Fight-or-flight: murine unilateral ureteral obstruction causes extensive proximal tubular degeneration, collecting duct dilatation, and minimal fibrosis

Abstract

Forbes MS, Thornhill BA, Minor JJ, Gordon KA, Galarreta CI, Chevalier RL. Fight-or-flight: murine unilateral ureteral obstruction causes extensive proximal tubular degeneration, collecting duct dilatation, and minimal fibrosis. Unilateral ureteral obstruction (UUO) is the most widely used animal model of progressive renal disease. Although renal interstitial fibrosis is commonly used as an end point, recent studies reveal that obstructive injury to the glomerulotubular junction leads to the formation of atubular glomeruli. To quantitate the effects of UUO on the remainder of the nephron, renal tubular and interstitial responses were characterized in mice 7 and 14 days after UUO or sham operation under anesthesia. Fractional proximal tubular mass, cell proliferation, and cell death were measured by morphometry. Superoxide formation was identified by nitro blue tetrazolium, and oxidant injury was localized by 4-hydroxynonenol and 8-hydroxydeoxyguanosine. Fractional areas of renal vasculature, interstitial collagen, ␣-smooth muscle actin, and fibronectin were also measured. After 14 days of UUO, the obstructed kidney loses 19% of parenchymal mass, with a 65% reduction in proximal tubular mass. Superoxide formation is localized to proximal tubules, which undergo oxidant injury, apoptosis, necrosis, and autophagy, with widespread mitochondrial loss, resulting in tubular collapse. In contrast, mitosis and apoptosis increase in dilated collecting ducts, which remain patent through epithelial cell remodeling. Relative vascular volume fraction does not change, and interstitial matrix components do not exceed 15% of total volume fraction of the obstructed kidney. These unique proximal and distal nephron cellular responses reflect differential "fight-or-flight" responses to obstructive injury and provide earlier indexes of renal injury than do interstitial compartment responses. Therapies to prevent or retard progression of renal disease should include targeting proximal tubule injury as well as interstitial fibrosis. apoptosis; fibrosis; oxidant injury; chronic kidney disease CHRONIC RENAL DISEASE, regardless of etiology, leads ultimately to nephron loss and renal fibrosis. The model of murine unilateral ureteral obstruction (UUO) has been widely employed to study the underlying mechanisms of progressive chronic kidney disease, most focusing on interstitial fibrosis as the final common pathway (43). Extensive formation of atubular glomeruli in this model was revealed by loss of Lotus tetragonolobus lectin binding from cells forming Bowman's capsule as well as from cells of the glomerulotubular junction (14). Through a process of epithelial cell phenotypic transition and remodeling, the urinary pole of Bowman's capsule is sealed off from the atrophic proximal tubular segment (14). To determine the temporal evolution of the lesions in the entire nephron, the present study was undertaken to examine the segmental renal tubular responses following 7 and 14 days of UUO. The results reveal segment-specific responses to UUO that c...

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