Tacrolimus Causes Hypertension by Increasing Vascular Contractility via RhoA (Ras Homolog Family Member A)/ROCK (Rho-Associated Protein Kinase) Pathway in Mice

作者：Xiaohua Wang, Shan Jiang, Lingyan Fei, Fang Dong, Lanyu Xie, Xingyu Qiu, Lei Yan, Jie Guo, Ming Zhong, Xiaoqiu Ren, Yi Yang, Liang Zhao, Gensheng Zhang, Honghong Wang, Chun Tang, Luyang Yu, Ruisheng Liu, Andreas Patzak, Pontus B. Persson, Michael Hultström, Qichun Wei, En Yin Lai, Zhihua Zheng · 发表于：Hypertension · 年份：2022 · DOI：10.1161/hypertensionaha.122.19189 · 被引用次数：30 · 研究领域：Renal Transplantation Outcomes and Treatments、Neurological Complications and Syndromes、Nitric Oxide and Endothelin Effects

Background: To provide tacrolimus is first-line treatment after liver and kidney transplantation. However, hypertension and nephrotoxicity are common tacrolimus side effects that limit its use. Although tacrolimus-related hypertension is well known, the underlying mechanisms are not. Here, we test whether tacrolimus-induced hypertension involves the RhoA (Ras homolog family member A)/ROCK (Rho-associated protein kinase) pathway in male C57Bl/6 mice. methods: Intra-arterial blood pressure was measured under anesthesia. The reactivity of renal afferent arterioles and mesenteric arteries were assessed in vitro using microperfusion and wire myography, respectively. Results: Tacrolimus induced a transient rise in systolic arterial pressure that was blocked by the RhoA/ROCK inhibitor Fasudil (12.0±0.9 versus 3.2±0.7; P <0.001). Moreover, tacrolimus reduced the glomerular filtration rate, which was also prevented by Fasudil (187±20 versus 281±8.5; P <0.001). Interestingly, tacrolimus enhanced the sensitivity of afferent arterioles and mesenteric arteries to Ang II (angiotensin II), likely due to increased intracellular Ca 2+ mobilization and sensitization. Fasudil prevented increased Ang II-sensitivity and blocked Ca 2+ mobilization and sensitization. Preincubation of mouse aortic vascular smooth muscle cells with tacrolimus activated the RhoA/ROCK/MYPT-1 (myosin phosphatase targeting subunit 1) pathway. Further, tacrolimus increased cytoplasmic reactive oxygen species generat...