Role of the downstream mediator of glucocorticoids, annexin A1, in the repair process of acute kidney injury
Final Report Abstract
The anti-inflammatory protein annexin A1 (AnxA1) and its formyl peptide receptor 2 (FPR2) may exert protective effects in organ fibrosis. The objective of this project was to test whether the AnxA1/FPR2 system acts renoprotectively in the setting of acute kidney injury, and whether its components may become the target for novel, organ-protective therapeutic strategies. In a rat model of late-onset hypertensive nephropathy and organ fibrosis caused by angiotensin receptor blockade during nephrogenesis, fibrotic foci contained CD73-positive fibroblasts, alpha-smooth muscle actin (alphaSMA)-positive myofibroblasts and CD68-positive macrophages. Here, transforming growth factor-ß (TGF-ß) along with AnxA1 and FPR2 expression levels were elevated. Conversely, AnxA1 deletion in isolated fibroblasts led to enhanced α-SMA and collagen-1 synthesis. Adding TGF-ß increased alpha-SMA and collagen 1A1 expression substantially in normal mouse or human fibroblasts; these increases were attenuated when AnxA1 was simultaneously overexpressed. AnxA1 and FPR2 in the renal interstitium may therefore cause antifibrotic effects in renal disease. Renoprotective effects of AnxA1 were further studied in experimental crescentic glomerulonephritis (GN) for its assumed anti-inflammatory role. GN was induced in mice receiving antiserum against rat glomerular constituents; wild type and AnxA1-/- mice were compared. AnxA1-/- mice showed more sclerotic glomeruli than the controls, aggravated tubulointerstitial damage, and CD45-positive leukocytes and neutrophils were stimulated along with proinflammatory prostaglandins. Data from human biopsies also suggested that AnxA1, apart from its interstitial control function, may exert protective effects in glomerular disease. RNA-Seq information confirmed that intrinsic AnxA1 had a protective effect via the control of inflammatory signals and neutrophil infiltration. In rat anti-Thy1.1 nephritis, renal AnxA1 biosynthesis was substantially increased, and M2-polarized macrophages and CD3-,4-,8-, and 20-positive lymphocytes augmented. Here, AnxA1-expressing macrophages showed a numerical peak on d15, and AnxA1-positive CD3- and CD4-positive T helper cells were stimulated. These results further supported the concept of AnxA1 controlling renal inflammatory processes. We concluded that AnxA1 signaling may be a novel target to protect the kidney during inflammatory renal disease.
Publications
- Annexin A2 mediates apical trafficking of renal Na⁺-K⁺-2Cl⁻ cotransporter. J Biol Chem 289(14): 9983-9997, 2014
Dathe C, Daigeler AL, Seifert W, Jankowski V, Mrowka R, Kalis R, Wanker E, Mutig K, Bachmann S, Paliege A
(See online at https://doi.org/10.1074/jbc.M113.540948) - Hyperkalemic hypertension-associated cullin 3 promotes WNK signaling by degrading KLHL3. J Clin Invest 124(11): 4723-4736, 2014
McCormick JA, Yang CL, Zhang C, Davidge B, Blankenstein KI, Terker AS, Yarbrough B, Meermeier NP, Park HJ, McCully B, West M, Borschewski A, Himmerkus N, Bleich M, Bachmann S, Mutig K, Argaiz ER, Gamba G, Singer JD, Ellison DH
(See online at https://doi.org/10.1172/JCI76126) - Sex-dependent hypertension and renal changes in aged rats with altered renal development. Am J Physiol Renal Physiol 307(4): F461-F470, 2014
Saez F., Reverte V., Paliege A., Moreno J.M., Llinás M.T., Bachmann S., Salazar F.J.
(See online at https://doi.org/10.1152/ajprenal.00198.2014) - Activation of annexin A1 signalling in renal fibroblasts exerts antifibrotic effects. Acta Physiol (Oxf) 215(3): 144-158, 2015
Neymeyer H., Labes R., Reverte V., Saez F., Stroh T., Dathe C., Hohberger S., Zeisberg M., Müller G.A., Salazar J., Bachmann S., Paliege A.
(See online at https://doi.org/10.1111/apha.12586) - Calcineurin and Sorting-Related Receptor with A-Type Repeats Interact to Regulate the Renal Na⁺-K⁺-2Cl⁻ Cotransporter. J Am Soc Nephrol 27(1): 107-119, 2016
Borschewski A, Himmerkus N, Boldt C, Blankenstein KI, McCormick JA, Lazelle R, Willnow TE, Jankowski V, Plain A, Bleich M, Ellison DH, Bachmann S, Mutig K
(See online at https://doi.org/10.1681/ASN.2014070728) - Demonstration of the functional impact of vasopressin signaling in the thick ascending limb by a targeted transgenic rat approach. Am J Physiol Renal Physiol 311(2): F411-F423, 2016
Mutig K, Borowski T, Boldt C, Borschewski A, Paliege A, Popova E, Bader M, Bachmann S
(See online at https://doi.org/10.1152/ajprenal.00126.2016) - AVP dynamically increases paracellular Na(+) permeability and transcellular NaCl transport in the medullary thick ascending limb of Henle's loop. Pflugers Arch 469(1): 149-158, 2017
Himmerkus N, Plain A, Marques RD, Sonntag SR, Paliege A, Leipziger J, Bleich M
(See online at https://doi.org/10.1007/s00424-016-1915-5) - Calcineurin inhibitor cyclosporine A activates renal Na-K-Cl cotransporters via local and systemic mechanisms. Am J Physiol Renal Physiol 312(3): F489-F501, 2017
Blankenstein K.I., Borschewski A., Labes R., Paliege A., Boldt C., McCormick J.A., Ellison D.H., Bader M., Bachmann S., Mutig K.
(See online at https://doi.org/10.1152/ajprenal.00575.2016) - Cyclosporin a induces renal episodic hypoxia. Acta physiologica (Oxf), 219: 625-639, 2017
Fähling, M., Mathia S., Scheidl J., Abramovitch R, Milman Z., Paliege A., Peters H., Persson P.B., Heyman S.N., Rosenberger C.
(See online at https://doi.org/10.1111/apha.12811) - Modern field emission scanning electron microscopy provides new perspectives for imaging kidney ultrastructure. Kidney Int 94(3): 625-631, 2018
Dittmayer C, Völcker E, Wacker I, Schröder RR, Bachmann S
(See online at https://doi.org/10.1016/j.kint.2018.05.017)
