A Distinct Population of Tubular Cells in the Distal S3 Segment Contributes to S3 Segment Regeneration in Rats following Acute Renal Failure Induced by Uranyl Acetate

Abstract

Background: We previously reported that early regenerating cells found at the distal area of the S3 segment of the nephron (designated as target cells) were label-retaining cells in uranyl acetate (UA)-induced acute renal failure (ARF) in rats. In this study, we examined the contribution of these target cells to S3 segment repair after UA treatment. We also discriminated target cells from bromodeoxyuridine (BrdU)-label-retaining cells labeled under normal conditions and examined their capacity to proliferate following a second insult and their resistance to 5-fluorouracil (5-FU). Methods: Target cells were labeled and tracked using a ³H-thymidine pulse/chase approach after UA (4 mg/kg) injection to rats. Normal rats were labeled with BrdU, and cells positive for BrdU and Ki67 were analyzed after UA treatment. The kinetics of target cells was examined after a second dose of UA and treatment with 5-FU. Results: The target cells were strongly labeled by ³H-thymidine and were predominantly found in the distal quarter of the S3 segment until 40 weeks after generating ‘label-diluted’ cells throughout the S3 segment. Cells labeled with BrdU under normal conditions did not express Ki67 after UA treatment but target cells were Ki67-positive. The target cells underwent further proliferation following the second treatment with UA and were transiently arrested by 5-FU treatment at G0/G1 after UA. Conclusions: The target cells are slow-cycling cells, resistant to 5-FU treatment and have the capacity to undergo further proliferation following a second insult with UA. These data suggest the presence of a distinct population of cells that can regenerate the S3 segment in UA-induced ARF.