Chronic kidney disease (CKD) in humans and cats is a major cause of death. In both species, tubulointerstitial fibrosis (TIF) is the major histopathological feature, which is the product of collagen accumulation and deposition in the extracellular matrix (ECM). Transglutaminase 2 (TG2) is a calcium-dependent enzyme, secreted by renal and inflammatory cells under stress. TG2 crosslinks collagen protein, promoting fibrosis deposition and progression of disease. In this research project, azotaemic and non-azotaemic feline kidney tissue were employed to determine the TG2 association with renal fibrosis and to test (in vitro) the feasibility of the TG2 inhibition. A rodent model of renal warm ischaemia was used to generate tubulointerstitial fibrosis without glomerulosclerosis and to determine the effect of transglutaminase inhibitors on the development of TIF. The transglutaminase pathway was associated with TIF in either the cat or the rat. In the feline kidney tissue, the inhibition of TG activity was achieved using both a TG2 inhibitory monoclonal antibody and a chemical TG inhibitor. In the rat model of RWI, reduction in TIF fibrosis deposition was achieved when using an intrarenal TG chemical inhibitor. Glomerular TG2 expression and fibrosis was not observed in either the cat or the rat. The TG pathway inhibition may represent a novel approach to reduce or stop the development of TIF in cats and humans. RWI rodent model may be an interventional model to study TIF in the cat. The understanding of the glomerular resistance to develop fibrosis in the cat with CKD and the rat following RWI may be of relevance in the generation of treatments to prevent or delay glomerulosclerosis in the man. The naturally occurring model of feline CKD may be an important research approach to study CKD in the man and to generate evidence based veterinary medicine.