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

局部产生的生长因子可能介导急性肾损伤后再生过程中的细胞分化。因此，我们研究了两种不同形式的肝素结合表皮生长因子（EGF）样生长因子（HB-EGF），生长因子家族的新成员，在急性损伤后的肾小管再生的参与。为了评价可溶性（s）HB-EGF的预防和治疗作用，在顺铂诱导的急性肾小管性肾衰竭（ATRF）发作之前或之后向BALB/c小鼠施用重组（r）人（h）s-HB-EGF（250 ng/kg）。ATRF发作后给药可抑制血尿素氮（BUN）和血清肌酐（Cr）的升高。用rh-s-HB-EGF预处理也有类似的效果。组织学上明显的肾小管损伤，其特征是上皮细胞坏死和细胞从肾小管基底膜脱离，在rh s-HB-EGF治疗的小鼠比未治疗的对照组要轻得多。此外，根据5-溴-21-脱氧尿苷（BrdUrd）掺入，rhs-HB-EGF刺激受损的肾上皮细胞中的DNA合成。为了确定HB-EGF的前体形式proHB-EGF在ATRF恢复中的参与，我们构建了稳定表达proHB-EGF（NRK 52 E）的NRK 52 E细胞系<proHB-EGF>，并在三维I型胶原凝胶中培养细胞。NRK 52 E<proHB-EGF>形成模拟肾小管的管状结构，不像仅用空载体转染的NRK 52 E细胞（NRK 52 E<vector>），其仅形成圆形集落。提示HB-EGF可能在抗ATRF和恢复ATRF中起重要作用，并可能具有治疗潜力。

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.