Salt-inducible kinase 1 is involved in high glucose-induced mesangial cell proliferation mediated by the ALK5 signaling pathway

Abstract

Abstract. High glucose levels can induce mesangial cell proliferation and extracellular matrix (ECM) accumulation through the type I activin receptor-like kinase 5 (ALK5) signaling pathway. Salt-inducible kinase 1 (SIK1) prevents fibrosis by downregulating ALK5, while the expression level of the SIK1 protein itself is downregulated by glucose in neuronal cells following ischemia. In this study, we investigated the correlation between SIK1 and the ALK5 signaling pathway in a rat glomerular mesangial cell line (HBZY-1 cells). We found that high glucose levels downregulated the expression level of SIK1 and suppressed the phosphorylation of SIK1 at Thr-182. The downregulation of SIK1 by high glucose was accompanied by the activation of the ALK5 signaling pathway, while the overexpression of SIK1 in the HBZY-1 cells resulted in a decrease in the ALK5 protein level, as well in the levels of its downstream targets, including fibronectin and plasminogen activator inhibitor type I. In conclusion, high glucose may activate the ALK5 signaling pathway by downregulating SIK1, and SIK1 may be a protective factor against cellular proliferation and ECM accumulation in glomerular mesangial cells under high glucose conditions.

Adenovirus-mediated expression of SIK1 improves hepatic glucose and lipid metabolism in type 2 diabetes mellitus rats

“…This is obviously the first report that suggests the potential of adenovirus-mediated SIK1 gene transfer in the management of hyperglycaemia in the HFD/STZ-induced T2DM rat model. More importantly, we for the first time demonstrated that SIK1 mRNA and protein expression were significantly reduced in the livers of HFD/STZ-induced diabetic rats, which was consistent with our previous in vitro studies [8, 18], suggesting that the expression of SIK1 is inhibited in diabetic states.…”

“…The Thr182 of SIK1 is phosphorylated by LKB1, resulting in conversion from inactive SIK1 to the active form [6]. Consistent with previous in vitro observations [8, 18], this in vivo study indicated that the level of Thr-182 phosphorylation, as well as the expression of SIK1 mRNA and protein, was downregulated in the livers of HFD/STZ-induced diabetic rats, suggesting that the SIK1 kinase activity may be suppressed in diabetic states. As expected, Ad-SIK1 treatment significantly elevated the level of pT182 SIK1 compared to the DM group.…”

“…Ser-577 is a determinant of the intracellular distribution of SIK1. Moreover, inactive SIK1 as well as CREB-repressing active SIK1 are present as Ser577-dephosphorylated forms and are localized in the nucleus [3, 6, 8]. Phosphorylation of SIK1 at Ser577, which causes the nucleus export of SIK1, leads to a reduction of the transcriptional modulating activity of SIK1 [6].…”

“…In addition, Liver kinase B 1 (LKB1), a major upstream kinase of AMPK, phosphorylates SIK1 at Thr182 in the activation loop (A-loop) of the kinase domain, which is essential for switching on the SIK1 kinase activity, thus resulting in the increase of the kinase activity of SIK1 [6, 7]. Treatment with adrenocorticotropic hormone (ACTH) and the subsequent phosphorylation of the regulatory domain at Ser-577 by protein kinase A (PKA) makes SIK1 translocate to the cytoplasm and lose its repressive properties[3, 8]. Knockdown of SIK1 in mice promoted both fasting hyperglycaemia and gluconeogenic gene expression.…”

An anti-cancer WxxxE-containing azurin polypeptide inhibits Rac1-dependent STAT3 and ERK/GSK-3β signaling in breast cancer cells

“…Then tumors were removed from mice and the tumor weight was recorded immediately. IHC was performed as previously described [54, 55]. …”