Abstract
BackgroundIncreased gene transcription of hypoxia‐induced mediators of fibrosis in renal tissue has been identified in experimentally induced, ischemic chronic kidney disease (CKD).ObjectiveTo characterize hypoxia‐induced profibrotic pathways in naturally occurring CKD in cats.AnimalsTwelve client‐owned cats with CKD and 8 healthy control cats.MethodsIn this prospective, cross‐sectional study, bilateral renal tissue samples were assessed histologically for inflammation, tubular atrophy, and fibrosis, and by reverse transcription‐quantitative PCR for characterization of transcript levels of hypoxia‐inducible factor‐1α (HIF1A), matrix metalloproteinases‐2 (MMP2), ‐7 (MMP7), and ‐9 (MMP9), tissue inhibitor of metalloproteinase‐1 (TIMP1), transforming growth factor‐β1 (TGFB1), and vascular endothelial growth factor‐A (VEGFA). Linear mixed models were used to compare gene transcription between diseased and healthy kidneys, and to examine the association between transcript levels and serum creatinine concentration for all cats, and between transcript levels and histologic scores of diseased kidneys.ResultsKidneys from cats with CKD had significantly higher transcript levels of HIF1A, MMP2, MMP7, MMP9, TIMP1, and TGFB1 (all P < .001), and lower levels of VEGFA (P = .006) than those from control cats. Transcript levels of MMP7 (P = .05) and TIMP1 (P = .005) were positively associated with serum creatinine in cats with CKD, but not in control cats. In diseased kidneys, transcript levels of MMP2 (P = .002), MMP7 (P = .02), and TIMP1 (P = .02) were positively, whereas those of VEGFA (P = .003) were negatively, associated with histologic score severity.Conclusion and Clinical SignificanceEvaluation of the expression of the corresponding proteins in larger populations could identify therapeutic targets and/or biomarkers of tubulointerstitial fibrosis in cats.
Highlights
Cats were considered for enrollment if they had documented or suspected chronic kidney disease (CKD), based on the presence of 1 or more of the following: urine specific gravity (USG) 14 μg/dL, or renal proteinuria
The present study describes upregulation of gene transcription for several fibrosis mediators, including gene for hypoxia-inducible factor-1α (HIF1A), matrix metalloproteinases-2 (MMP2), MMP7, MMP9, tissue inhibitor of metalloproteinase-1 (TIMP1), and gene for transforming growth factor-β1 (TGFB1), as well as downregulation of the proangiogenic factor vascular endothelial growth factor-A (VEGFA), in renal tissues from cats with naturally occurring CKD, when compared to those from healthy control cats
Gene transcript levels of MMP2, MMP7, and TIMP1 were positively associated with worsening histologic lesion scores
Summary
Tubulointerstitial fibrosis, a key histologic feature of chronic kidney disease (CKD) in cats,[1] is correlated with the degree of functional renal impairment.[2,3] Across mammalian species, this pattern of histologic change is commonly observed in the advanced and end-stages of CKD.[4,5] in cats, renal fibrosis is present from the early stages of disease.[1,3]Growing evidence has emphasized the critical role of tubulointerstitial hypoxia in the development and progression of renal fibrosis and CKD.[6,7,8] the processes leading to fibrosis can initially promote normal tissue repair in response to renal injury,[9] the development of fibrosis has been proposed as a maladaptive response. Accumulation of hypoxia-inducible factor (HIF)-1α in hypoxic regions initiates hypoxia-adaptive responses,[8] and is a key driving force for the progression of CKD in rodents.[11] Vascular endothelial growth factor (VEGF)-A, a potent proangiogenic factor, is stimulated by renal hypoxia via HIF-1α.12,13 Both underexpression and overexpression of VEGF-A have been associated with worsening of kidney disease, demonstrating this cytokine's complex pathophysiologic role.[14] Other fibrogenic factors that have been suggested as central to the development of renal fibrosis under hypoxic conditions include transforming growth factor (TGF)β1,7,15 the matrix metalloproteinases (MMPs), MMP-2, -7, and -9, and their tissue inhibitors (TIMPs).[16,17].
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