Fluvastatin inhibits activation of JAK and STAT proteins in diabetic rat glomeruli and mesangial cells under high glucose conditions.
OBJECTIVE
The aim of the present study was to further elucidate the mechanism of the protective role of fluvastatin on diabetic nephropathy.


METHODS
Streptozotocin-induced diabetic rats were treated daily with fluvastatin (4 mg/kg body weight) by gavage. The animals were killed 4 weeks later and urine and blood samples were collected. The kidney tissues were removed and subjected to the following experiments. Rat glomerular mesangial cells (GMC) were cultured under normal glucose (5.5 mmol/L), high glucose (HG, 30 mmol/L), HG+AG490 (10 micromol/L), or HG with fluvastatin (1 micromol/L). Glomeruli or the GMC lysate was immunoprecipitated and/or immunoblotted with antibodies against Janus kinase 2 (JAK2), SH2-domain containing tyrosine phosphatase-1 (SHP-1), phosphospecific SHP-2, and signal transducer and activators of transcription (STAT), respectively. Transforming growth factor-beta (TGF-beta1) mRNA was measured by RT-PCR. The protein synthesis of TGF-beta1 and fibronectin in the culture medium of GMC was detected by ELISA.


RESULTS
The phosphorylation levels of JAK2, STAT1, STAT3, and SHP-2 increased significantly, and SHP-1 phosphorylation was reduced in glomeruli of diabetic rats. Treatment with fluvastatin reduced phosphorylation levels of JAK2, STAT1, STAT3, and SHP-2 in glomeruli of diabetic rats, but it had no effect on the dephosphorylation of SHP-1. The exposure of GMC to 30 mmol/L glucose caused the activation of JAK2, STAT1, STAT3, and SHP-2. It upregulated TGF-beta1 expression and increased protein synthesis of fibronectin. These high glucose-induced changes were suppressed by fluvastatin, as well as AG490, a JAK2 inhibitor.


CONCLUSIONS
The regulation of the phosphorylation of JAK/STAT by fluvastatin may be responsible for its renal protective effects on diabetic nephropathy.
Shi
Yong-hong
YH
Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China.
Zhao
Song
S
Wang
Chen
C
Li
Ying
Y
Duan
Hui-jun
HJ
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001483:Base Sequence; D017931:DNA Primers; D003930:Diabetic Retinopathy / Q000201:enzymology / Q000378:metabolism*; D004789:Enzyme Activation; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000924:Anticholesteremic Agents; D017931:DNA Primers; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D050791:STAT Transcription Factors; D000077340:Fluvastatin; D053612:Janus Kinases