Regeneration of acutely injured renal tubules is promoted by a heparin-binding epidermal growth factor-like growth factor (HB-EGF)

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Locally produced growth factors may mediate cell differentiation during regeneration following acute renal injury. Thus, we examined the participation of two different forms of heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), a new member of EGF family of growth factor, in regeneration of renal tubules after acute injury. To evaluate preventive and therapeutic effects of soluble (s) HB-EGF, recombinant (r) human (h) s-HB-EGF (250 ng/kg) was administered to BALB/c mice prior to or after onset of cisplatin-induced acute tubular renal failure (ATRF). Administration after onset of ATRF suppressed increases in blood urea nitrogen (BUN) and serum creatinine (Cr). Pretreatment with rh s-HB-EGF showed a similar effect. Histologically evident tubular injuries, characterized by epithelial cell necrosis and detachment of cells from the tubular basement membrane were much milder in rh s-HB-EGF-treated mice than in untreated controls. Additionally, rh s-HB-EGF stimulated DNA synthesis in damaged renal epithelial ceils according to 5-bromo-21-deoxyuridine (BrdUrd) Incorporation. To determine involvement of a precursor form of HB-EGF, proHB-EGF, in recovery from ATRF, we constructed a line of NRK 52E cells stably expressing proHB-EGF (NRK^<proHB-EGF>) and cultured cells in three-dimensional type I collagen gels. NRK^<proHB-EGF> formed tubule-like structures mimicking renal tubules, unlike NRK 52E cells transfected with empty vector alone (NRK^<vector>), which formed only round colonies. These results Indicates that HB-EGF may function importantly in resistance to and recovery from ATRF, and may have therapeutic potential.