Identification of the glomerular podocyte as a target for growth hormone action.
GH excess in both the human and transgenic animal models is characterized by significant changes in blood pressure and renal function. The GH/GH receptor (GHR) axis is also implicated in the development of diabetic nephropathy. However, it is not clear whether GH's actions on renal function are due to indirect actions mediated via changes in blood pressure and vascular tone or due to direct action of GH on the kidney. We hypothesized that functional GHRs are expressed on the glomerular podocyte enabling direct actions of GH on glomerular function. Real-time PCR, immunohistochemistry, and Western blot analysis of murine podocyte cells (MPC-5) and kidney glomeruli demonstrated expression of GHR mRNA and protein. Exposure of both murine and human podocytes to GH (50-500 ng/ml) resulted in an increase in abundance of phosphorylated signal transducer and activator of transcription-5, Janus kinase-2, and ERK1/2 proteins. Exposure of podocytes to GH also caused changes in the intracellular distribution of the Janus kinase-2 adapter protein Src homology 2-Bbeta, stimulation of focal adhesion kinase, increase in reactive oxygen species, and GH-dependent changes in the actin cytoskeleton. We conclude that glomerular podocytes express functional GHRs and that GH increases levels of reactive oxygen species and induces reorganization of the actin cytoskeleton in these cells. These results provide a novel mechanistic link between GH's actions and glomerular dysfunction in disorders such as acromegaly and diabetic glomerulosclerosis.
Reddy
Gaddameedi R
GR
Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109-0718, USA.
Pushpanathan
Mary J
MJ
Ransom
Richard F
RF
Holzman
Lawrence B
LB
Brosius
Frank C
FC
Diakonova
Maria
M
Mathieson
Peter
P
Saleem
Moin A
MA
List
Edward O
EO
Kopchick
John J
JJ
Frank
Stuart J
SJ
Menon
Ram K
RK
D000172:Acromegaly / Q000473:pathology / Q000503:physiopathology; D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002461:Cell Line, Transformed; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology; D015870:Gene Expression; D013006:Growth Hormone / Q000494:pharmacology* / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050199:Podocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D011108:Polymers; D017382:Reactive Oxygen Species / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism
D011108:Polymers; D017382:Reactive Oxygen Species; D011986:Receptors, Somatotropin; D013006:Growth Hormone