A neutralizing IL-11 antibody improves renal function and increases lifespan in a mouse model of alport syndrome

Item Type:	Article
Title:	A neutralizing IL-11 antibody improves renal function and increases lifespan in a mouse model of alport syndrome
Creators Name:	Widjaja, A.A. and Shekeran, S. and Adami, E. and Goh, J. and Tan, J. and Viswanathan, S. and Lim, S.Y. and Tan, P.H. and Hübner, N. and Coffman, T. and Cook, S.
Abstract:	BACKGROUND: Alport syndrome is a genetic disorder characterized by a defective glomerular basement membrane, tubulointerstitial fibrosis, inflammation, and progressive renal failure. IL-11 was recently implicated in fibrotic kidney disease but its role in Alport syndrome is unknown Methods: We determined IL-11 expression by molecular analyses and in an Alport syndrome mouse model. We assessed the effects of a neutralizing IL-11 antibody (X203) versus an IgG control in Col4a3-/- mice (lacking the gene encoding a type IV collagen component) on renal tubule damage, function, fibrosis, and inflammation. Effects on lifespan of X203, the IgG control, an angiotensin-converting enzyme inhibitor (ramipril), or ramipril+X203 were also studied. RESULTS: In Col4a3 mice, as kidney failure advanced, renal IL-11 levels increased and IL-11 expression localized to tubular epithelial cells. The IL-11 receptor IL11RA is expressed in tubular epithelial cells and podocytes and is upregulated in tubular epithelial cells of Col4a3 mice. Administration of X203 reduced albuminuria, improved renal function, and preserved podocyte numbers and levels of key podocyte proteins that are reduced in Col4a3 mice; these effects were accompanied by reduced fibrosis and inflammation, attenuation of epithelial-tomesenchymal transition, and increased expression of regenerative markers. X203 attenuated pathogenic ERK and STAT3 pathways, which were activated in Col4a3 mice. Median lifespan of Col4a3 mice was prolonged 22% by ramapril, 44% with X203, and 99% with amipril+X203. CONCLUSIONS: In an Alport syndrome mouse model, renal IL-11 is upregulated, and neutralization of IL-11 reduces epithelial-to-mesenchymal transition, fibrosis, and inflammation, while improving renal function. Anti-IL-11 combined with ACE inhibition synergistically extends lifespan. This suggests that a therapeutic approach targeting IL-11 holds promise for progressive kidney disease in Alport syndrome.
Keywords:	Alport Syndrome, Fibrosis, Interleukin 11, Podocyte, Therapy, Glomerular Disease, Glomerulosclerosis, Chronic Kidney Disease, Animals, Mice
Source:	Journal of the American Society of Nephrology
ISSN:	1046-6673
Publisher:	American Society of Nephrology
Volume:	33
Number:	4
Page Range:	718-730
Date:	April 2022
Additional Information:	Copyright © 2022 by the American Society of Nephrology
Official Publication:	https://doi.org/10.1681/ASN.2021040577
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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