ALTERED GROWTH-FACTOR EXPRESSION DURING TOXIC PROXIMAL TUBULAR-NECROSIS AND REGENERATION

Growth factor expression was investigated during the regenerative resp onse after toxic proximal tubular necrosis. Therefore, gentamicin was administered to rats to achieve an experimental model, characterized b y the appearance of segment-specific proximal tubular necrosis, that i s followed by a regenerative response leading to functional and morpho logical 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 affect ed by severe toxic necrosis one day after the treatment, while maximal necrosis was observed at days 2 to 4. Only minor injuries were notice d in the other renal compartments. The proliferative response started in the interstitial cells first. The major proliferative wave was loca lized in the convoluted part of the proximal tubules at days 6 to 8, a lthough proliferation was also prominent among non-proximal tubular ce lls. A profound interstitial infiltration of leukocytes, including mac rophages and T lymphocytes, was observed. Ten days after the treatment the functional and morphological recovery were completed. Slot blot h ybridization revealed a decreased EGF and IGF-I mRNA expression from t he 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 obse rvations, No major changes in the expression of TGF-alpha, TGF-beta1 a nd c-fos were detected. Renal EGF-immunoreactivity disappeared from th e luminal plasma membrane of the distal tubular cells analogous to the results obtained at the messenger level. However, EGF-staining was lo st in the cortex first, hence a topographical association between the loss of EGF-immunoreactivity in the distal tubules and the observed ne crotic lesions in the proximal tubules was found. Immunoreactive EGF w as never observed in proximal tubular cells from normal, injured or re generating rat kidneys. We conclude that in this experimental rat mode l, EGF and IGF-I mRNA expression is decreased during the regenerative response upon severe toxic tubular necrosis. No evidence for a partici pation of EGF or IGF-I of renal origin in the recovery of the kidney i s found.