Abstract
Chronic kidney disease (CKD) is common in both geriatric cats and aging humans, and is pathologically characterised by chronic tubulointerstitial inflammation and fibrosis in both species. Cats with CKD may represent a spontaneously occurring, non-rodent animal model of human disease, however little is known of feline renal cell biology. In other species, TGF-β1 signalling in the proximal tubular epithelium is thought to play a key role in the initiation and progression of renal fibrosis. In this study, we first aimed to isolate and characterise feline proximal tubular epithelial cells (FPTEC), comparing them to human primary renal epithelial cells (HREC) and the human proximal tubular cell line HK-2. Secondly, we aimed to examine and compare the effect of human recombinant TGF-β1 on cell proliferation, pro-apoptotic signalling and genes associated with epithelial-to-mesenchymal transition (EMT) in feline and human renal epithelial cells. FPTEC were successfully isolated from cadaverous feline renal tissue, and demonstrated a marker protein expression profile identical to that of HREC and HK-2. Exposure to TGF-β1 (0–10 ng/ml) induced a concentration-dependent loss of epithelial morphology and alterations in gene expression consistent with the occurrence of partial EMT in all cell types. This was associated with transcription of downstream pro-fibrotic mediators, growth arrest in FPTEC and HREC (but not HK-2), and increased apoptotic signalling at high concentrations of TGF- β1. These effects were inhibited by the ALK5 (TGF-β1RI) antagonist SB431542 (5 μM), suggesting they are mediated via the ALK5/TGF-β1RII receptor complex. Taken together, these results suggest that TGF-β1 may be involved in epithelial cell dedifferentiation, growth arrest and apoptosis in feline CKD as in human disease, and that cats may be a useful, naturally occurring model of human CKD.
Highlights
Chronic kidney disease (CKD) is common in geriatric cats, with a reported prevalence of 28– 50% [1, 2]
human primary renal epithelial cells (HREC) cultures were initially heterogeneous before forming a cuboidal monolayer which was maintained over the range of guaranteed population doublings (Fig 1I)
The first goal of the present study was to validate a method for the culture of feline PTEC, and these cells were characterised alongside primary HREC and HK-2—a human cell line which has been reported to retain characteristics of proximal tubular cells in vitro [17, 33]
Summary
Chronic kidney disease (CKD) is common in geriatric cats, with a reported prevalence of 28– 50% [1, 2]. A cell culture model of the feline tubular epithelium would be a valuable tool for elucidating the molecular mechanisms underlying the effects of factors associated with disease progression at the whole animal level. This would provide new insights into the pathogenesis of feline CKD, potentially informing future development of novel treatments for the management of veterinary cases and providing insight into the suitability of the cat as a model of human disease. There are currently no well-characterised feline tubular epithelial cell lines available, or published studies describing primary renal cell cultures from feline tissue
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