HYPERPLASIA, HYPERTROPHY, AND PHENOTYPIC ALTERATIONS IN THE DISTAL NEPHRON AFTER ACUTE PROXIMAL TUBULAR INJURY IN THE RAT

BACKGROUND: Little is known about the impact of acute proximal tubular injury and dysfunction on the distal nephron. EXPERIMENTAL DESIGN: Se lective necrosis of the kidney proximal convoluted tubule (PCT) was in duced in rats by subcutaneous injection of the aminoglycoside gentamic in during 2 days. Damage and repair were measured until complete morph ologic recovery after 10 days. Special attention was given to structur al and biochemical alterations in the distal nephron. RESULTS: In cont rol animals, cellular turnover, measured by immunohistochemical staini ng for proliferating cell nuclear antigen, was higher in distal than i n proximal tubules. After injury, the strongly increased cell prolifer ation in regenerating necrotic PCT was preceded by an equally importan t proliferation in the distal tubules of the cortex and outer stripe o f the outer medulla in the absence of necrosis but displaying enhanced apoptosis. Yet, epithelial vimentin expression was restricted to rege nerating PCT. A temporary loss in the amount of immunostainable epider mal growth factor in the distal nephron was paralleled by a similar re duction in Tamm- Horsfall protein and transferrin receptor staining an d in peanut and Helix pomatia lectin binding. Furthermore, the epithel ial area/nucleus in the cortical distal tubules was increased by 71%, 6 days after the onset of acute renal failure; this hypertrophic condi tion was confirmed ultrastructurally. After full recovery of the PCT, a second burst in proliferative activity occurred in the hypertrophic distal segments in the absence of apoptosis. In the regenerated PCT, a n excess cell number was accompanied by increased apoptotic activity. CONCLUSIONS: Development of distal tubular hypertrophy after PCT necro sis may be a compensatory response to a transient loss of proximal tub ular function. The early reduction in staining for epidermal growth fa ctor and other distal tubular markers in the presence of apoptosis and hyperplasia indicates transient phenotypic simplification and implies that renal epidermal growth factor is unlikely to control PCT regener ation.