Impaired phosphorylation of JAK2-STAT5b signaling in fibroblasts from uremic children

Ugarte, Francisca; Irarrázabal, Carlos E.; Oh, Jun; Dettmar, Anne; Ceballos, María L; Rojo, Angélica; Ibacache, Maria Jose; Suazo, Cristián; Lozano, Mauricio; Delgado, Iris; Cavada, Gabriel; Azócar, Marta; Delucchi, Angela; Cano, Francisco

doi:10.1007/s00467-015-3289-x

Cited by 7 publications

(3 citation statements)

References 38 publications

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“…Our research group published an in vitro study of intracellular GH axis in children with CKD. The results showed a significant decreased JAK-2 phosphorylation and a decreased STAT-5b translocation to the nucleus, resulting in a decreased expression of target proteins such as IGFBP3 42 . These defects are consistent with Schaefer et al findings in experimental models in uremic rats, observing a decreased phosphorylation of JAK-2 and STAT-5; decreased translocation of phosphorylated STAT proteins to the nucleus and increased SOCS inhibitory proteins compared to healthy rats 43 .…”

Section: Discussionmentioning

confidence: 95%

Eje somatotrópico y marcadores moleculares del metabolismo mineral en niños en diálisis peritoneal crónica

Osorio

Schuffeneger

2016

Revista Chilena de Pediatría

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Eje somatotrópico y marcadores moleculares del metabolismo mineral en niños en diálisis María Luisa Ceballos Osorio, Francisco Cano Schuffeneger AbstractGrowth failure is one of the most relevant complications in children with chronic kidney disease (CKD). Among others, growth hormone (GH) resistance and bone mineral disorders have been identified as the most important causes of growth retardation. Objectives: 1. To characterize bone mineral metabolism and growth hormone bio-markers in CKD children treated with chronic peritoneal dialysis (PD). 2. To evaluate height change with rhGH treatment. Patients and Method: A longitudinal 12-month follow-up in prepuberal PD children. Exclusion criteria: Tanner stage > 1, nephrotic syndrome, genetic disorders, steroids, intestinal absorption disorders, endocrine disturbances, treatment with GH to the entry of the study. Demographic and anthropometric data were registered. FGF23, Klotho, VitD, IGF-1, IGFBP3, and GHBP were measured to evaluate mineral and growth metabolism. Results: 15 patients, 7 male, age 6.9 ± 3.0 y were included. Time on PD was 14.33 ± 12.26 months. Height/age Z score at month 1 was -1.69 ± 1.03. FGF23 and Klotho: 131.7 ± 279.4 y 125.9 ± 24.2 pg/ml, respectively. 8 patients were treated with GH during 6-12 months, showing a non-significant increase in height/age Z-score during the treatment period. Bivariate analysis showed a positive correlation between Klotho and delta ZT/E, and between GHBP vs growth velocity index (p < .05). Conclusions: FGF23 values were high and Klotho values were reduced in children with CKD in PD, comparing to healthy children. Somatotropic axis variables were normal or elevated. rhGH tends to improve height and there is a positive correlation of GHBP and growth velocity in these children.

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Section: Discussionmentioning

confidence: 95%

Eje somatotrópico y marcadores moleculares del metabolismo mineral en niños en diálisis peritoneal crónica

Osorio

Schuffeneger

2016

Revista Chilena de Pediatría

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“…Western blot was realized as was previously published with some modifications [27][28][29]. Briefly, the renal cortex and medulla were dissected and homogenized with an Ultra-Turrax homogenizer in ice-cooled 10 mM Tris•HCl buffer at pH 7.4, supplemented with 1 mM EDTA, 1 mM EGTA, 0.25 M sucrose, 1% vol/vol Triton X-100, and a protease inhibitor cocktail (Complete Mini, Roche Applied Science).…”

Section: Western Blot Assaymentioning

confidence: 99%

The Ischemia and Reperfusion Injury Involves the Toll-Like Receptor-4 Participation Mainly in the Kidney Cortex

