Profibrotic gene transcription in renal tissues from cats with ischemia-induced chronic kidney disease

Abstract

OBJECTIVE To characterize transcription of profibrotic mediators in renal tissues of cats with ischemia-induced chronic kidney disease (CKD). SAMPLE Banked renal tissues from 6 cats with experimentally induced CKD (RI group) and 8 healthy control cats. PROCEDURES For cats of the RI group, both kidneys were harvested 6 months after ischemia was induced for 90 minutes in 1 kidney. For control cats, the right kidney was evaluated. All kidney specimens were histologically examined for fibrosis, inflammation, and tubular atrophy. Renal tissue homogenates underwent reverse transcription quantitative PCR assay evaluation to characterize gene transcription of hypoxia-inducible factor-1α (HIF-1α), matrix metalloproteinase (MMP)-2, MMP-7, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), transforming growth factor-β1, and vascular endothelial growth factor A. Gene transcription and histologic lesions were compared among ischemic and contralateral kidneys of the RI group and control kidneys. RESULTS Ischemic kidneys had greater transcript levels of MMP-7, MMP-9, and transforming growth factor-β1 relative to control kidneys and of MMP-2 relative to contralateral kidneys. Transcription of TIMP-1 was upregulated and that of vascular endothelial growth factor A was downregulated in ischemic and contralateral kidneys relative to control kidneys. Transcription of HIF-1α did not differ among kidney groups. For ischemic kidneys, there were strong positive correlations between transcription of HIF-1α, MMP-2, MMP-7, and TIMP-1 and severity of fibrosis. CONCLUSIONS AND CLINICAL RELEVANCE Transcription of genes involved in profibrotic pathways remained altered in both kidneys 6 months after transient renal ischemia. This suggested that a single unilateral renal insult can have lasting effects on both kidneys.

Renal Senescence, Telomere Shortening and Nitrosative Stress in Feline Chronic Kidney Disease

“…Specifically in cats, normal tubules contain large amounts of lipid, and when damage occurs, lipid is released into the interstitium, thus becoming a nidus for inflammation [3]. When considered together with similar observations in human CKD patients [38][39][40][41][42], it is not surprising that telomeres are shortened in cats with CKD, a scenario that would eventually result in critically short telomeres and the triggering of replicative senescence [36,37,[43][44][45].…”

“…In studies assessing gene transcription in feline CKD (both ischemia-induced and naturally occurring), kidneys from CKD cats have been shown to have significantly higher transcript levels of HIF1A, MMPs, and TGF-β [37,45]. VEGF is decreased in feline CKD [37,45,65], which differs from other SASP literature [11]. Nonetheless, there are data to support the induction of senescence and the further exacerbation of disease via the development of SASP in feline CKD.…”

“…Elevated concentrations of IL-8 and TGF-β have been found in the urine of cats with CKD, and urinary TGF-β has been associated with both the degree of fibrosis and inflammation on histopathology, as well as with the initial development of azotemic CKD [65,66]. In studies assessing gene transcription in feline CKD (both ischemia-induced and naturally occurring), kidneys from CKD cats have been shown to have significantly higher transcript levels of HIF1A, MMPs, and TGF-β [37,45]. VEGF is decreased in feline CKD [37,45,65], which differs from other SASP literature [11].…”

Mutual Antagonism of Hypoxia-Inducible Factor Isoforms in Cardiac, Vascular, and Renal Disorders

“…However, prolonged HIF-1α activation exerts deleterious effects on the kidney, even if the causal mechanism is hypoxia or ischemia ( Figure 2 ) ( 72 ). Sustained upregulation of HIF-1α promotes epithelial to mesenchymal transition in renal tubular epithelial cells ( 73 ).…”

“…Sustained upregulation of HIF-1α promotes epithelial to mesenchymal transition in renal tubular epithelial cells ( 73 ). In chronic kidney disease, sustained signaling through HIF-1α promotes proinflammatory and profibrotic pathways in the glomerulus and renal tubules ( 72 , 74 , 75 ), which is characterized by activation of inflammation-related cytokines, profibrotic gene transcription, macrophage infiltration and collagen deposition, mesangial cell proliferation, and tubulo-interstitial inflammation ( 74 , 75 , 76 , 77 ). Experimental suppression of HIF-1α attenuates mesangial matrix expansion and glomerulosclerosis and alleviates tubulointerstitial fibrosis ( 75 , 76 , 78 ).…”