Combination therapy with telmisartan and oxacalcitriol suppresses the progression of murine adriamycin nephropathy.
Combination therapy with telmisartan and oxacalcitriol suppresses the progression of murine adriamycin nephropathy.
复制标题
替米沙坦和奥沙骨化三醇的联合治疗可抑制小鼠阿霉素肾病的进展。
作者：
Jeong KH;Asanuma K;Lydia A;Takagi M;Asao R;Kodama F;Asanuma E;Tomino Y.
背景肾素-血管紧张素系统的阻断在抑制肾脏疾病的进展中起着关键作用。在阿霉素(ADR)诱导的肾病模型中，这种疗法是否与维生素D或其类似物联合使用是否具有额外的效果尚不清楚。方法我们评估了血管紧张素II 1型受体阻滞剂(替米沙坦)和维生素D类似物(草钙化三醇)联合使用对小鼠ADR诱导的肾病(9.5 mg/kg单次静脉注射)的影响。结果ADR肾病患者在30天内出现进行性蛋白尿和肾小球硬化，并伴有裂隙隔(SD)相关蛋白表达减少、足细胞数量减少和收缩压升高。单独使用替米沙坦或草钙化三醇治疗可适度改善肾脏损伤。联合治疗最有效地减少了蛋白尿和肾小球硬化。这些效应伴随着SD相关蛋白的恢复，足细胞凋亡的减少，以及防止肾小球中足细胞的枯竭。替米沙坦、草钙化三醇和联合治疗对收缩压有相似的降低作用。在培养的小鼠足细胞中，阿霉素刺激Bax/Bcl2的表达，Hoechst 33342染色检测细胞凋亡。替米沙坦或草钙三醇可有效地抑制这些变化，但联合治疗最有效地减少了这些影响。结论这些数据表明，肾素-血管紧张素系统阻滞剂和维生素D类似物的应用有效地预防了ADR肾病的肾脏损伤。观察到的肾脏损伤的改善可能部分归因于足细胞的抗凋亡作用。
BackgroundBlockade of the renin-angiotensin system plays a key role in suppressing the progression of renal diseases. It has not been well established whether this therapy provides additional effects when combined with vitamin D or its analog in a model of adriamycin (ADR)-induced nephropathy.MethodsWe evaluated the effect of an angiotensin II subtype 1 receptor blocker (telmisartan) combined with a vitamin D analog (oxacalcitriol) on mice ADR-induced nephropathy (9.5 mg/kg single intravenous injection). We also tested immortalized murine podocytes to examine the effects on podocyte apoptosis.ResultsMice with ADR-induced nephropathy developed progressive albuminuria and glomerulosclerosis within 30 days accompanied by decreased expression of slit diaphragm (SD)-associated proteins (nephrin and podocin), reduced numbers of podocytes, and increased systolic blood pressure. Treatment with telmisartan or oxacalcitriol alone moderately ameliorated kidney injury. The combined treatment most effectively reduced the albuminuria and glomerulosclerosis. These effects were accompanied by the restoration of SD-associated proteins, reduction of podocyte apoptosis, and prevention of podocyte depletion in the glomeruli. Treatment with telmisartan, oxacalcitriol, and the combination therapy resulted in similar reductions in systolic blood pressure. In cultured murine podocytes, ADR stimulated the expression of Bax/Bcl-2 and apoptosis as determined by Hoechst 33342 staining. These changes were effectively inhibited by telmisartan or oxacalcitriol, but the combination treatment most effectively reduced these effects.ConclusionsThese data demonstrated that application of a renin-angiotensin system blocker plus a vitamin D analog effectively prevented renal injury in ADR-induced nephropathy. The observed amelioration of renal injury may be partly attributable to antiapoptotic effects in podocytes.