Hyperplasia, hypertrophy, and phenotypic alterations in the distal nephron after acute proximal tubular injury in the rat

Abstract

Background: Little is known about the impact of acute proximal tubular injury and dysfunction on the distal nephron.

Experimental design: Selective necrosis of the kidney proximal convoluted tubule (PCT) was induced in rats by subcutaneous injection of the aminoglycoside gentamicin during 2 days. Damage and repair were measured until complete morphologic recovery after 10 days. Special attention was given to structural and biochemical alterations in the distal nephron.

Results: In control animals, cellular turnover, measured by immunohistochemical staining for proliferating cell nuclear antigen, was higher in distal than in proximal tubules. After injury, the strongly increased cell proliferation in regenerating necrotic PCT was preceded by an equally important proliferation in the distal tubules of the cortex and outer stripe of the outer medulla in the absence of necrosis but displaying enhanced apoptosis. Yet, epithelial vimentin expression was restricted to regenerating PCT. A temporary loss in the amount of immunostainable epidermal growth factor in the distal nephron was paralleled by a similar reduction in Tamm- Horsfall protein and transferrin receptor staining and in peanut and Helix pomatia lectin binding. Furthermore, the epithelial area/nucleus in the cortical distal tubules was increased by 71%, 6 days after the onset of acute renal failure; this hypertrophic condition 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, an excess cell number was accompanied by increased apoptotic activity.

Conclusions: Development of distal tubular hypertrophy after PCT necrosis may be a compensatory response to a transient loss of proximal tubular function. The early reduction in staining for epidermal growth factor 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 regeneration.