重用感受受体激活剂药物cinacalcet用于ADPKD治疗
Pattareeya Yottasan1, Tifany Chu1, Parth D Chhetri1
1Department of Pediatrics, University of California, San Francisco, 513 Parnassus Avenue, HSE 1244, San Francisco, CA, 94143, United States.
Translational research : the journal of laboratory and clinical medicine
|November 22, 2023
概括
作为CaSR激活剂的cinacalcet对治疗自体主导多囊性脏病 (ADPKD) 有前途. 它有效地减少了ADPKD模型中的囊生长和细胞增殖,提供了潜在的新疗法选择.
科学领域:
- 腎臟病學 (nephrology) 是一種醫學.
- 药理学 药理学是指药理学的学科.
- 细胞生物学 细胞生物学
背景情况:
- 自体主导多囊性病 (ADPKD) 是一种遗传性疾病,其特征是逐渐的囊发育和扩大,最终导致功能衰竭.
- 目前用于ADPKD的治疗方法,如托尔瓦普坦,具有局限性,包括严重的副作用,如肝毒性,突出了对更安全和更有效疗法的未满足的临床需求.
- 细胞外感应受体 (CaSR) 在上皮离子运输中发挥作用,其通过FDA批准的cinacalcet激活可能提供一种新的治疗方法.
研究的目的:
- 调查CaSR激活剂cinacalcet作为自身主导多囊性病 (ADPKD) 的潜在治疗方法的疗效.
- 在ADPKD的临床前模型中评估cinacalcet对囊形成,细胞增殖和离子运输的影响.
主要方法:
- 利用麦丁-达比犬 (MDCK) 细胞和ADPKD的小鼠模型 (Pkd1flox/flox;Ksp-Cre) 来评估cinacalcet的治疗潜力.
- 测量短路电流 (Isc) 以评估化物 (Cl-) 分泌和CFTR活性,cAMP水平,细胞增殖和细胞生成对cinacalcet治疗的反应.
- 向ADPKD小鼠进行皮下注射cinacalcet,并评估脏囊指数.
主要成果:
- 西纳卡塞特显著降低了MDCK细胞中cAMP诱导的Cl-分泌和CFTR活性.
- 用cinacalcet治疗抑制了福斯科林诱导的cAMP在MDCK细胞中的60%升高,而固醇酶 (PDE) 抑制剂可以逆转效应.
- 在ADPKD的细胞和动物模型中,cinacalcet证明了细胞增殖,囊形成和囊扩大的度依赖性降低,小鼠囊指数降低了20%.
- 在人类ADPKD细胞中观察到囊扩大和细胞增殖的显著减少.
结论:
- 西纳卡塞特有效地减轻ADPKD的关键病理机制,包括减少离子分泌,cAMP水平,细胞增殖和囊生长.
- 这些发现表明,使用已确定的安全性概况,可以将cinacalcet重新定位为ADPKD的新有效治疗方法.
- 需要对用于ADPKD治疗的cinacalcet进行进一步的临床研究.
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