Indian Hedgehog release from TNF-activated renal epithelia drives local and remote organ fibrosis.

in Science translational medicine by Eoin D O'Sullivan, Katie J Mylonas, Cuiyan Xin, David P Baird, Cyril Carvalho, Marie-Helena Docherty, Ross Campbell, Kylie P Matchett, Scott H Waddell, Alexander D Walker, Kevin M Gallagher, Siyang Jia, Steve Leung, Alexander Laird, Julia Wilflingseder, Michaela Willi, Maximilian Reck, Sarah Finnie, Angela Pisco, Sabrina Gordon-Keylock, Alexander Medvinsky, Luke Boulter, Neil C Henderson, Kristina Kirschner, Tamir Chandra, Bryan R Conway, Jeremy Hughes, Laura Denby, Joseph V Bonventre, David A Ferenbach

TLDR

  • The study investigates how inflammation can cause tissue damage and scarring in the kidney and heart. The study found that a protein called Indian Hedgehog (IHH) is involved in this process and can be targeted with therapies to prevent scarring.

Abstract

Progressive fibrosis is a feature of aging and chronic tissue injury in multiple organs, including the kidney and heart. Glioma-associated oncogene 1 expressing (Gli1) cells are a major source of activated fibroblasts in multiple organs, but the links between injury, inflammation, and Gli1cell expansion and tissue fibrosis remain incompletely understood. We demonstrated that leukocyte-derived tumor necrosis factor (TNF) promoted Gli1cell proliferation and cardiorenal fibrosis through induction and release of Indian Hedgehog (IHH) from renal epithelial cells. Using single-cell-resolution transcriptomic analysis, we identified an "inflammatory" proximal tubular epithelial (iPT) population contributing to TNF- and nuclear factor κB (NF-κB)-induced IHH production in vivo. TNF-induced Ubiquitin D () expression was observed in human proximal tubular cells in vitro and during murine and human renal disease and aging. Studies using pharmacological and conditional genetic ablation of TNF-induced IHH signaling revealed that IHH activated canonical Hedgehog signaling in Gli1cells, which led to their activation, proliferation, and fibrosis within the injured and aging kidney and heart. These changes were inhibited in mice bydeletion in-expressing cells or by pharmacological blockade of TNF, NF-κB, or Gli1 signaling. Increased amounts of circulating IHH were associated with loss of renal function and higher rates of cardiovascular disease in patients with chronic kidney disease. Thus, IHH connects leukocyte activation to Gli1cell expansion and represents a potential target for therapies to inhibit inflammation-induced fibrosis.

Overview

  • The study investigates the link between injury, inflammation, and Gli1cell expansion in tissue fibrosis, specifically in the kidney and heart. The study uses single-cell-resolution transcriptomic analysis and pharmacological and conditional genetic ablation to understand the mechanisms underlying this link. The primary objective of the study is to identify the role of Indian Hedgehog (IHH) in Gli1cell activation, proliferation, and fibrosis in the injured and aging kidney and heart.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions, including the effects of leukocyte-derived tumor necrosis factor (TNF) on Gli1cell proliferation and cardiorenal fibrosis. The study identifies an
  • proximal tubular epithelial (iPT) population contributing to TNF- and nuclear factor κB (NF-κB)-induced IHH production in vivo. TNF-induced Ubiquitin D () expression was observed in human proximal tubular cells in vitro and during murine and human renal disease and aging. Studies using pharmacological and conditional genetic ablation of TNF-induced IHH signaling revealed that IHH activated canonical Hedgehog signaling in Gli1cells, which led to their activation, proliferation, and fibrosis within the injured and aging kidney and heart. These changes were inhibited in mice by deletion of IHH-expressing cells or by pharmacological blockade of TNF, NF-κB, or Gli1 signaling. Increased amounts of circulating IHH were associated with loss of renal function and higher rates of cardiovascular disease in patients with chronic kidney disease. The study's findings suggest that IHH connects leukocyte activation to Gli1cell expansion and represents a potential target for therapies to inhibit inflammation-induced fibrosis.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The study identifies a potential target for therapies to inhibit inflammation-induced fibrosis, which could have a significant impact on the treatment of chronic kidney disease and other age-related diseases. The study also highlights the importance of understanding the mechanisms underlying tissue fibrosis and the role of inflammation in this process. Future research directions could include further investigation of the role of IHH in tissue fibrosis, the development of targeted therapies to inhibit IHH signaling, and the exploration of other potential targets for the treatment of inflammation-induced fibrosis.
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