Department of Nephrology and Center for Cardiovascular Research, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany.
J Urol. 2011 Sep;186(3):1142-9. doi: 10.1016/j.juro.2011.04.108. Epub 2011 Jul 23.
The antifibrotic effects of soluble guanylate cyclase stimulation and cyclic guanosine monophosphate production have been observed in cases of anti-thy1-induced renal disease. We analyzed the action of the specific soluble guanylate cyclase stimulator BAY 41-8543 on the renal recovery phase in rats with unilateral ureteral obstruction after obstruction was relieved.
Sprague-Dawley® rats underwent reversible unilateral ureteral obstruction for 5 days, after which obstruction was relieved. Rats were randomly assigned to unilateral ureteral obstruction and unilateral ureteral obstruction plus BAY 41-8543 (10 mg/kg body weight daily). Seven days after relief of obstruction we determined treatment effects on renal atrophy, apoptosis, fibrosis and nitric oxide/cyclic guanosine monophosphate signaling.
Untreated obstructed rats showed mildly increased systolic blood pressure, marked tubular atrophy and apoptosis, tubulointerstitial macrophage infiltration and fibrosis. Plasma cyclic guanosine monophosphate levels were unaltered in untreated rats with obstruction while renal soluble guanylate cyclase mRNA expression was increased. BAY 41-8543 administration significantly increased plasma cyclic guanosine monophosphate, which was paralleled by significant decreases in systolic blood pressure, renal tubular diameter, apoptosis and renal macrophage infiltration. Also, soluble guanylate cyclase stimulation decreased tubulointerstitial fibrosis, as shown by tubulointerstitial volume, matrix protein accumulation, α-smooth muscle actin expression, collagen IV deposition and transforming growth factor-β1 mRNA expression.
Soluble guanylate cyclase stimulation by BAY 41-8543 increases cyclic guanosine monophosphate production and subsequently enhances renal recovery after unilateral ureteral obstruction relief through an array of pathways. This finding suggests that soluble guanylate cyclase stimulation may serve as a novel treatment approach to restore or preserve renal structure and function in cases of obstructive kidney disease.
在抗 Thy1 诱导的肾病中观察到可溶性鸟苷酸环化酶刺激和环鸟苷酸生成的抗纤维化作用。我们分析了特异性可溶性鸟苷酸环化酶刺激剂 BAY 41-8543 在单侧输尿管梗阻解除后大鼠肾恢复阶段的作用。
Sprague-Dawley®大鼠进行可逆性单侧输尿管梗阻 5 天，然后解除梗阻。大鼠随机分为单侧输尿管梗阻和单侧输尿管梗阻加 BAY 41-8543（每日 10mg/kg 体重）。梗阻解除后 7 天，我们确定了治疗对肾萎缩、细胞凋亡、纤维化和一氧化氮/环鸟苷酸信号的影响。
未经治疗的梗阻大鼠显示出轻度升高的收缩压、明显的肾小管萎缩和细胞凋亡、肾小管间质巨噬细胞浸润和纤维化。未治疗的梗阻大鼠的血浆环鸟苷酸水平没有改变，而肾可溶性鸟苷酸环化酶 mRNA 表达增加。BAY 41-8543 给药显著增加了血浆环鸟苷酸，同时收缩压、肾小管直径、细胞凋亡和肾巨噬细胞浸润显著降低。此外，可溶性鸟苷酸环化酶刺激降低了肾小管间质纤维化，表现为肾小管间质体积、基质蛋白积累、α-平滑肌肌动蛋白表达、胶原 IV 沉积和转化生长因子-β1 mRNA 表达降低。
BAY 41-8543 刺激可溶性鸟苷酸环化酶增加环鸟苷酸生成，随后通过多种途径增强单侧输尿管梗阻解除后的肾脏恢复。这一发现表明，可溶性鸟苷酸环化酶刺激可能成为恢复或保留梗阻性肾病中肾脏结构和功能的一种新的治疗方法。
