Effect of simvastatin on high glucose- and angiotensin II-induced activation of the JAK/STAT pathway in mesangial cells.
In the current study, we investigated the effect of simvastatin on the ability of high glucose (HG) and ANG II to activate the JAK2-STAT signaling cascade and induce glomerular mesangial cell (GMC) growth. We found that pretreatment with simvastatin significantly inhibited HG- and ANG II-induced collagen IV production, JAK2 activation, and phosphorylation of STAT1 and STAT3 in GMC. We also found that the activation of JAK2 by HG and ANG II was dependent on the Rho family of GTPases. Consistent with these in vitro results, both albumin protein excretion and phosphorylation of JAK2, STAT1, and STAT3 were attenuated in renal glomeruli by administration of simvastatin in a streptozotocin-induced rat model of HG diabetes. This study demonstrates that simvastatin blocks ANG II-induced activation of the JAK/STAT pathway in the diabetic environment, in vitro and in vivo, and, thereby, provides new insights into the molecular mechanisms underlying early diabetic nephropathy.
Banes-Berceli
Amy K
AK
Vascular Biology Center, Department of Physiology, Medical College of Georgia, Augusta, GA 30912-2300, USA.
Shaw
Sean
S
Ma
Guochuan
G
Brands
Michael
M
Eaton
Douglas C
DC
Stern
David M
DM
Fulton
David
D
Caldwell
R William
RW
Marrero
Mario B
MB
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001786:Blood Glucose / Q000502:physiology*; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D053614:Janus Kinase 2; D008297:Male; D050527:Mesangial Cells / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D013729:Terpenes / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000502:physiology
D000924:Anticholesteremic Agents; D001786:Blood Glucose; D024141:Collagen Type IV; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494081:Stat1 protein, rat; C494088:Stat3 protein, rat; D013729:Terpenes; D000804:Angiotensin II; D019821:Simvastatin; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D020741:rho GTP-Binding Proteins