Preprint Article Version 3 Preserved in Portico This version is not peer-reviewed

Epigenetic Modulation of Gremlin-1/NOTCH Pathway in Experimental Crescentic Immune-Mediated Glomerulonephritis

Version 1 : Received: 14 December 2021 / Approved: 17 December 2021 / Online: 17 December 2021 (14:35:42 CET)
Version 2 : Received: 20 December 2021 / Approved: 20 December 2021 / Online: 20 December 2021 (15:48:29 CET)
Version 3 : Received: 23 December 2021 / Approved: 23 December 2021 / Online: 23 December 2021 (14:40:45 CET)

A peer-reviewed article of this Preprint also exists.

Tejedor-Santamaria, L.; Morgado-Pascual, J.L.; Marquez-Exposito, L.; Suarez-Alvarez, B.; Rodrigues-Diez, R.R.; Tejera-Muñoz, A.; Marchant, V.; Mezzano, S.; Lopez-Larrea, C.; Sola, A.; Fernandez-Juarez, G.M.; Ortiz, A.; Rayego-Mateos, S.; Ruiz-Ortega, M. Epigenetic Modulation of Gremlin-1/NOTCH Pathway in Experimental Crescentic Immune-Mediated Glomerulonephritis. Pharmaceuticals 2022, 15, 121. Tejedor-Santamaria, L.; Morgado-Pascual, J.L.; Marquez-Exposito, L.; Suarez-Alvarez, B.; Rodrigues-Diez, R.R.; Tejera-Muñoz, A.; Marchant, V.; Mezzano, S.; Lopez-Larrea, C.; Sola, A.; Fernandez-Juarez, G.M.; Ortiz, A.; Rayego-Mateos, S.; Ruiz-Ortega, M. Epigenetic Modulation of Gremlin-1/NOTCH Pathway in Experimental Crescentic Immune-Mediated Glomerulonephritis. Pharmaceuticals 2022, 15, 121.

Journal reference: Pharmaceuticals 2022, 15, 121
DOI: 10.3390/ph15020121

Abstract

Crescentic glomerulonephritis is a devastating autoimmune disease that without early and properly treat-ment may rapidly progress to end-stage renal disease and death. Current immunosuppressive treatment provided limited efficacy and an important burden of adverse events. Epigenetic drugs are a source of novel therapeutic tools. Among them, bromodomain and extraterminal domain (BET) inhibitors (iBETs) block the interaction between bromodomains and acetylated proteins, including histones and transcription factors. iBETs have demonstrated protective effects on malignancy, inflammatory conditions and experi-mental kidney disease. Recently, Gremlin-1 was proposed as a urinary biomarker of disease progression in human anti-neutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis. We have now evaluated whether iBETs regulate Gremlin-1 in experimental anti-glomerular basement membrane nephritis induced by nephrotoxic serum (NTS) in mice, a model of human crescentic glomerulonephritis. In NTS-injected mice, the iBET JQ1 inhibited renal Gremlin-1 overexpression and diminished glomerular damage, including podocyte loss. Chromatin immunoprecipitation assay demonstrated BRD4 enrichment of the Grem-1 gene promoter in injured kidneys, consistent with Gremlin-1 epigenetic regulation. Moreover, JQ1 blocked BRD4 binding and inhibited Grem-1 gene transcription. The beneficial effect of iBETs was also mediated by targeting NOTCH signaling pathway. JQ1 inhibited the gene expression of the NOTCH effec-tors Hes-1 and Hey-1 in NTS-injured kidneys. Our results further support the role for epigenetic drugs, such as iBETs, in the treatment of rapidly progressive crescentic glomerulonephritis.

Keywords

crescentic glomerulonephritis; BET proteins; NOTCH; GREMLIN; Chronic kidney disease; Bromodomain

Subject

LIFE SCIENCES, Molecular Biology

Comments (1)

Comment 1
Received: 23 December 2021
Commenter: Lucia Tejedor-Santamaria
Commenter's Conflict of Interests: Author
Comment: Some figures were not displayed correctly.
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