Related Experiment Video For ANCA-associated vasculitis
Updated: Jun 4, 2025
Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway
Published on: August 23, 2024
aPKC/Par3/Par6 polarity complexes regulate podocyte motility and crescent formation in the progression of
Rong Zou1,2, Chen Wang1, Wei Geng2
1Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
Objectives:
Podocyte bridging may be a key initial event occurring early in crescent formation. This study aims to probe the underlying mechanism of atypical protein kinase C (aPKC)/protease-activated receptor 3(Par3)/Par6 polarity complexes on podocyte motility and crescent formation during the progression of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).
Methods:
The effects of anti-TNF-α monoclonal antibody (mAb) on the crescent formation, localization and expression of aPKC/Par3/Par6 polarity complexes, and activities of small GTPases (Rho/Rac1/Cdc42) were explored in an AAV mouse model. Podocytes were stimulated in vitro by TNF-α and myeloperoxidase (MPO)-ANCA positive serum collected from patients with microscopic polyangiitis (MPA). Then, podocyte motility, aPKC/Par3/Par6 polarity protein expression and small GTPases activity were measured. The impacts of heat shock protein 70 (HSP70), a type of molecular chaperone, on the phosphorylation of aPKC was evaluated.
Results:
Anti-TNF-α mAb inhibited crescent formation and restored the localization of aPKC/Par3/Par6 polarity complexes in the glomerulus of the AAV mouse model. Both MPO-ANCA-positive serum and TNF-α stimulation significantly induced podocyte motility by inhibiting of aPKC phosphorylation and detachment of aPKC/Par3/Par6 polarity complexes. Overexpression of HSP70 increased p-aPKC level and inhibited podocyte motility stimulated by either MPO-ANCA-positive serum or TNF-α.
Conclusion:
The podocyte polarity preserved by aPKC/Par3/Par6 polarity complexes, especially the phosphorylation status of aPKC, may play an important role in the crescent formation of AAV. The inhibition of TNF-α prevents the crescent formation in AAV via, at least partly, inhibiting podocyte polarity loss and motility.
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