Investigation of the transforming growth factor-beta 1 signalling pathway as a possible link between hyperphosphataemia and renal fibrosis in feline chronic kidney disease

Lawson, J.S.; Syme, H.M.; Wheeler-Jones, C.P.D.; Elliott, J.

Abstract

Chronic kidney disease (CKD) is common in geriatric cats, and is characterised in the majority of cases by tubulointerstitial inflammation and fibrosis. Hyperphosphataemia is a frequent complication of CKD and is independently associated with severity of renal fibrosis and disease progression. Transforming growth factor-beta 1 (TGF-β1) signalling is thought to be a convergent pathway which mediates the progression of renal fibrosis in CKD. The aims of this study were to explore the interaction between increased extracellular phosphate and the TGF-β1 signalling pathway by investigating: (a) the effect of a commercially available, phosphate-restricted, diet on urinary TGF-β1 excretion in cats with CKD; and (b) the role of increased extracellular phosphate in regulating proliferation, apoptosis, and expression of genes related to TGF-β1 signalling and extracellular matrix (ECM) production in feline proximal tubular epithelial cells (FPTEC) and cortical fibroblasts from cats with azotaemic CKD (CKD-FCF).

The dietary intervention study revealed no effect of dietary phosphate restriction on urinary active TGF-β1 excretion after 4–8 weeks (P = 0.98), despite significantly decreasing serum phosphate (P < 0.001). There was no effect of increased growth media phosphate concentration (from 0.95 mM to 2 mM and 3.5 mM) on proliferation (P = 0.99) and apoptotic activity in FPTEC (P = 0.22), or expression of genes related to ECM production and the TGF-β1 signalling pathway in FPTEC and CKD-FCF (P > 0.05). These findings suggest the beneficial effects of dietary phosphate restriction on progression of feline CKD may not occur through modulation of renal TGF-β1 production, and do not support a direct pro-fibrotic effect of increased extracellular phosphate on feline renal cells.

Citation

Lawson, J., Syme, H., Wheeler-Jones, C., & Elliott, J. (2020). Investigation of the transforming growth factor-beta 1 signalling pathway as a possible link between hyperphosphataemia and renal fibrosis in feline chronic kidney disease. The Veterinary Journal, 267, 105582. https://doi.org/10.1016/j.tvjl.2020.105582

• Journal Article Type: Article
• Acceptance Date: Nov 16, 2020
• Publication Date: Nov 28, 2020
• Deposit Date: Jun 21, 2021
• Publicly Available Date: Jun 21, 2021
• Journal: The Veterinary Journal
• Print ISSN: 1090-0233
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 267
• Pages: 105582
• DOI: https://doi.org/10.1016/j.tvjl.2020.105582
• Keywords: Animal Science and Zoology; General Veterinary
• Public URL: https://rvc-repository.worktribe.com/output/1549418
• Additional Information: This article is maintained by: Elsevier; Article Title: Investigation of the transforming growth factor-beta 1 signalling pathway as a possible link between hyperphosphataemia and renal fibrosis in feline chronic kidney disease; Journal Title: The Veterinary Journal; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.tvjl.2020.105582; Content Type: article; Copyright: © 2021 The Authors. Published by Elsevier Ltd.