Targeting endogenous kidney regeneration using anti-IL11 therapy in acute and chronic models of kidney disease

Anissa A. Widjaja (), Sivakumar Viswanathan, Shamini G. Shekeran, Eleonora Adami, Wei-Wen Lim, Sonia Chothani, Jessie Tan, Joyce Wei Ting Goh, Hui Mei Chen, Sze Yun Lim, Carine M. Boustany-Kari, Julie Hawkins, Enrico Petretto, Norbert Hübner, Sebastian Schafer, Thomas M. Coffman and Stuart A. Cook ()
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Anissa A. Widjaja: Duke-National University of Singapore Medical School
Sivakumar Viswanathan: Duke-National University of Singapore Medical School
Shamini G. Shekeran: Duke-National University of Singapore Medical School
Eleonora Adami: Duke-National University of Singapore Medical School
Wei-Wen Lim: Duke-National University of Singapore Medical School
Sonia Chothani: Duke-National University of Singapore Medical School
Jessie Tan: National Heart Centre Singapore
Joyce Wei Ting Goh: Duke-National University of Singapore Medical School
Hui Mei Chen: Duke-National University of Singapore Medical School
Sze Yun Lim: Duke-National University of Singapore Medical School
Carine M. Boustany-Kari: CardioMetabolic Disease Research
Julie Hawkins: CardioMetabolic Disease Research
Enrico Petretto: Duke-National University of Singapore Medical School
Norbert Hübner: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Sebastian Schafer: Duke-National University of Singapore Medical School
Thomas M. Coffman: Duke-National University of Singapore Medical School
Stuart A. Cook: Duke-National University of Singapore Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract The kidney has large regenerative capacity, but this is compromised when kidney damage is excessive and renal tubular epithelial cells (TECs) undergo SNAI1-driven growth arrest. Here we investigate the role of IL11 in TECs, kidney injury and renal repair. IL11 stimulation of TECs induces ERK- and p90RSK-mediated GSK3β inactivation, SNAI1 upregulation and pro-inflammatory gene expression. Mice with acute kidney injury upregulate IL11 in TECs leading to SNAI1 expression and kidney dysfunction, which is not seen in Il11 deleted mice or in mice administered a neutralizing IL11 antibody in either preemptive or treatment modes. In acute kidney injury, anti-TGFβ reduces renal fibrosis but exacerbates inflammation and tubule damage whereas anti-IL11 reduces all pathologies. Mice with TEC-specific deletion of Il11ra1 have reduced pathogenic signaling and are protected from renal injury-induced inflammation, fibrosis, and failure. In a model of chronic kidney disease, anti-IL11 therapy promotes TEC proliferation and parenchymal regeneration, reverses fibroinflammation and restores renal mass and function. These data highlight IL11-induced mesenchymal transition of injured TECs as an important renal pathology and suggest IL11 as a therapeutic target for restoring stalled endogenous regeneration in the diseased kidney.

Date: 2022
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DOI: 10.1038/s41467-022-35306-1

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