Human Lupus Nephritis

Reduction in clearance of chromatin is a major factor contributing to the pathogenesis of SLE. The occurrence of chromatin fragments in the kidney may be explained by malfunctioning clearance of apoptotic or necrotic chromatin due to reduced renal endonuclease activity. The main nuclease in the kidney is DNase I as it accounts for 80% of total renal endonuclease activity. Recent data from our research group have demonstrated an acquired error of renal chromatin degradation, possibly due to the loss of renal DNase I enzyme activity.

This translational project aims to get more detailed knowledge about the molecular mechanisms behind SLE and investigate the role and impact DNase I have in this disease. One of our hypotheses is that decreased urinary DNase I activity can predict kidney inflammation. 

Publications:

Pedersen HL, Horvei KD, Thiyagarajan D, Norby GE, Seredkina N, Moroni G, Eilertsen GØ, Holdaas H, Strøm EH, Bakland G, Meroni PL, Rekvig OP. Lupus nephritis: low urinary DNase I levels reflect loss of renal DNase I and may be utilized as a biomarker of disease progression. J Pathol Clin Res. 2018 Jul;4(3):193-203. doi: 10.1002/cjp2.99. Epub 2018 Apr 6. PMID: 29624903; PMCID: PMC6065113.

Thiyagarajan D, Pedersen HL, Seredkina N, Horvei KD, Arranz L, Sonneveld R, Nijenhuis T, van der Vlag J, Rekvig OP. IL-1β Promotes a New Function of DNase I as a Transcription Factor for the Fas Receptor Gene. Front Cell Dev Biol. 2018 Feb 6;6:7. doi: 10.3389/fcell.2018.00007. PMID: 29468159; PMCID: PMC5807897.

Horvei KD, Pedersen HL, Fismen S, Thiyagarajan D, Schneider A, Rekvig OP, Winkler TH, Seredkina N. Lupus nephritis progression in FcγRIIB-/-yaa mice is associated with early development of glomerular electron dense deposits and loss of renal DNase I in severe disease. PLoS One. 2017 Nov 30;12(11):e0188863. doi: 10.1371/journal.pone.0188863. PMID: 29190833; PMCID: PMC5708736.

Rekvig OP, Thiyagarajan D, Pedersen HL, Horvei KD, Seredkina N. Future Perspectives on Pathogenesis of Lupus Nephritis: Facts, Problems, and Potential Causal Therapy Modalities. Am J Pathol. 2016 Nov;186(11):2772-2782. doi: 10.1016/j.ajpath.2016.06.026. Epub 2016 Sep 21. PMID: 27664472.

Due to the potential role of DNase I and NETs in SLE pathogenesis, targeting DNase I and NET proteins is a possible treatment strategy.

Publications:

Blanco LP, Pedersen HL, Wang X, Lightfoot YL, Seto N, Carmona-Rivera C, Yu ZX, Hoffmann V, Yuen PST, Kaplan MJ. Improved Mitochondrial Metabolism and Reduced Inflammation Following Attenuation of Murine Lupus With Coenzyme Q10 Analog Idebenone. Arthritis Rheumatol. 2020 Mar;72(3):454-464. doi: 10.1002/art.41128. Epub 2020 Jan 27. PMID: 31566908; PMCID: PMC7050361.

Wang X, Blanco LP, Carmona-Rivera C, Nakabo S, Pedersen HL, Yu ZX, Kaplan MJ. Effects of Gasdermin D in Modulating Murine Lupus and its Associated Organ Damage. Arthritis Rheumatol. 2020 Dec;72(12):2118-2129. doi: 10.1002/art.41444. Epub 2020 Oct 17. PMID: 32692482; PMCID: PMC8498992.

Fortner KA, Blanco LP, Buskiewicz I, Huang N, Gibson PC, Cook DL, Pedersen HL, Yuen PST, Murphy MP, Perl A, Kaplan MJ, Budd RC. Targeting mitochondrial oxidative stress with MitoQ reduces NET formation and kidney disease in lupus-prone MRL-lpr mice. Lupus Sci Med. 2020 Apr;7(1):e000387. doi: 10.1136/lupus-2020-000387. Epub 2020 Apr 16. Erratum in: Lupus Sci Med. 2020 Apr;7(1): PMID: 32343673; PMCID: PMC7199895.

Pedersen HL, Horvei KD, Thiyagarajan D, Seredkina N, Rekvig OP. Murine and Human Lupus Nephritis: Pathogenic Mechanisms and Theoretical Strategies for Therapy. Semin Nephrol. 2015 Sep;35(5):427-38. doi: 10.1016/j.semnephrol.2015.08.004. PMID: 26573545.