Kidney Damage in Long COVID: Studies in Experimental Mice

SIMPLE SUMMARY: In this study, we investigated the long-term effects of COVID-19 on the kidneys using mice infected with a similar coronavirus. We examined markers in the kidneys related to inflammation, scarring, and damage. We identified that certain markers linked to scarring and inflammation remained high in the mice’s kidneys even after the initial infection, suggesting kidney damage. However, other markers did not show significant changes (e.g., mRNA levels of TNFR-1, WFDC2, B2M, likely due to factors influencing their half-life and translation rate). To explore treatments, we tested a drug called SPIKENET (SPK), a 15-amino acid synthetic peptide, that blocks the virus from attaching and entering cells. When we gave SPK to the mice, it decreased the certain marker levels in their kidneys in both the group of mice that were treated shortly after infection and the group that received treatment a year after the infection. These findings indicate that kidney scarring may begin early in COVID-19 and that targeting specific markers and proteins with treatments like SPK could help prevent kidney damage in both early and long-term COVID-19 cases. ABSTRACT: Signs and symptoms involving multiple organ systems which persist for weeks or months to years after the initial SARS-CoV-2 infection (also known as PASC or long COVID) are common complications of individuals with COVID-19. We recently reported pathophysiological changes in various organs post-acute infection of mice with mouse hepatitis virus-1 (MHV-1, a coronavirus) (7 days) and after long-term post-infection (12 months). One of the organs severely affected in this animal model is the kidney, which correlated well with human studies showing kidney injury post-SARS-CoV-2 infection. Our long-term post-infection pathological observation in kidneys includes the development of edema and inflammation of the renal parenchyma, severe acute tubular necrosis, and infiltration of macrophages and lymphocytes, in addition to changes observed in both acute and long-term post-infection, which include tubular epithelial cell degenerative changes, peritubular vessel congestion, proximal and distal tubular necrosis, hemorrhage in the interstitial tissue, and vacuolation of renal tubules. These findings strongly suggest the possible development of renal fibrosis, in particular in the long-term post-infection. Accordingly, we investigated whether the signaling system that is known to initiate the above-mentioned changes in kidneys in other conditions is also activated in long-term post-MHV-1 infection. We found increased TGF-β1, FGF23, NGAL, IL-18, HIF1-α, TLR2, YKL-40, and B2M mRNA levels in long-term post-MHV-1 infection, but not EGFR, TNFR1, BCL3, and WFDC2. However, only neutrophil gelatinase-associated lipocalin (NGAL) increased in acute infection (7 days). Immunoblot studies showed an elevation in protein levels of HIF1-α, TLR-2, and EGFR in long-term post-MHV-1 infection, while KIM-1 and MMP-7 protein levels are increased in acute infection. Treatment with a synthetic peptide, SPIKENET (SPK), which inhibits spike protein binding, reduced NGAL mRNA in acute infection, and decreased TGF-β1, BCL3 mRNA, EGFR, HIF1-α, and TLR-2 protein levels long-term post-MHV-1 infection. These findings suggest that fibrotic events may initiate early in SARS-CoV-2 infection, leading to pronounced kidney fibrosis in long COVID. Targeting these factors therapeutically may prevent acute or long-COVID-associated kidney complications.