Indian Hedgehog release from renal epithelia drives local and remote organ fibrosis

Abstract Chronic kidney disease (CKD) and ageing inhibit tissue regeneration and increase risks of organ fibrosis and cardiovascular disease. Increased numbers of leukocytes are present in the circulation and within the kidney of ageing individuals and patients with CKD where they correlate with progressive fibrosis. The involvement of activated leukocytes in progressive renal and systemic fibrosis remains incompletely understood. Here we show that renal leukocyte derived tumour necrosis factor alpha (TNFα) promotes renal and cardiac fibrosis via downstream induction of Indian Hedgehog (IHH). We identify the Ubiquitin D expressing ‘inflammatory’ proximal tubular epithelia (iPT) population responsible for TNFα/NFκB induced IHH production. iPT cells are upregulated in the kidney in experimental murine and human renal disease and ageing. iPT derived IHH activates canonical Hedgehog signalling in Gli1+ stromal cells, inducing their activation, proliferation and fibrosis in the surrounding kidney and in remote organs including the heart. This can be inhibited by selective genetic Ihh deletion from Pax8 expressing renal epithelia, or pharmacological blockade of TNFα, NFκB or Hedgehog signalling. This data connects inflammation to progressive renal and cardiac fibrosis and identifies new targets for anti-fibrotic therapies.