Abstract
Aim: Kidney impairment is observed in patients with COVID-19. The effect of anti-COVID-19 agent remdesivir on kidneys is currently unknown. We aimed to determine the effect of remdesivir on renal fibrosis and its downstream mechanisms. Methods: Remdesivir and its active nucleoside metabolite GS-441524 were used to treat TGF-β stimulated renal fibroblasts (NRK-49F) and human renal epithelial (HK2) cells. Vehicle or remdesivir were given by intraperitoneal injection or renal injection through the left ureter in unilateral ureteral obstruction (UUO) mice. Serum and kidneys were harvested. The concentrations of remdesivir and GS-441524 were measured using LC-MS/MS. Renal and liver function were assessed. Renal fibrosis was evaluated by Masson’s trichrome staining and Western blotting. Results: Remdesivir and GS-441524 inhibited the expression of fibrotic markers (fibronectin and aSMA) in NRK-49F and HK2 cells. Intraperitoneal injection or renal injection of remdesivir attenuated renal fibrosis in UUO kidneys. Renal and liver function were unchanged in remdesivir treated UUO mice. Two remdesivir metabolites were detected after injection. Phosphorylation of Smad3 that was enhanced in cell and animal models for renal fibrosis was attenuated by remdesivir. In addition, the expression of Smad7, an anti-fibrotic factor, was increased after remdesivir treatment in vitro and in vivo. Moreover, knockdown of Smad7 blocked the antifibrotic effect of GS and RDV on renal cells. Conclusion: Remdesivir inhibits renal fibrosis in obstructed kidneys.
Highlights
A novel coronavirus (2019-nCoV) reported in Wuhan in late December 2019 has rapidly spread to the rest of the world (Zhou et al, 2020)
Patients with Chronic kidney disease (CKD) might be more vulnerable to COVID19 because a recent study shows that COVID-19 patients in the intensive care unit were more likely to Remdesivir Inhibits Renal Fibrosis have comorbidities (72.2 vs. 37.3%) than patients not in the intensive care unit (Wang D. et al, 2020)
It has been found that angiotensinconverting enzyme 2 (ACE2), which mediates the entry of 2019nCoV into human cells is highly expressed in renal tubular cells, implying that 2019-nCoV may directly bind to ACE2-positive cells in the kidney and induce kidney injuries (Fan et al, 2020)
Summary
A novel coronavirus (2019-nCoV) reported in Wuhan in late December 2019 has rapidly spread to the rest of the world (Zhou et al, 2020). A clinical study reported that 27.06% of patients with COVID-19 exhibited acute renal failure (ARF), and elderly patients (≥60 years) were more likely to develop ARF (65.22 vs 24.19%) (Diao et al, 2020). A further immunohistochemistry analysis revealed that the antigen for 2019-nCoV accumulates in renal tubules (Diao et al, 2020). Another clinical study with 59 COVID-19 patients showed that proteinuria occurred in 63% of patients (Li et al, 2020). A consecutive cohort study with 710 COVID-19 patients further shows that the prevalence of renal impairment is high, which is associated with in-hospital death (Cheng et al, 2020)
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