of the American Society of Nephrology

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Growth hormone (GH) is required to maintain normal cardiac structure and function and has a positive effect on cardiac remodeling in experimental and possibly human disease. Cardiac resistance to GH develops in the uremic state, perhaps predisposing to the characteristic cardiomyopathy associated with uremia. It was hypothesized that administration of low-dosage GH may have a salutary effect on the cardiac remodeling process in uremia, but because high levels of GH have adverse cardiac effects, administration of high-dosage GH may worsen uremic cardiomyopathy. In rats with chronic renal failure, quantitative cardiac morphology revealed a decrease in total capillary length and capillary length density and an increase in mean intercapillary distance and fibroblast volume density evident. Low-dosage GH prevented these changes. Collagen and TGF-␤ immunostaining, increased in chronic renal failure, were also reduced by GH, suggesting a mechanism for its salutary action. Low-dosage GH also prevented thickening of the carotid artery but did not affect aortic pathology. In contrast, high-dosage GH worsened several of these variables. These results suggest that low-dosage GH may benefit the heart and possibly the carotid arteries in chronic renal failure.

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Impaired JAK-STAT signal transduction contributes to growth hormone resistance in chronic uremia

Cited by 50 publications

References 47 publications

The growth hormone–insulin-like growth factor-I axis in chronic kidney disease

The growth hormone–insulin-like growth factor-I axis in chronic kidney disease

Growth Hormone–Mediated Janus Associated Kinase–Signal Transducers and Activators of Transcription Signaling in the Growth Hormone–Resistant Potassium-Deficient Rat

Low-Dose Growth Hormone is Cardioprotective in Uremia

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