Abstract
Chronic kidney disease (CKD) is a common outcome of many kidney diseases. Interstitial fibrosis and tubular atrophy (IFTA) is a histologic hallmark of CKD. Hematuria is a common symptom in many human kidney diseases. Free hemoglobin may affect tubular epithelial cells by generating reactive oxygen species (ROS). Epithelial–mesenchymal transition (EMT) of the tubular epithelial cells has been shown to play an important role in the IFTA development. The aim of this study was to determine the effects of chronic hematuria on the CKD progression in 5/6 nephrectomy (5/6NE) rat model of CKD. 5/6 NE rats were treated with oral warfarin (0.5 mg/kg/day) or vehicle (control). The animals were monitored for 26 weeks, while prothrombin time (PT), serum creatinine (SCr), and hematuria were measured weekly. Staining for iron, trichrome, and EMT (vimentin, E-cadherin, smooth muscle actin) markers was performed on the remnant kidneys. ROS were detected in the kidneys by protein carbonyl assay and immunohistochemistry for heme oxygenase 1 (HMOX1), at the end of the study. Apoptosis was detected by TUNEL assay. Warfarin treatment resulted in a PT increase 1.5–2.5 times from control and an increase in hematuria and SCr. Histologically, warfarin-treated animals had more iron-positive tubular epithelial cells and increased IFTA as compared to control (42.9 ± 17% vs. 18.3 ± 2.6%). ROS were increased in the kidney in warfarin-treated rats. The number of tubules that show evidence of EMT was significantly higher in warfarin-treated 5/6NE as compared to control 5/6NE rats. The number of apoptotic tubular epithelial cells was higher in warfarin-treated 5/6 NE rats. Chronic hematuria results in increased iron-positive tubular epithelial cells, EMT, apoptosis, and more prominent IFTA in CKD rats. Our data suggest an important role of chronic hematuria in the progression of CKD.
Highlights
Chronic kidney disease (CKD) is a significant health burden that is associated with premature mortality, decreased quality of life, and increased healthcare expenditures
We have previously demonstrated an important role of oxidative stress in the pathogenesis of acute kidney injury (AKI) associated with acute glomerular hemorrhage [5]
Throughout the study period, both groups experienced a steady rise in SCr, but the elevation was higher in 5/6 NE rats treated with warfarin compared to the control group on water
Summary
Chronic kidney disease (CKD) is a significant health burden that is associated with premature mortality, decreased quality of life, and increased healthcare expenditures. Many kidney disorders are characterized by hematuria and exposure of the tubular epithelial cells to free hemoglobin and iron. Some patients, such as those with IgA nephropathy and thin basement membrane disease, have chronic microscopic hematuria, and some diseases, such as crescentic and necrotizing glomerulonephritis, are accompanied by short-lived but large hematuria. The 5/6 nephrectomy (5/6NE) model is a widely accepted model of CKD, and it is characterized by progressive glomerular injury and increased IFTA [11,12,13] Using this model, we showed in previous studies that a single episode of large hematuria does not affect the progression of CKD [14]
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