Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University , Uppsala , Sweden.
Department of Medical Cell Biology, Division of Integrative Physiology, Uppsala University , Uppsala , Sweden.
Am J Physiol Renal Physiol. 2018 Mar 1;314(3):F439-F444. doi: 10.1152/ajprenal.00498.2017. Epub 2017 Nov 1.
About one-third of patients with type 1 diabetes develops kidney disease. The mechanism is largely unknown, but intrarenal hypoxia has been proposed as a unifying mechanism for chronic kidney disease, including diabetic nephropathy. The endothelin system has recently been demonstrated to regulate oxygen availability in the diabetic kidney via a pathway involving endothelin type A receptors (ETA-R). These receptors mainly mediate vasoconstriction and tubular sodium retention, and inhibition of ETA-R improves intrarenal oxygenation in the diabetic kidney. Endothelin type B receptors (ETB-R) can induce vasodilation of the renal vasculature and also regulate tubular sodium handling. However, the role of ETB-R in kidney oxygen homeostasis is unknown. The effects of acute intrarenal ETB-R activation (sarafotoxin 6c for 30-40 min; 0.78 pmol/h directly into the renal artery) on kidney function and oxygen metabolism were investigated in normoglycemic controls and insulinopenic male Sprague-Dawley rats administered streptozotocin (55 mg/kg) 2 wk before the acute experiments. Intrarenal activation of ETB-R improved oxygenation in the hypoxic diabetic kidney. However, the effects on diabetes-induced increased kidney oxygen consumption could not explain the improved oxygenation. Rather, the improved kidney oxygenation was due to hemodynamic effects increasing oxygen delivery without increasing glomerular filtration or tubular sodium load. In conclusion, increased ETB-R signaling in the diabetic kidney improves intrarenal tissue oxygenation due to increased oxygen delivery secondary to increased renal blood flow.
大约三分之一的 1 型糖尿病患者会发展为肾脏疾病。其机制在很大程度上尚不清楚，但肾内缺氧已被提出作为慢性肾脏病（包括糖尿病肾病）的统一机制。最近已经证明，内皮素系统通过涉及内皮素 A 受体（ETA-R）的途径来调节糖尿病肾脏中的氧气供应。这些受体主要介导血管收缩和管状钠潴留，并且抑制 ETA-R 可改善糖尿病肾脏中的肾内氧合。内皮素 B 受体（ETB-R）可引起肾血管扩张，并且还调节管状钠处理。然而，ETB-R 在肾脏氧平衡中的作用尚不清楚。在正常血糖对照和 2 周前给予链脲佐菌素（55mg/kg）的胰岛素缺乏雄性 Sprague-Dawley 大鼠中，研究了急性肾内 ETB-R 激活（30-40 分钟内 sarafotoxin 6c；0.78pmol/h 直接进入肾动脉）对肾功能和氧代谢的影响。肾内 ETB-R 的激活改善了缺氧性糖尿病肾脏的氧合。然而，其对糖尿病引起的肾脏耗氧量增加的影响并不能解释氧合的改善。相反，改善的氧合是由于增加了氧输送而没有增加肾小球滤过率或管状钠负荷的血液动力学效应所致。总之，糖尿病肾脏中增加的 ETB-R 信号转导可通过增加肾血流量而增加氧输送来改善肾内组织氧合。
