Light and electron microscopic characterization of the proliferative response induced by tobramycin in rat kidney...

Administration of aminoglycoside antibiotics is frequently associated with tubular necrosis which can eventually lead to renal dysfunction. Previously, we have shown that renal tissue injury due to aminoglycoside nephrotoxicity elicits a process of tissue repair characterized by stimulation of cell proliferation. The present study was undertaken to examine both quantitatively and qualitatively the cell proliferation associated with renal tissue repair. Female Sprague-Dawley rats (180-200 g body weight) were treated ip for 10 days with various doses of tobramycin (10, 20, or 50 mg/kg twice daily). Each animal received 200 microCi [3H]thymidine 1 hr before sacrifice to evaluate the extent of cell proliferation in renal cortex. The rate of DNA synthesis in renal cortex was estimated by measuring the specific radioactivity of the nucleic acid. The frequency and localization of S-phase cells in cortex tissue were determined on paraffin and plastic tissue sections processed for histoautoradiography. In addition, the ultrastructure of proliferating cells was characterized by electron microscopic examination of consecutive ultrathin sections. An excellent correlation (r = 0.993) was found between the rate of DNA synthesis and the frequency of S-phase cells evaluated in rats receiving various doses of tobramycin. The stimulation of cell proliferation involved mostly proximal tubular cells and interstitial cells. The latter cells had the ultrastructural appearance of fibroblasts at various stages of differentiation. Similarly, S-phase cells in proximal tubules were either fully differentiated epithelial cells or immature elements. Taken together, the present experimental data illustrate the capacity of the kidney to trigger complex tissue reactions in response to nephrotoxic injury.