Division of Nephrology, RWTH Aachen University Hospital, Germany.
J Pathol. 2013 Apr;229(5):672-84. doi: 10.1002/path.4151. Epub 2013 Mar 5.
Mesangioproliferative glomerulonephritis is the most common nephritis worldwide. We examined the effects of low- and high-dose telmisartan, an angiotensin II receptor blocker, in rats with progressive anti-Thy1.1 mesangioproliferative glomerulonephritis in a clinically relevant situation of established renal damage. Uninephrectomized nephritic rats were randomized on day 28 to remain untreated (control treatment; CT), or to receive low- (0.1 mg/kg/day, LT) or high-dose telmisartan (10 mg/kg/day, HT), hydrochlorothiazide + hydralazine (8 + 32 mg/kg/day, HCT + H), or atenolol (100 mg/kg/day, AT). CT and LT rats were hypertensive, whereas HT, HCT + H and AT treatment normalized blood pressures. On day 131, despite similar blood lowering effects, only HT, but not AT or HCT + H, prevented loss of renal function and reduced proteinuria compared to CT. Only HT potently ameliorated glomerulosclerosis, tubulointerstitial damage, cortical matrix deposition, podocyte damage and macrophage infiltration. HT reduced cortical expression of platelet derived growth factor receptor-α and -β as well as transforming growth factor-β1. LT exhibited minor but significant efficacy even in the absence of antihypertensive effects. Transcript array analyses revealed a four-fold down-regulation of renal cortical chemokine (C-C motif) receptor 6 (CCR6) mRNA by HT, which was confirmed at the protein level. Silencing of CCR6 did not alter podocyte function in vitro, thus indicating a predominant role in the tubulo-interstitium. In human kidney biopsies, CCR6 mRNA and mRNA of its ligand chemokine (C-C motif) ligand 20 was up-regulated in patients with progressive IgA nephropathy compared to stable disease. Thus, delayed treatment with high-dose telmisartan exerted a pronounced benefit in progressive mesangioproliferative glomerulonephritis, which extended beyond that of equivalent blood pressure lowering. We identified down-regulation of platelet-derived growth factor receptors and CCR6 as potential mediators of telmisartan-related renoprotection. CCR6 may also regulate the renal outcome in human mesangioprolfierative glomerulonephritis.
系膜增生性肾小球肾炎是全球最常见的肾炎。我们在一种临床相关的已建立的肾损伤情况下，检查了低剂量和高剂量替米沙坦（一种血管紧张素 II 受体阻滞剂）在进行性抗 Thy1.1 系膜增生性肾小球肾炎大鼠中的作用。在第 28 天，进行了单侧肾切除术的肾炎大鼠被随机分为未治疗（对照治疗；CT）组，或接受低剂量（0.1mg/kg/天，LT）或高剂量替米沙坦（10mg/kg/天，HT），氢氯噻嗪+肼屈嗪（8+32mg/kg/天，HCT+H）或阿替洛尔（100mg/kg/天，AT）治疗。CT 和 LT 大鼠患有高血压，而 HT、HCT+H 和 AT 治疗使血压正常化。在第 131 天，尽管有相似的降压效果，但只有 HT 而不是 AT 或 HCT+H 能够防止肾功能丧失和蛋白尿减少，与 CT 相比。只有 HT 能够强有力地改善肾小球硬化、肾小管间质损伤、皮质基质沉积、足细胞损伤和巨噬细胞浸润。HT 降低了皮质血小板衍生生长因子受体-α和-β以及转化生长因子-β1 的表达。LT 即使在没有降压作用的情况下，也表现出轻微但显著的疗效。转录谱分析显示，HT 将肾皮质趋化因子（C-C 基序）受体 6（CCR6）mRNA 的表达下调了四倍，这在蛋白质水平上得到了证实。在体外，CCR6 的沉默并没有改变足细胞的功能，因此表明其在肾小管间质中起主要作用。在人类肾活检中，与稳定疾病相比，进展性 IgA 肾病患者的 CCR6 mRNA 和其配体趋化因子（C-C 基序）配体 20 的 mRNA 上调。因此，延迟使用高剂量替米沙坦在进行性系膜增生性肾小球肾炎中产生了显著的益处，超出了等效降压的范围。我们确定了血小板衍生生长因子受体和 CCR6 的下调是替米沙坦相关肾保护作用的潜在介质。CCR6 也可能调节人类系膜增生性肾小球肾炎的肾脏结局。
