High glucose transactivates the EGF receptor and up-regulates serum glucocorticoid kinase in the proximal tubule


Autoria(s): Saad, S.; Stevens, V. A.; Wassef, L.; Poronnik, P.; Kelly, D. J.; Gilbert, R. E.; Pollock, C. A.
Data(s)

01/01/2005

Resumo

Background. Serum glucocorticoid regulated kinase (SGK-1) is induced in the kidney in diabetes mellitus. However, its role in the proximal tubule is unclear. This study determined the expression and functional role of SGK-1 in PTCs in high glucose conditions. As the epidermal growth factor (EGF) receptor is activated by both EGF and other factors implicated in diabetic nephropathy, the relationship of SGK-1 with EGFR activity was assessed. Methods. mRNA and protein expression of SGK-1 and mRNA expression of the sodium hydrogen exchanger NHE3 were measured in human PTCs exposed to 5 mmol/L (control) and 25 mmol/L (high) glucose. The effects of SGK-1 on cell growth, apoptosis, and progression through the cell cycle and NHE3 mRNA were examined following overexpression of SGK-1 in PTCs. The role of EGFR activation in observed changes was assessed by phospho-EGFR expression, and response to the EGFR blocker PKI166. SGK-1 expression was then assessed in vivo in a model of streptozotocin-induced diabetes mellitus type 2. Results. A total of 25 mmol/L glucose and EGF (10 ng/mL) increased SGK-1 mRNA (P < 0.005 and P < 0.002, respectively) and protein (both P < 0.02) expression. High glucose and overexpression of SGK-1 increased NHE3 mRNA (P < 0.05) and EGFR phosphorylation (P < 0.01), which were reversed by PKI166. SGK-1 overexpression increased PTC growth (P < 0.0001), progression through the cell cycle (P < 0.001), and increased NHE3 mRNA (P < 0.01), which were all reversed with PKI166. Overexpression of SGK-1 also protected against apoptosis induced in the PTCs (P < 0.0001). Up-regulation of tubular SGK-1 mRNA in diabetes mellitus was confirmed in vivo. Oral treatment with PKI166 attenuated this increase by 51%. No EGF protein was detectable in PTCs, suggestive of phosphorylation of the EGFR by high glucose and downstream induction of SGK-1. Conclusion. The effects of high glucose on PTC proliferation, reduced apoptosis and increased NHE3 mRNA levels are mediated by EGFR-dependent up-regulation of SGK-1.

Identificador

http://espace.library.uq.edu.au/view/UQ:75694

Idioma(s)

eng

Publicador

Blackwell Publishing

Palavras-Chave #Sgk #High Glucose #Proximal Tubule #Egfr #Urology & Nephrology #Epidermal-growth-factor #Inducible Protein-kinase #Smooth-muscle-cells #Epithelial-cells #Activation #Expression #Apoptosis #Kidney #Gene #C1 #270104 Membrane Biology #320602 Cell Physiology #780105 Biological sciences #730115 Urogenital system and disorders
Tipo

Journal Article