Renal proximal tubular reabsorption is reduced in adult spontaneously hypertensive rats: roles of superoxide and Na+/H+ exchanger 3.
Renal proximal tubular reabsorption is reduced in adult spontaneously hypertensive rats: roles of superoxide and Na+/H+ exchanger 3.
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DOI：
10.1161/hypertensionaha.109.134783
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发表时间：
2009-12
期刊：
影响因子：
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通讯作者：
Welch WJ
中科院分区：
文献类型：
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作者：
Panico C;Luo Z;Damiano S;Artigiano F;Gill P;Welch WJ
近端小管重吸收受全身和内在机制的调节，包括局部产生的自分泌物。NADPH氧化酶（NOX）产生的超氧化物（O2−）增强了Henle袢和集合管中的NaCl转运，但其在PT中的作用尚不清楚。我们测量了WKY大鼠的PT液体重吸收（Jv），并将其与SHR（肾脏O2-产生增强的模型）的Jv进行比较。用NOX抑制剂apocynin（Apo）或针对NOX的关键亚基p22 phox的小干扰RNA（siRNA）处理大鼠。与WKY相比，SHR的Jv较低（WKY：2.4±0.3 vs SHR：1.1±0.2 nl/min/mm，n=9-11，p<0.001）。载脂蛋白和siRNA对p22 phox正常化SHR的Jv，但在WKY没有影响。在WKY中，但在SHR中，用S-1611灌注的近端小管中Jv降低，S-1611是Na+/H+交换器3（NHE 3）的高选择性抑制剂，NHE 3是近端小管中的主要Na+摄取途径。Apo预处理恢复了S-1611降低SHR Jv的作用（SHR+Apo：2.9±0.4 vs SHR+Apo+S-1611：1.0±0.3 nl/min/mm，p<0.001）。然而，由于SHR和WKY之间NHE 3的表达相似，这表明O2-影响NHE 3活性。直接微灌注tempol或夹竹桃麻素到PT也恢复了SHR的Jv。总之，NOX产生的O2-抑制SHR近端小管液体重吸收。这一发现意味着PT液体重吸收受氧化还原平衡的调节，这可能对高血压肾中的离子和液体稳态产生深远的影响。
Proximal tubule reabsorption is regulated by systemic and intrinsic mechanisms, including locally produced autacoids. Superoxide (O2−), produced by NADPH oxidase (NOX) enhances NaCl transport in the loop of Henle and the collecting duct, but its role in the PT is unclear. We measured PT fluid reabsorption (Jv) in WKY rats and compared that to Jv in SHR, a model of enhanced renal O2− generation. Rats were treated with the NOX inhibitor apocynin (Apo), or with small interfering RNA (siRNA) for p22phox, which is the critical subunit of NOX. Jv was lower in SHR compared to WKY (WKY: 2.4±0.3 vs SHR: 1.1±0.2 nl/min/mm, n=9–11, p<0.001). Apo and siRNA to p22phox normalized Jv in SHR yet had no effect in WKY. Jv was reduced in proximal tubules perfused with S-1611, a highly selective inhibitor of the Na+/H+ exchanger 3 (NHE3), the major Na+ uptake pathway in the proximal tubule, in WKY but not in SHR. Pretreatment with Apo restored an effect of S-1611 to reduce Jv in the SHR (SHR+Apo: 2.9±0.4 vs SHR+Apo+S-1611: 1.0±0.3 nl/min/mm, p<0.001). However, since expression of NHE3 was similar between SHR and WKY, this suggests that O2− affects NHE3 activity. Direct microperfusion of tempol or apocynin into the PT also restored Jv in SHR. In conclusion, O2− generated by NOX, inhibits proximal tubule fluid reabsorption in SHR. This finding implies that PT fluid reabsorption is regulated by redox balance, which may have profound effects on ion and fluid homeostasis in the hypertensive kidney.