Abstract
Tacrolimus-induced chronic nephrotoxicity (TIN) hinders its long-term use in patients. However, there are no drugs available in the clinic to relieve it at present. Astragaloside IV (AS-IV) is a saponin extract of the Astragalus which is widely used in the treatment of kidney disease. This study aimed to investigate the effect of AS-IV on TIN and its underlying mechanism. Herein, C57BL/6 mice were treated with tacrolimus and/or AS-IV for 4 weeks, and then the renal function, fibrosis, oxidative stress and p62-Keap1-Nrf2 pathway were evaluated to ascertain the contribution of AS-IV and p62-Keap1-Nrf2 pathway to TIN. Our results demonstrated that AS-IV significantly improved renal function and alleviated tubulointerstitial fibrosis compared with the model group. The expression of fibrosis-related proteins, including TGF-β1, Collagen I and α-SMA, were also decreased by AS-IV. Furthermore, AS-IV relieved the inhibition of tacrolimus on antioxidant enzymes. The data in HK-2 cells also proved that AS-IV reduced tacrolimus-induced cell death and oxidative stress. Mechanistically, AS-IV markedly promoted the nuclear translocation of Nrf2 and the renal protective effects of AS-IV were abolished by Nrf2 inhibitor. Further researches showed that phosphorylated p62 was significantly increased after AS-IV pretreatment. Moreover, AS-IV failed to increase nuclear translocation of Nrf2 and subsequent anti-oxidative stress in HK-2 cells transfected with p62 siRNA. Collectively, these findings indicate that AS-IV relieve TIN by enhancing p62 phosphorylation, thereby increasing Nrf2 nuclear translocation, and then alleviating ROS accumulation and renal fibrosis.
Highlights
Tacrolimus is an immunosuppressant drug which is extensively used in organ transplantation and other autoimmune diseases (Hart et al, 2019; Gao et al, 2020)
Astragaloside IV (AS-IV) at 20 or 40 mg/kg/d restored the levels of SCr and blood urea nitrogen (BUN) (p < 0.01), and no significant difference was found between the two groups
HE and Masson trichrome staining of paraffin-embedded kidney tissue indicated that neither inflammation nor tubulointerstitial fibrosis was observed in the control group (Figure 1A)
Summary
Tacrolimus is an immunosuppressant drug which is extensively used in organ transplantation and other autoimmune diseases (Hart et al, 2019; Gao et al, 2020). Tacrolimus therapy is often associated with irreversible nephrotoxicity that eventually progresses to chronic kidney disease (CKD) (Ojo et al, 2003). It is estimated that 16.5% of patients develop. Astragaloside IV Alleviates Tacrolimus Nephrotoxicity tacrolimus-induced chronic nephrotoxicity (TIN) (Chapman, 2011). There are no drugs available in the clinic to relieve TIN. The most commonly used risk mitigation strategies like monitoring levels to guide dosing and tacrolimus dose limitation were usually associated with increased rejection risk (Sawinski et al, 2016). It is necessary to discover a drug that can alleviate TIN and is safe for long-term use
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