Role of Transcription Factors and Growth Factors in Renal Fibrosis in Felines with Kidney Dysfunction

Objectives Renal fibrosis, a key feature of progressive chronic kidney dysfunction, is characterized by an excessive deposition of extracellular matrix proteins following injury. It is generally the result of sustained glomerular or tubular injury induced by several factors including pro-inflammatory proteins and oxidative stress. We investigated changes in gene expression that could contribute to renal fibrosis in cats with kidney disease or calcium oxalate stone formers (CaOx) at necropsy Methods At the time of death the circulating levels of creatinine, SDMA, as well as blood urea nitrogen, all markers of kidney decline in cats, were significantly higher in cats with renal disease (n = 11) or CaOx (n = 12) when compared to controls (n = 19). Results Using RNAseq in renal cortex tissue, we found a significant decrease in Krüppel-like factor 15 (KLF15), a zinc-finger transcription factor in cats with kidney disease (–1.99 fold, P < 0.001) and CaOx (–1.89, P < 0.001) when compared to controls. Given that KLF15 can attenuate fibrosis by inhibiting the actions of TGF-β, a key regulator of fibrosis, our results indicate that a lower level of KLF15 in kidney disease and CaOx may contribute to renal fibrosis. Consistent with this, there was an increase in all three forms of transforming growth factor-β (TGF-β1, TGF-β2, and TGF-β3), a potent initiator of renal fibrosis, in both groups compared to controls. There was also a significant increase in the expression of BMP-1, a growth factor belonging to the TGF-β superfamily and pro-fibrotic, in cats with kidney disease (2.48 fold) and stone formers (1.72 fold), compared to controls (both P < 0.01). Further, BMP-7, an endogenous inhibitor of TGF-β signaling in fibrosis and whose potential therapeutic role in treating CKD and reversing fibrosis has been documented, was modestly decreased in both groups (both less than 1.5 fold) compared to controls. A decrease was also seen in CRIM 1, a protein associated with podocyte filtration function and whose reduction is associated with fibrosis, in both groups Conclusions Our data show evidence of renal fibrosis markers that could have contributed to a progressive decline in kidney function. In summary, a nutritional therapy to slow the progression of kidney dysfunction may benefit from the inclusion of dietary ingredients that attenuate renal fibrosis in cats. Funding Sources Funded by Hills PNC, Inc.