Apelin Alleviated Endothelial-To-Mesenchymal Transition via Increasing BKCa in Diabetic Nephropathy

Area of Science:

• Nephrology
• Cell Biology
• Endocrinology

Background:

• Endothelial-to-mesenchymal transition (EndMT) is a key process in fibrotic kidney diseases, including diabetic nephropathy (DN).
• Large conductance calcium-activated potassium (BKCa) channels are implicated in EndMT.
• Apelin, an adipokine, may modulate EndMT in DN via BKCa channels.

Purpose of the Study:

• To investigate the role of apelin in inhibiting glomerular EndMT in diabetic nephropathy.
• To determine the involvement of BKCa channels in the protective effects of apelin.
• To elucidate the signaling pathways, including Wnt/β-Catenin, regulated by apelin and BKCa in diabetic glomerular endothelial cells (GECs).

Main Methods:

• In vivo and in vitro studies using diabetic models.
• Assessment of endothelial (CD31, VE-Cadherin) and mesenchymal (α-SMA, Desmin) markers.
• Specific APJ knockout in endothelial cells.
• Pharmacological inhibition of BKCa channels using Iberiotoxin (IBTX).
• Analysis of Wnt/β-Catenin signaling pathway components and SP1 translocation.

Main Results:

• Apelin inhibited diabetic glomerular fibrosis and EndMT, restoring endothelial markers and reducing mesenchymal markers.
• These effects were abrogated by APJ knockout in GECs.
• Apelin increased BKCa channel activity.
• BKCa inhibition by IBTX reversed apelin's suppression of the Wnt/β-Catenin pathway.
• IBTX also inhibited SP1 nuclear translocation and increased DKK1 expression in apelin-treated GECs.

Conclusions:

• Apelin alleviates EndMT and fibrosis in diabetic nephropathy by activating BKCa channels.
• This activation inhibits the Wnt/β-Catenin pathway, mediated by SP1 translocation and subsequent DKK1 upregulation in GECs.
• Apelin represents a potential therapeutic target for diabetic kidney disease.