Histone methyltransferase Suv39h1 attenuates high glucose-induced fibronectin and p21(WAF1) in mesangial cells.

Abstract Suppressor of variegation 3⿿9 homolog 1 (Suv39h1) is a histone methyltransferase that trimethylates lysine 9 of histone H3 (H3K9me3), which results in gene silencing. A previous study found that H3K9me3 and Suv39h1 were decreased in diabetic mouse vascular smooth muscle cells whereas Suv39h1 overexpression attenuated ischemic myocardial injury. Moreover, high glucose (HG) decreased H3K9me3 and Suv39h1 levels in some cells. Thus, we studied the roles of Suv39h1 in HG-induced effects in MES13 (mouse mesangial) cells. We found that HG, chaetocin (a Suv39h1 inhibitor) and Suv39h1 siRNA decreased Suv39h1 while increasing fibronectin and p21 WAF1 protein levels. HG increased mRNA while chaetocin increased transcription of fibronectin and p21 WAF1 genes. Both HG and chaetocin decreased histone H3K9me3 levels at the promoters of fibronectin and p21 WAF1 genes. Additionally, Suv39h1 overexpression attenuated HG-induced fibronectin and p21 WAF1 mRNA and protein expressions while attenuating HG-induced cell hypertrophy. Suv39h1 overexpression also attenuated HG-suppressed histone H3K9me3 levels at the promoters of fibronectin and p21 WAF1 genes. Moreover, LY294002 or the dominant-negative phosphoinositide 3-kinase (PI3K) mutant (οp85) attenuated HG-decreased Suv39h1 and HG-induced fibronectin and p21 WAF1 protein expressions. We concluded that HG decreased Suv39h1 via the PI3K pathway in mesangial cells. Inhibition of Suv39h1 increased fibronectin and p21 WAF1 expressions. Moreover, Suv39h1 overexpression attenuated HG-induced fibronectin and p21 WAF1 expressions and cell hypertrophy while attenuating HG-suppressed histone H3K9me3 levels at the promoters of fibronectin and p21 WAF1 genes.