AMPK-mediated downregulation of connexin43 and premature senescence of mesangial cells under high-glucose conditions

• We evaluated the expression of p-AMPK, Cx43 and p21 in normal/diabetic nephropathy kidney.
• Cx43 expression and the AMPK/mTOR signaling pathway changed in glomerular mesangial cells (GMC) cultured in high glucose.
• Inhibiting or activating AMPK both affected the Cx43 expression and GMC senescence.
• AMPK played an important role in regulating the Cx43 expression and premature senescence in GMC.

Diabetic nephropathy is associated with premature senescence. Our previous study showed that glomerular mesangial cells (GMCs) appeared to take on senescent phenotypes under high-glucose conditions in conjunction with the downregulation of connexin43 (Cx43). In this study, we investigated whether AMPK-mediated Cx43 expression and premature senescence in diabetic nephropathy are associated with mTOR activation. From in vivo and in vitro studies, we found decreased expression of Cx43 and p-AMPK but increased expression of p21 both in the glomeruli of diabetic nephropathy and in primary GMCs cultured in high glucose. Activating AMPK or inhibiting mTOR prevented the downregulation of Cx43 and reversed GMC senescence. Dominant-negative AMPK expression both reduced Cx43 expression and induced GMC senescence. Furthermore, AMPK regulated Cx43 expression and GMC senescence mainly through the inhibition of mTOR, although other pathways cannot be ruled out. This study demonstrated that AMPK signaling pathways play an important role in the regulation of the Cx43 expression that accompanies GMC senescence under high-glucose conditions.