Impaired renal growth hormone JAK/STAT5 signaling in chronic kidney disease.
BACKGROUND
Treatment with recombinant human growth hormone (GH) is the standard therapy for short stature in children with chronic kidney disease (CKD). However, concerns have been raised on the potential renal fibrogenic effects of GH. There is no information regarding the renal GH receptor (GHR)-JAK-STAT signaling pathway in CKD.


METHODS
Subtotal nephrectomized (CKD) and pair-fed sham-operated control (C) juvenile rats were treated with subcutaneous GH or saline for 2 weeks. A single intravenous GH bolus or vehicle was provided prior to euthanasia.


RESULTS
Reduced body weight in CKD was improved with GH therapy. The remnant kidney showed glomerular hypertrophy and early interstitial fibrosis without inflammatory infiltration. Treatment of CKD rats with GH did not worsen renal function or fibrosis. Kidney GHR mRNA and protein levels were reduced and basal phosphorylation of JAK2 and STAT5 was significantly impaired. However, intravenous GH administration prior to sacrifice normalized STAT5 phosphorylation. Basal renal IL6 mRNA and phosphorylation of its downstream signaling molecule STAT3 were increased as was the product of its action, the suppressor of cytokine signaling 3 (SOCS3) mRNA.


CONCLUSIONS
Despite known unaltered circulating GH levels, remnant kidneys of uremic growth retarded juvenile rats show impaired basal signaling along the GH-activated JAK2/STAT5 signaling pathway. This may well be a consequence of the reduced GHR level and the inhibitory effect of the increase in IL-6-mediated SOCS3 expression. This renal GH insensitivity, if present in humans, may protect against the potential adverse renal effects of GH administration in CKD patients.
Shraga Segal Department of Microbiology and Immunology, Ben Gurion University of the Negev, Beer Sheva, Israel.
Debbie
D
Wiezel
Mohammed Hani
MH
Assadi
Daniel
D
Landau
Ariel
A
Troib
Leonid
L
Kachko
Ralph
R
Rabkin
Yael
Y
Segev
D000293:Adolescent; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D019382:Human Growth Hormone / Q000008:administration & dosage*; D006801:Humans; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D015850:Interleukin-6 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000096:biosynthesis / Q000235:genetics*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects
D015850:Interleukin-6; D012333:RNA, Messenger; D011994:Recombinant Proteins; D050799:STAT5 Transcription Factor; D019382:Human Growth Hormone; D053614:Janus Kinase 2
IL-6; SOCS3; STAT5; chronic kidney disease; growth hormone