aPKC/Par3/Par6 polarity complexes regulate podocyte motility and crescent formation in the progression of ANCA-associated vasculitis

Rong Zou; Chen Wang; Wei Geng; Mark A Little; Min Chen

doi:10.1093/rheumatology/keae700

aPKC/Par3/Par6 polarity complexes regulate podocyte motility and crescent formation in the progression of ANCA-associated vasculitis

Rheumatology (Oxford). 2024 Dec 19:keae700. doi: 10.1093/rheumatology/keae700. Online ahead of print.

Authors

Rong Zou^{1

2}, Chen Wang¹, Wei Geng², Mark A Little³, Min Chen¹

Affiliations

¹ Renal 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.
² Renal Division, Department of Medicine, Hubei Provincial Hospital of Integrated Chinese and Western Medicine, Wuhan, China.
³ Trinity Kidney Centre, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.

PMID: 39700430
DOI: 10.1093/rheumatology/keae700

Abstract

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.

Keywords: ANCA-associated vasculitis; HSP70; aPKC/Par3/Par6 polarity complexes; crescent formation; podocyte motility.