Altered growth factor expression during toxic proximal tubular necrosis and regeneration

Abstract

Growth factor expression was investigated during the regenerative response after toxic proximal tubular necrosis. Therefore, gentamicin was administered to rats to achieve an experimental model, characterized by the appearance of segment-specific proximal tubular necrosis, that is followed by a regenerative response leading to functional and morphological recovery in a limited time. Four days after the administration of the highest dose, serum creatinine rose to a mean value of 5.8 mg/dl and returned to normal values ten days after the treatment. The S1-S2 segment of the proximal tubules in the cortex became clearly affected by severe toxic necrosis one day after the treatment, while maximal necrosis was observed at days 2 to 4. Only minor injuries were noticed in the other renal compartments. The proliferative response started in the interstitial cells first. The major proliferative wave was localized in the convoluted part of the proximal tubules at days 6 to 8, although proliferation was also prominent among non-proximal tubular cells. A profound interstitial infiltration of leukocytes, including macrophages and T lymphocytes, was observed. Ten days after the treatment the functional and morphological recovery were completed. Slot blot hybridization revealed a decreased EGF and IGF-I mRNA expression from the start of the observation period. While IGF-I mRNA had regained its normal expression at day 10, EGF mRNA was still below control levels. The PDGF-B transcript became more abundant towards the end of our observation. No major changes in the expression of TGF-alpha, TGF-beta 1 and c-fos were detected. Renal EGF-immunoreactivity disappeared from the luminal plasma membrane of the distal tubular cells analogous to the results obtained at the messenger level. However, EGF-staining was lost in the cortex first, hence a topographical association between the loss of EGF-immunoreactivity in the distal tubules and the observed necrotic lesions in the proximal tubules was found. Immunoreactive EGF was never observed in proximal tubular cells from normal, injured or regenerating rat kidneys. We conclude that in this experimental rat model, EGF and IGF-I mRNA expression is decreased during the regenerative response upon severe toxic tubular necrosis. No evidence for a participation of EGF or IGF-I of renal origin in the recovery of the kidney is found.