Annexin A1 exerts renoprotective effects in experimental crescentic glomerulonephritis

Robert Labes; Lei Dong; Ralf Mrowka; Sebastian Bachmann; Sibylle von Vietinghoff; Alexander Paliege

doi:10.3389/fphys.2022.984362

Annexin A1 exerts renoprotective effects in experimental crescentic glomerulonephritis

Front Physiol. 2022 Oct 12:13:984362. doi: 10.3389/fphys.2022.984362. eCollection 2022.

Authors

Robert Labes¹, Lei Dong², Ralf Mrowka³, Sebastian Bachmann¹, Sibylle von Vietinghoff⁴, Alexander Paliege^{5

6}

Affiliations

¹ Department of Anatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
² Nephrology Department, Tongji Hospital, Tongji College, Huazhong University of Science and Technology, Wuhan, China.
³ Klinik für Innere Medizin III, AG Experimentelle Nephrologie, Universitätsklinikum Jena, Jena, Germany.
⁴ Nephrology Section, First Medical Clinic, University Clinic and Rheinische Friedrich-Wilhelms Universität Bonn, Bonn, Germany.
⁵ Division of Nephrology, Department of Internal Medicine III, Technische Universität Dresden, Dresden, Germany.
⁶ Berlin Institute of Health (BIH), Berlin, Germany.

Abstract

Non-resolving inflammation plays a critical role during the transition from renal injury towards end-stage renal disease. The glucocorticoid-inducible protein annexin A1 has been shown to function as key regulator in the resolution phase of inflammation, but its role in immune-mediated crescentic glomerulonephritis has not been studied so far. Methods: Acute crescentic glomerulonephritis was induced in annexin A1-deficient and wildtype mice using a sheep serum against rat glomerular basement membrane constituents. Animals were sacrificed at d5 and d10 after nephritis induction. Renal leukocyte abundance was studied by immunofluorescence and flow cytometry. Alterations in gene expression were determined by RNA-Seq and gene ontology analysis. Renal levels of eicosanoids and related lipid products were measured using lipid mass spectrometry. Results: Histological analysis revealed an increased number of sclerotic glomeruli and aggravated tubulointerstitial damage in the kidneys of annexin A1-deficient mice compared to the wildtype controls. Flow cytometry analysis confirmed an increased number of CD45⁺ leukocytes and neutrophil granulocytes in the absence of annexin A1. Lipid mass spectrometry showed elevated levels of prostaglandins PGE2 and PGD2 and reduced levels of antiinflammatory epoxydocosapentaenoic acid regioisomers. RNA-Seq with subsequent gene ontology analysis revealed induction of gene products related to leukocyte activation and chemotaxis as well as regulation of cytokine production and secretion. Conclusion: Intrinsic annexin A1 reduces proinflammatory signals and infiltration of neutrophil granulocytes and thereby protects the kidney during crescentic glomerulonephritis. The annexin A1 signaling cascade may therefore provide novel targets for the treatment of inflammatory kidney disease.

Keywords: annexin A1 (AnxA1); crescentic glomerulonephritis; epoxydocosapentaenoic acids (EDPs); nephrotoxic serum nephritis; neutrophil granulocyte (PMN); prostaglandin E2 (PGE2); renal fibrosis; resolution of inflammation.