Tacrolimus Causes Hypertension by Increasing Vascular Contractility via RhoA (Ras Homolog Family Member A)/ROCK (Rho-Associated Protein Kinase) Pathway in Mice. Issue 10 (8th August 2022)

• Record Type: Journal Article
• Authors: Wang, Xiaohua; Jiang, Shan; Fei, Lingyan; Dong, Fang; Xie, Lanyu; Qiu, Xingyu; Lei, Yan; Guo, Jie; Zhong, Ming; Ren, Xiaoqiu; Yang, Yi; Zhao, Liang; Zhang, Gensheng; Wang, Honghong; Tang, Chun; Yu, Luyang; Liu, Ruisheng; Patzak, Andreas; Persson, Pontus B.; Hultström, Michael; Wei, Qichun; Lai, En Yin; Zheng, Zhihua
• Is Part Of: Hypertension. Volume 79:Issue 10(2022)
• Page Start: 2228
• Page End: 2238
• Publication Date: 2022-08-08
• Subjects: angiotensin II -- hypertension -- reactive oxygen species -- tacrolimus -- vasoconstriction; Hypertension -- Periodicals; Hypertension -- Treatment -- Periodicals; 616.132005
• DOI: 10.1161/HYPERTENSIONAHA.122.19189
• Languages: English
• ISSNs: 0194-911X

Abstract

Abstract : 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 generation in afferent arterioles (107±5.9 versus 163±6.4; P <0.001) and in cultured mouse aortic vascular smooth muscle cells (100±7.5 versus 160±23.2; P <0.01). Finally, the reactive oxygen species scavenger Tempol inhibited tacrolimus-induced Ang II hypersensitivity in afferent arterioles and mesenteric arteries. Conclusions: The RhoA/ROCK pathway may play an important role in tacrolimus-induced hypertension by enhancing Ang II-specific vasoconstriction, and reactive oxygen species may participate in this process by activating the RhoA/ROCK pathway.