2022

Cell Physiol Biochem

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BACKGROUND/AIMS: The renal inflammatory response and kidney regeneration in ischemia-reperfusion injury (IRI) are associated with Toll-like receptor 4 (TLR4). Here we study the role of TLR4 during IRI in the renal cortex and medulla separately, using wild-type (TLR4-WT) and Knockout (TLR4-KO) TLR4 mice. METHODS: We used 30 minutes of bilateral renal ischemia, followed by 48 hours of reperfusion in C57BL/6 mice. We measured the expression of elements associated with kidney injury, inflammation, macrophage polarization, mesenchymal transition, and proteostasis in the renal cortex and medulla by qRT-PCR and Western blot. In addition, we studied kidney morphology by H/E and PAS. RESULTS: Renal ischemia (30min) and reperfusion (48hrs) induced the mRNA and protein of TLR4 in the renal cortex. In addition, Serum Creatinine (SCr), blood urea nitrogen (BUN), Neutrophil gelatinase-associated lipocalin (NGAL), and acute tubular necrosis (ATN) were increased in TLR4-WT by IRI. Interestingly, the SCr and BUN had normal levels in TLR-KO during IRI. However, ATN and high levels of NGAL were present in the kidneys of TLR4-KO mice. The pro-inflammatory (IL-6 and TNF-α) and anti-inflammatory (Foxp3 and IL-10) markers increased by IRI only in the cortex of TLR4-WT but not in TLR4-KO mice. Furthermore, the M1 (CD38 and Frp2) and M2 (Arg-I, Erg-2, and c-Myc) macrophage markers increased by IRI only in the cortex of TLR4-WT. The TLR4-KO blunted the IRI-upregulation of M1 but not the M2 macrophage polarization. Vimentin increased in the renal cortex and medulla of TLR4-WT animals but not in the cortex of TLR4-KO mice. In addition, iNOS and clusterin were increased by IRI only in the cortex of TLR4-WT, and the absence of TLR4 inhibited only clusterin upregulation. Finally, Hsp27 and Hsp70 protein levels increased by IRI in the cortex and medulla of TLR4-WT and TRL4-KO lost the IRI-upregulation of Hsp70. In summary, TLR4 participates in renal ischemia and reperfusion through pro-inflammatory and anti-inflammatory responses inducing impaired kidney function (SCr and BUN). However, the IRI-upregulation of M2 macrophage markers (cortex), iNOS (cortex), IL-6 (medulla), vimentin (medulla), and Hsp27 (cortex and medulla) were independent of TLR4. CONCLUSION: The TLR4 inactivation during IRI prevented the loss of renal function due to the inactivation of inflammation response, avoiding M1 and preserving the M2 macrophage polarization in the renal cortex.

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“…Nevertheless, the potential genetic target is not achieved in most cases [20,21]. The defects in impaired phosphorylation of JAK2/STAT signaling and IGFBP concentrations after rhGH administration seem to persist, resulting in lower IGF-1 bioavailability than normally expected, even if sound clinical evidence is as yet missing [22]. A meta-analysis including 16 randomized controlled clinical trials suggested a dose of 28 IU/m 2 (0.35 mg/kg) per week as optimal [23], and this is the recommended and approved dose for treatment of growth failure in CKD [2,[24][25][26].…”

mentioning

confidence: 99%

Growth hormone axis in patients with chronic kidney disease

et al. 2018

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Impaired phosphorylation of JAK2-STAT5b signaling in fibroblasts from uremic children

Cited by 7 publications

References 38 publications

Eje somatotrópico y marcadores moleculares del metabolismo mineral en niños en diálisis peritoneal crónica

Eje somatotrópico y marcadores moleculares del metabolismo mineral en niños en diálisis peritoneal crónica

The Ischemia and Reperfusion Injury Involves the Toll-Like Receptor-4 Participation Mainly in the Kidney Cortex

Growth hormone axis in patients with chronic kidney disease

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