A Neutralizing IL-11 Antibody Improves Renal Function and Increases Lifespan in a Mouse Model of Alport Syndrome

  • J Am Soc Nephrol. 2022 Apr;33(4):718-730. doi: 10.1681/ASN.2021040577.
Anissa A Widjaja  1 ,  Shamini G Shekeran  1 ,  Eleonora Adami  1  2 ,  Joyce G Wei Ting  1 ,  Jessie Tan  3 ,  Sivakumar Viswanathan  1 ,  Sze Yun Lim  1 ,  Puay Hoon Tan  1  4  5 ,  Norbert Hübner  2  6  7 ,  Thomas Coffman  1 ,  Stuart A Cook  1  3  8
Affiliations
  • 1. Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore.
  • 2. Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
  • 3. National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore.
  • 4. Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore.
  • 5. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 6. DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.
  • 7. Charité-Universitätsmedizin, Berlin, Germany.
  • 8. MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London, UK.
PMID: 35140116 DOI: 10.1681/ASN.2021040577
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 (×203) 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 of ×203, the IgG control, an angiotensin-converting enzyme (ACE) inhibitor (ramipril), or ramipril+X203 on lifespan 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 (IL-11RA1) is expressed in tubular epithelial cells and podocytes and is upregulated in tubular epithelial cells of Col4a3-/- mice. Administration of ×203 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-to-mesenchymal transition, and increased expression of regenerative markers. X203 attenuated pathogenic ERK and STAT3 pathways, which were activated in Col4a3-/- mice. The median lifespan of Col4a3-/- mice was prolonged 22% by ramipril, 44% with ×203, and 99% with ramipril+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; chronic kidney disease; fibrosis; glomerular disease; glomerulosclerosis; interleukin 11; podocyte; therapy.
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