Liu Yufeng, Li Lanying, Qiu Minzi, Tan Lishan, Zhang Mengbi, Li Jiawen, Zhu Hongguo, Jiang Shaoling, Su Xiaoyan, Li Aiqing
State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University Guangzhou, China.
Nephropathy Department, Tungwah Hospital of Sun Yat-sen University Dongguan 523110, China.
Am J Transl Res. 2019 May 15;11(5):2925-2939. eCollection 2019.
The diabetes mellitus has posed a grave threat on human health, and is bound to result in renal trauma by uncertain mechanisms. Increasing evidences indicated that the activation of the renin-angiotensin system plays a pivotal role during the progression of diabetic kidney disease. In streptozotocin (STZ)-induced type 1 diabetic rat model, the losartan (a selective angiotensin II type 1 (AT1) receptor antagonist) and tempol (4-Hydroxy-TEMPO, reactive oxygen species scavenger) were administrated through intracerebroventricular injection or intragastric gavage. Intracerebroventricular administration of clonidine or renal denervation was carried out to block sympathetic nerve traffic. Compared with non-diabetic rats, the reno-cerebral axis was over-activated, including activity of renin-angiotensin system (RAS), oxidative stress, and sympathetic activity in diabetic rats. Central blockade of RAS inhibited the central oxidative stress and sympathetic activity, which led to decrease of intrarenal RAS activity and oxidative stress. Meanwhile, central administration of tempol reduced brain RAS, thus downregulated renal RAS activity and oxidative stress. Importantly, oral administration by intragastric gavage of high dose of losartan and tempol achieved the same effect. The results suggested that there is a cross-talk between renal and cerebral RAS/reactive oxygen species, contributing to the progression of diabetic kidney disease. The subfornical organ, paraventricular nucleus, and supraoptic nucleus in the forebrain also play a key role in development and progression of renal trauma through reno-cerebral reflex axis.
糖尿病对人类健康构成了严重威胁，并且必然会通过不确定的机制导致肾脏损伤。越来越多的证据表明，肾素-血管紧张素系统的激活在糖尿病肾病的进展过程中起着关键作用。在链脲佐菌素（STZ）诱导的1型糖尿病大鼠模型中，通过脑室内注射或灌胃给予氯沙坦（一种选择性血管紧张素II 1型（AT1）受体拮抗剂）和tempol（4-羟基-TEMPO，活性氧清除剂）。进行脑室内注射可乐定或肾去神经支配以阻断交感神经传导。与非糖尿病大鼠相比，糖尿病大鼠的肾脑轴过度激活，包括肾素-血管紧张素系统（RAS）活性、氧化应激和交感神经活性。RAS的中枢阻断抑制了中枢氧化应激和交感神经活性，从而导致肾内RAS活性和氧化应激降低。同时，脑室内给予tempol降低了脑RAS，从而下调了肾RAS活性和氧化应激。重要的是，高剂量氯沙坦和tempol灌胃口服给药也达到了相同的效果。结果表明，肾和脑RAS/活性氧之间存在相互作用，这有助于糖尿病肾病的进展。前脑的穹窿下器官、室旁核和视上核也通过肾脑反射轴在肾脏损伤的发生和发展中起关键作用。
