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

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.

• Authors: Sonia Saad, Veronica A Stevens, Lesley Wassef, Philip Poronnik, Darren J Kelly, Richard E Gilbert, Carol A Pollock
• Journal: Kidney international (Kidney Int) Vol. 68 Issue 3 Pg. 985-97 (Sep 2005) ISSN: 0085-2538 [Print] United States
• PMID: 16105029 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Immediate-Early Proteins
• RNA, Messenger
• SLC9A3 protein, human
• Slc9a3 protein, rat
• Sodium-Hydrogen Exchanger 3
• Sodium-Hydrogen Exchangers
• Epidermal Growth Factor
• ErbB Receptors
• Protein Serine-Threonine Kinases
• serum-glucocorticoid regulated kinase
• Glucose

Topics

• Animals
• Cells, Cultured
• Diabetes Mellitus, Experimental (metabolism, physiopathology)
• Diabetes Mellitus, Type 2 (metabolism, physiopathology)
• Diabetic Nephropathies (metabolism, physiopathology)
• Epidermal Growth Factor (metabolism, pharmacology)
• ErbB Receptors (metabolism)
• Glucose (pharmacology)
• Humans
• Immediate-Early Proteins (genetics, metabolism)
• Kidney Tubules, Proximal (drug effects, enzymology)
• Phosphorylation
• Protein Serine-Threonine Kinases (genetics, metabolism)
• RNA, Messenger (analysis)
• Rats
• Sodium-Hydrogen Exchanger 3
• Sodium-Hydrogen Exchangers (genetics, metabolism)
• Up-Regulation (drug effects)