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  3. Tacrolimus Induced Hypertension and Vascular Remodeling Includes Mechanisms of Cellular Senescence-The Protective Effect of Valsartan

Tacrolimus Induced Hypertension and Vascular Remodeling Includes Mechanisms of Cellular Senescence-The Protective Effect of Valsartan

  • Acta Physiol (Oxf). 2026 Apr;242(4):e70189. doi: 10.1111/apha.70189.
Lingyan Fei 1,  Xiaohua Wang 1,  Lingyi Kong 2,  Tianjiao Cui 1,  Pratik H Khedkar 3,  Yunxiu Xiang 1,  Dongliang Zhao 4,  Junxuan Fang 1,  Yulin Liang 1,  Yangyang Zhang 1,  Nan Xu 5,  Xingyu Qiu 6,  Liang Zhao 6 7,  Gensheng Zhang 7,  Yan Lei 1,  Chun Tang 1,  Kongyang Ma 8,  Liwei Lu 9,  Jin Wei 10,  En Yin Lai 1 6,  Pontus B Persson 3,  Andreas Patzak 3,  Zhihua Zheng 1,  Shan Jiang 1
Affiliations

Affiliations

  • 1 Department of Nephrology, Center of Kidney and Urology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
  • 2 Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
  • 3 Institute of Translational Physiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.
  • 4 Department of Pathology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
  • 5 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Henan University, Kaifeng, China.
  • 6 Department of Physiology, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China.
  • 7 Department of Nephrology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, and Key Laboratory of Diagnosis and Treatment of Neonatal Diseases of Zhejiang Province, Hangzhou, China.
  • 8 Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, Centre for Infection and Immunity Studies (CIIS), School of Medicine, the Seventh Affiliated Hospital, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, Guangdong, China.
  • 9 Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China.
  • 10 Section of Nephrology, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts, USA.
PMID: 41814130 DOI: 10.1111/apha.70189
Abstract

Aim: Calcineurin inhibitors (CNI) such as tacrolimus (Tac) are the first-line treatment to prevent transplant rejection. However, CNI have adverse effects on blood vessels and renal function, which may be linked to cellular senescence. Valsartan, a common angiotensin II type 1 receptor (AT1R) blocker, exhibits anti-senescence properties. We tested the hypothesis that tacrolimus causes hypertension and microvascular remodeling that involves induction of senescence, and that valsartan is protective.

Methods: Microperfusion and wire myography were employed to assess the contractile and dilatory functions of renal afferent arterioles (Af-Art) and mesenteric arteries, respectively. The expression of components of the renin-angiotensin system (Ras) and senescence-associated biomarkers was investigated using qPCR and immunohistochemistry.

Results: Long-term administration of Tac activated the Ras. Tac-induced microvascular remodeling in mesenteric arteries and Af-Art was mitigated by treatment with valsartan. Mice treated with Tac exhibited increased vasoconstriction in response to angiotensin II and reduced dilation to acetylcholine. Both effects were abolished by valsartan. Additionally, senescence-associated biomarkers were upregulated in mesenteric and renal resistance arteries from Tac-treated mice. Co-administration of Tac with valsartan or ABT-263, a senolytic agent, rescued Tac-induced microvascular injury and reduced hypertension (conscious mice, noninvasive tail-cuff system). Treatment with the antihypertensive drug amlodipine normalized blood pressure and downregulated senescence-associated beta-galactosidase in mesenteric arteries.

Conclusion: These findings suggest that cellular senescence contributes to Tac-induced microvascular injury and hypertension and demonstrate the effectiveness of senolytic treatment for protection. Valsartan could reduce senescence indirectly by lowering blood pressure; a direct anti-senescence effect might also play a role in this context.

Keywords

cellular senescence; microvascular dysfunction; senolytic drug; tacrolimus; valsartan.

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