Modulation of Wnt and Hedgehog Signaling Pathways Is Linked to Retinoic Acid‐Induced Amelioration of Chronic Allograft Dysfunction

• Published in: American journal of transplantation Vol. 12; no. 1; pp. 55 - 68
• Main Authors: von Toerne, C., Bedke, J., Safi, S., Porubsky, S., Gretz, N., Loewe, R., Nelson, P. J., Gröne, H.‐J.
• Format: Journal Article
• Language: English
• Published: Malden, USA Blackwell Publishing Inc 01.01.2012; Wiley
• Subjects: Animals; Biological and medical sciences; Chronic allograft dysfunction; Hedgehog Proteins - metabolism; Hedgehog signaling; Medical sciences; Rats; Rats, Inbred F344; renal transplantation; retinoic acid; Signal Transduction; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the urinary system; Tretinoin - metabolism; Wnt Proteins - metabolism; Wnt signaling; Protein wnt; renal transplantation; Retinoid; Homograft; Hedgehog signaling; Homotransplantation; Kidney; Signal transduction; Chronic; Wnt signaling; Treatment; Urinary system; Signaling pathway; Dysfunction; Hedgehog protein; Surgery; Modulation; Graft; Retinoic acid; Chronic allograft dysfunction; Kidney transplantation
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2011.03776.x

Chronic renal allograft damage (CAD) is manifested by a smoldering inflammatory process that leads to transplant glomerulopathy, diffuse interstitial fibrosis and tubular atrophy with loss of tubular structures. Using a Fischer 344 (RT1lvl) to Lewis (RT1l) rat renal allograft model, transcriptomic profiling and pathway mapping, we have previously shown that dynamic dysregulation of the Wnt signaling pathways may underlie progressive CAD. Retinoic acid, an important regulator of differentiation during vertebrate embryogenesis, can moderate the damage observed in this experimental model of CAD. We show here that subsets of the Hedgehog (Hh) and canonical Wnt signaling pathways are linked to the pathophysiology of progressive fibrosis, loss of cilia in epithelia and chronic dysfunction. Oral treatment with 13cis retinoic acid (13cRA) was found to selectively ameliorate the dysregulation of the Hh and canonical Wnt pathways associated with CAD, and lead to a general preservation of cilial structures. Interplay between these pathways helps explain the therapeutic effects of retinoic acid treatment in CAD, and suggests future targets for moderating chronic fibrosing organ damage. Dysregulation of Wnt and Hedgehog signaling pathways may underlie important aspects of progressive experimental allograft damage, and explain the mollifying effects of retinoic acid treatment on chronic damage. See editorial by Fabian and Humphreys on page 5.