Renal Sciences, Department of Inflammation Biology, King's College London, Renal Medicine 10 Cutcombe Road, London, SE5 9RJ, UK.
Barts Health Renal Centre, The Royal London Hospital, E1 1BB, London, UK.
BMC Nephrol. 2020 May 19;21(1):187. doi: 10.1186/s12882-020-01842-5.
T-type calcium channels (TTCC) are involved in mesangial cell proliferation. In acute thy-1 nephritis in the rat TTCC inhibition reduces glomerular damage and cell proliferation. This work is extended here by a study of the non-selective TTCC inhibitor TH1177 in a chronic model of proliferative glomerulonephritis (GN) including late treatment starting after the initial inflammation has resolved. The objective was to determine the effects of TH1177 in a model of chronic mesangioproliferative renal disease.
Chronic GN was induced in WKY rats by unilateral nephrectomy (day - 7) followed by day 0 injection of Ox7 thy-1 mAb. Treatment with TH1177 (10-20 mg/Kg daily IP) was started on day 2 (early treatment) or on day 14 (late treatment) and compared to vehicle-treated controls until sacrifice at day 42. Glomerular disease was assessed with a damage score, fibrosis assay, cellular counts and renal function measured by serum creatinine.
Treatment with TH11777 was associated with reduced serum creatinine, less glomerular damage, reduced fibrosis and reduced glomerular cellularity. The results for early and late TH1177 treatments were essentially the same and differed significantly from vehicle.
The ion-channel modulator TH1177 is capable of improving glomerular outcome in chronic rat GN even when treatment starts 14 days after initiation of the disease. These data are discussed in the context of the possible targets of TH1177 including TTCC, TRP family, Stim/Orai group and other cation channels. The work supports the use of genetic models to examine the roles of individual cation channels in progressive glomerulonephritis to further define the targets of TH1177.
T 型钙通道（TTCC）参与系膜细胞增殖。在大鼠的急性 thy-1 肾炎中，TTCC 抑制可减少肾小球损伤和细胞增殖。本研究将非选择性 TTCC 抑制剂 TH1177 扩展到增生性肾小球肾炎（GN）的慢性模型中，包括在初始炎症消退后开始的晚期治疗。目的是确定 TH1177 在慢性间质性增生性肾病模型中的作用。
通过单侧肾切除术（第-7 天）诱导 WKY 大鼠慢性 GN，然后在第 0 天注射 Ox7 thy-1 mAb。TH1177（每天 10-20mg/kg 腹腔注射）治疗于第 2 天（早期治疗）或第 14 天（晚期治疗）开始，并与 vehicle 治疗的对照组进行比较，直至第 42 天处死。通过损伤评分、纤维化测定、细胞计数和血清肌酐测定评估肾小球疾病。
TH1177 治疗与血清肌酐降低、肾小球损伤减少、纤维化减少和肾小球细胞减少有关。早期和晚期 TH1177 治疗的结果基本相同，与 vehicle 相比差异显著。
即使在疾病开始后 14 天开始治疗，离子通道调节剂 TH1177 也能改善慢性大鼠 GN 的肾小球结局。这些数据在讨论 TH1177 的可能靶点时，包括 TTCC、TRP 家族、Stim/Orai 组和其他阳离子通道，考虑了这些数据。这项工作支持使用遗传模型来研究单个阳离子通道在进行性肾小球肾炎中的作用，以进一步确定 TH1177 的靶点。
