Abstract: FR-PO369
Mitochondrial Dysfunction-Related Glycogen Synthase Kinase 3β (GSK3β) Overexpression Drives Early Diabetic Tubulopathy
Session Information
- Diabetic Kidney Disease: Basic - I
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Author
- Wang, Pei, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
Background
Over these years, the traditional “glomerulocentric” paradigm of DKD has partly shifted to diabetic tubulopathy (DT) because of renal insufficiency and prognosis of patients is closely related to tubular atrophy and interstitial fibrosis. New insights indicate that mitochondria dysfunction represent an early event in DT, but the precise mechanism for such pathological process is not clear.
Methods
The present study was designed by using high-fat diet (HFD)-fed combine with STZ mice as an insulin resistance model of tubular injury in T2DM. We also reported the expression of GSK3β in human proximal renal tubular (HK-2) cells.
Results
As a potential novel biomarker for predicting a variety of renal diseases, glycogen synthase kinase 3β (GSK3β) is overexpressed and hyperactive with mitochondrial dysfunction in proximal tubular epithelium, correlating with functional and histological signs of renal tubular injury in diabetes mellitus (DM). Moreover, tubule-specific ablation of GSK3β substantially attenuated mitochondrial damage and early tubular lesions in mice. Multiple regulatory mechanisms of mitochondrial damage, such as mitochondrial biology, mitochondrial dynamics, mitophagy and oxidative stress, are closely related to the hyperactivation of GSK3β. In addition, therapeutic targeting of GSK3β by TDZD-8 ameliorated mitochondrial dysfunction and delayed early stage of DT in mice.
Conclusion
Thus, GSK3β appears to play a key role in early DT by modulating mitochondrial dysfunction and may be an actionable target for intervention to delay DKD in advance.
GSK3β hyperactivity exacerbated HG-induced mitochondrial dysfunction in HK-2 cells