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| Item Type: | Article |
|---|---|
| Title: | Targeting endogenous kidney regeneration using anti-IL11 therapy in acute and chronic models of kidney disease |
| Creators Name: | Widjaja, A.A. and Viswanathan, S. and Shekeran, S.G. and Adami, E. and Lim, W.W. and Chothani, S. and Tan, J. and Goh, J.W.T. and Chen, H.M. and Lim, S.Y. and Boustany-Kari, C.M. and Hawkins, J. and Petretto, E. and Hübner, N. and Schafer, S. and Coffman, T.M. and Cook, S.A. |
| 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. |
| Keywords: | Acute Kidney Injury, Fibrosis, Inflammation, Interleukin-11 Receptor alpha Subunit, Kidney, Kidney Tubules, Nephritis, Regeneration, Animals, Mice |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 13 |
| Number: | 1 |
| Page Range: | 7497 |
| Date: | 5 December 2022 |
| Official Publication: | https://doi.org/10.1038/s41467-022-35306-1 |
| PubMed: | View item in PubMed |
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