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

Saad, S., Stevens, V. A., Wassef, L., Poronnik, P., Kelly, D. J., Gilbert, R. E. and Pollock, C. A. (2005) High glucose transactivates the EGF receptor and up-regulates serum glucocorticoid kinase in the proximal tubule. Kidney International, 68 3: 985-997. doi:10.1111/j.1523-1755.2005.00492.x


Author Saad, S.
Stevens, V. A.
Wassef, L.
Poronnik, P.
Kelly, D. J.
Gilbert, R. E.
Pollock, C. A.
Title High glucose transactivates the EGF receptor and up-regulates serum glucocorticoid kinase in the proximal tubule
Journal name Kidney International   Check publisher's open access policy
ISSN 0085-2538
Publication date 2005-01-01
Sub-type Article (original research)
DOI 10.1111/j.1523-1755.2005.00492.x
Volume 68
Issue 3
Start page 985
End page 997
Total pages 13
Place of publication Oxford
Publisher Blackwell Publishing
Collection year 2005
Language eng
Subject C1
270104 Membrane Biology
320602 Cell Physiology
780105 Biological sciences
730115 Urogenital system and disorders
Abstract 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.
Keyword Sgk
High Glucose
Proximal Tubule
Egfr
Urology & Nephrology
Epidermal-growth-factor
Inducible Protein-kinase
Smooth-muscle-cells
Epithelial-cells
Activation
Expression
Apoptosis
Kidney
Gene
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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Created: Wed, 15 Aug 2007, 16:00:27 EST