GLP-1 Receptor Agonists Alleviate Diabetic Kidney Injury via β-Klotho-Mediated Ferroptosis Inhibition

Area of Science:

• Biochemistry
• Molecular Biology
• Nephrology

Background:

• Diabetic kidney disease (DKD) is a major complication of diabetes.
• Semaglutide, a GLP-1 receptor agonist, shows renal protective effects in DKD.
• The precise mechanism of Semaglutide's kidney protection is not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanism underlying Semaglutide's protective effects in DKD.
• To identify key molecular targets involved in Semaglutide-mediated kidney protection.
• To investigate the role of ferroptosis in DKD and its modulation by Semaglutide.

Main Methods:

• Transcriptome sequencing to identify key targets.
• Inhibition of ferroptosis in patients, animal models, and HK-2 cells.
• Analysis of signaling pathways including cAMP, PKA, CREB, and AMPK.

Main Results:

• β-Klotho (KLB) was identified as a critical target for Semaglutide's kidney protection.
• Semaglutide treatment significantly increased KLB mRNA expression via the cAMP/PKA/CREB pathway.
• Activation of AMPK by Semaglutide reprogrammed ferroptosis-related metabolic processes, reducing inflammation and fibrosis.

Conclusions:

• Semaglutide alleviates diabetic kidney injury by inhibiting ferroptosis through KLB upregulation.
• The cAMP and AMPK signaling pathways are crucial mediators of Semaglutide's effects.
• Targeting GLP-1RAs and KLB presents a promising therapeutic strategy for DKD.