Fig 1: Mechanisms of cytokine storm–related glomerular injury.(A) Common Cold (C. Cold) cocktail X/2–induced albuminuria in Il4ra–/– (BALB/cJ background; n = 4 mice/group) and control BALB/cJ mice (n = 9 mice/group). (B) Cocktail C X/2–induced albuminuria in Il4ra–/– (n = 8 mice/group) and control BALB/cJ mice (n = 5 mice/group) (left) and percentage increase in day 1 albuminuria from baseline (right). (C) Western blots to assess activation of p-STAT6 signaling in wild-type and ZHX2 hypomorph (CRISPR B) cultured human podocytes incubated with human counterparts of Cocktail C (upper) or Common Cold cocktail (lower; final concentration X/100,000; n = 3 dishes/condition). Positive control for the Common Cold cocktail incubation study was 30-minute Cocktail C incubation in wild-type podocytes. Numbers on right represent kilodaltons. (D) Densitometry of Western blots from C, upper. (E) Confocal images of glomeruli from control saline–, Common Cold cocktail X/2–, or Cocktail D X/2–injected BALB/c and BALB/cJ mice, showing increased podocyte nuclear presence of ZHX1 (white arrows, upper panel) exclusively in Common Cold cocktail– and Cocktail D–injected BALB/cJ mice. Some podocyte nuclei in BALB/cJ mice injected with Cocktail D also showed increased ZHX3 (white arrows, lower panel). (F) Common Cold cocktail X/5 induced albuminuria (upper) and percentage increase in baseline albuminuria (lower) in Zhx2def/def, Enpep–/–, and dual Zhx2def/def Enpep–/– mice in mixed background (n = 7 to 12 mice/group). def, deficient. (G) Schematic for potential binding of COVID-19 cocktail components to specific receptors in glomerular endothelial cells and feedback loops (red) between these cells. (H) Schematic for potential binding of Common Cold cocktail components to specific receptors in glomerular endothelial cells and potential feedback loops (red) between these cells. Confocal microscopy scale bars: 10 µm. * P < 0.05; ** P < 0.01; *** P < 0.001; **** P < 0.0001, determined by multiple t test comparisons (Holm-Šídák, A, B, F top), simple t test 2-tail (A, B, D), simple t test 1-tail (green, B), 1-way Anova (Dunnett D; Tukey F bottom). Data represent mean ± SEM.
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