SGK1-mediated fibronectin formation in diabetic nephropathy.
The serum and glucocorticoid inducible kinase SGK1 has been shown to be up regulated in fibrosing tissue including diabetic nephropathy. The present study has been performed to determine the time course of SGK1 transcription in mouse kidneys following induction of diabetes by streptozotocin (STZ). Moreover, the study aimed to explore whether SGK1 may play an active role in the stimulation of matrix protein formation during hyperglycemia. The induction of diabetes in 8 weeks old male C57Bl/6 mice was indeed followed by a significant (p< 0.001) increase of SGK1 transcript levels (up to 2.5-fold) and protein abundance (up to 2.8-fold) both peaking 4 weeks after STZ treatment. The SGK1 transcript levels and protein abundance declined thereafter but remained significantly elevated up to 12 weeks (p<0.05). Exposure to high extracellular glucose concentration (25 mM) significantly increased SGK1 transcript levels in human mesangial cells (HMCs). At low extracellular glucose concentration (5.5 mM), transfection with constitutively active (S422D)SGK1 and transdominant inhibitory (K127N)SGK1 did not significantly modify fibronectin formation by HMCs. Exposure to high extracellular glucose concentration stimulated fibronectin formation (by 2.2 fold), an effect abrogated by transfection with inactive (K127N)SGK1 (1.2 fold) and markedly enhanced by transfection with (S422D)SGK1 (4.7 fold). In conclusion, hyperglycemia of diabetes mellitus leads to partially transient increase of SGK1 transcription and translation. SGK1 overexpression alone has little effect on fibronectin formation but potentiates the effect of hyperglycemia. Thus, SGK1 is upregulated in diabetic nephropathy and actively participates in the stimulation of matrix protein deposition in this common deleterious complication of diabetic hyperglycemia.
Feng
Yuxi
Y
5th Medical Clinic, Faculty of Clinical Medicine, University of Heidelberg, Germany.
Wang
Quansheng
Q
Wang
Yumei
Y
Yard
Benito
B
Lang
Florian
F
D000818:Animals; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D005353:Fibronectins / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D050527:Mesangial Cells / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
D005353:Fibronectins; D005947:Glucose; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases