Remdesivir Inhibits Tubulointerstitial Fibrosis in Obstructed Kidneys

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.

Nucleoside analog GS‐441524: pharmacokinetics in different species, safety, and potential effectiveness against Covid‐19

“…Moreover, GS‐441524 at a concentration as high as 50 μM was required to produce alteration in the in vitro antigen‐induced memory T cell proliferation 38 . Consistent with this, concentrations of GS‐441524 in the range between 10 and 100 µM were necessary to inhibit proliferation of NRK‐49F cells and HK‐2 cells, derived from rat and human kidneys, after stimulation with transforming growth factor‐β, whereas marked inhibition of the protein expression of fibrotic markers such as fibronectin was detected at a concentration of this nucleoside analog of 10 µM 39 …”

“… 38 Consistent with this, concentrations of GS‐441524 in the range between 10 and 100 µM were necessary to inhibit proliferation of NRK‐49F cells and HK‐2 cells, derived from rat and human kidneys, after stimulation with transforming growth factor‐β, whereas marked inhibition of the protein expression of fibrotic markers such as fibronectin was detected at a concentration of this nucleoside analog of 10 µM. 39 …”

Remdesivir for COVID‐19 pneumonia in patients with severe chronic kidney disease: A Case series and review of the literature

“… 12 On the other hand, animal studies demonstrated potential, beneficial, renal effects in reversing obstructive renal fibrosis. 13 Of note, such cohort of patients with chronic kidney disease at significant risks of acquisition and complications of COVID‐19 disease as highlighted from multiple observational studies. 14 Such circumstances require developing management strategies for such population including careful evaluation, trials of therapy then sharing the experience.…”

Tanshinone I attenuates fibrosis in fibrotic kidneys through down-regulation of inhibin beta-A

“…before UUO operation. UUO model was established by ligation of the left ureter as described previously [ 20 , 21 ]. Mice were randomly divided into four groups: 1) Sham/DMSO ( n = 9), 2) Sham/Tan-I ( n = 8), 3) UUO/DMSO ( n = 8), and 4) UUO/Tan-I ( n = 11) group.…”

“…Normal rat kidney 49F (NRK-49F) cells, a rat kidney interstitial fibroblast cell line, were purchased from national infrastructure of cell line resource, Chinese academy of medical sciences. NRK-49F cells were cultured in DMEM/F12 medium containing 10% fetal bovine serum and 0.5% penicillin and streptomycin in an atmosphere of 5% CO2 and 95% air at 37 °C according to previous studies [ 20 , 21 ]. To study the anti-fibrotic effect of Tan I, NRK-49F cells were seeded in 6-well plates to 40–50% confluence and were starved with DMEM/F12 medium containing 0.5% fetal bovine serum overnight before the experiment.…”