Renal sympathetic denervation suppresses de novo podocyte injury and albuminuria in rats with aortic regurgitation.
Renal sympathetic denervation suppresses de novo podocyte injury and albuminuria in rats with aortic regurgitation.
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DOI：
10.1161/circulationaha.111.064097
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发表时间：
2012-03-20
期刊：
影响因子：
37.8
通讯作者：
Nishiyama A
中科院分区：
文献类型：
--
作者：
Rafiq K;Noma T;Fujisawa Y;Ishihara Y;Arai Y;Nabi AH;Suzuki F;Nagai Y;Nakano D;Hitomi H;Kitada K;Urushihara M;Kobori H;Kohno M;Nishiyama A
慢性肾脏疾病的存在是慢性心力衰竭（CHF）患者预后不良的重要独立危险因素。然而，这种相互作用背后的机制和介质知之甚少。在这项研究中，我们测试了我们的假设，慢性心脏容量超负荷导致新发肾功能不全，共激活交感神经系统（SNS）和肾脏中的肾素-血管紧张素系统（RAS）。我们还研究了肾脏去神经支配和RAS抑制对CHF肾损伤的治疗潜力。Sprague-Dawley大鼠发生主动脉瓣反流（AR），并接受溶媒、奥美沙坦[血管紧张素II（AngII）受体阻滞剂]或肼苯哒嗪治疗6个月。在6个月时，AR大鼠的蛋白尿和肾小球足细胞损伤显著增加。这些变化与尿血管紧张素原排泄增加、肾脏AngII和去甲肾上腺素（NE）水平增加、血管紧张素原和血管紧张素1a型受体基因表达增强以及肾皮质组织氧化应激相关。去肾神经AR大鼠蛋白尿和肾小球足细胞损伤减少，这与肾脏NE、血管紧张素原、AngII和氧化应激减少有关。去肾神经联合奥美沙坦可预防AR引起的足细胞损伤和蛋白尿。在这种慢性心脏容量超负荷动物模型中，SNS的激活增强了肾脏RAS和氧化应激，这是关键的心肾介质。去肾神经和奥美沙坦预防肾损伤的发生和进展，为心肾综合征的治疗提供了新的见解。
The presence of chronic kidney disease is a significant independent risk factor for poor prognosis in patients with chronic heart failure (CHF). However, the mechanisms and mediators underlying this interaction are poorly understood. In this study, we tested our hypothesis that chronic cardiac volume overload leads to de novo renal dysfunction by co-activating the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS) in the kidney. We also examined the therapeutic potential of renal denervation and RAS inhibition to suppress renal injury in CHF. Sprague-Dawley rats underwent aortic regurgitation (AR) and were treated for 6 months with either vehicle, olmesartan [an angiotensin II (AngII) receptor blocker], or hydralazine. At 6 months, albuminuria and glomerular podocyte injury were significantly increased in AR rats. These changes were associated with increased urinary angiotensinogen excretion, kidney AngII and norepinephrine (NE) levels, as well as enhanced angiotensinogen and angiotensin type 1a receptor gene expression, and oxidative stress in renal cortical tissues. AR rats with renal denervation had decreased albuminuria and glomerular podocyte injury, which were associated with reduced kidney NE, angiotensinogen, AngII and oxidative stress. Renal denervation combined with olmesartan prevented podocyte injury and albuminuria induced by AR. In this chronic cardiac volume overload animal model, activation of the SNS augments kidney RAS and oxidative stress, which act as crucial cardio-renal mediators. Renal denervation and olmesartan prevent the onset and progression of renal injury, providing new insight into the treatment of cardio-renal syndrome.