Ginkgetin alleviates high glucose-evoked mesangial cell oxidative stress injury, inflammation, and extracellular matrix (ECM) deposition in an AMPK/mTOR-mediated autophagy axis.

Abstract

Diabetic nephropathy constitutes the leading cause for end-stage kidney disease. Ginkgetin is a common natural non-toxic biflavone and fulfills pleiotropic pharmacological characterizations, such as anti-inflammation and kidney injury. Nevertheless, its efficacy in diabetic nephropathy remains elusive. Here, ginkgetin exhibited little cytotoxicity in glomerular mesangial cells. Of note, ginkgetin restrained high glucose (HG)-induced mesangial cell proliferation and oxidative stress by inhibiting ROS and malonaldehyde levels, but enhancing antioxidant SOD activity. Additionally, ginkgetin suppressed HG-evoked transcript and release of inflammatory cytokine TNF-α, IL-1β, and IL-6. Concomitantly, the increased extracellular matrix (ECM) deposition in HG-treated glomerular mesangial cells was attenuated by ginkgetin via decreasing expression of collagen IV, fibronectin, and laminin. Intriguingly, ginkgetin-restored HG-impaired autophagy; whereas blocking autophagy by its inhibitor 3-MA overturned ginkgetin function against HG-evoked mesangial cell dysfunction. Mechanistically, ginkgetin-mediated AMPK/mTOR axis accounted for HG-impaired autophagy. Importantly, blockage of AMPK signaling reversed ginkgetin-restored autophagy and its protective efficacy against HG-induced dysfunction in mesangial cells. Thus, these findings highlight that ginkgetin may attenuate HG-evoked mesangial cell hyperplasia, oxidative stress, inflammation, and ECM accumulation by activating AMPk/mTOR-mediated autophagy pathway. Therefore, ginkgetin may alleviate the progression of diabetic nephropathy by regulating glomerular mesangial cell dysfunction, supporting a promising therapeutic agent against diabetic nephropathy.

• Authors: Lin Wei, Pan Jian, Huang Erjiong, Zhu Qihan
• Journal: Chemical biology & drug design (Chem Biol Drug Des) Vol. 98 Issue 4 Pg. 620-630 (10 2021) ISSN: 1747-0285 [Electronic] England
• PMID: 34148304 (Publication Type: Journal Article)
• Copyright: © 2021 John Wiley & Sons Ltd.

Chemical References

• Anti-Inflammatory Agents
• Antioxidants
• Biflavonoids
• Fibronectins
• ginkgetin
• Malondialdehyde
• Collagen
• Superoxide Dismutase
• TOR Serine-Threonine Kinases
• AMP-Activated Protein Kinases
• Glucose

Topics

• AMP-Activated Protein Kinases (metabolism)
• Anti-Inflammatory Agents (pharmacology)
• Antioxidants (pharmacology)
• Autophagy (drug effects)
• Biflavonoids (pharmacology)
• Collagen (metabolism)
• Diabetic Nephropathies (drug therapy)
• Extracellular Matrix (drug effects)
• Fibronectins (metabolism)
• Glucose (metabolism)
• Humans
• Inflammation (drug therapy)
• Malondialdehyde (metabolism)
• Mesangial Cells
• Oxidative Stress (drug effects)
• Signal Transduction
• Superoxide Dismutase (metabolism)
• TOR Serine-Threonine Kinases (metabolism)