Kidney Week

Abstract: TH-PO1087

Common Cold-Induced Cytokines Storm Induces Glomerular Disease Relapse in the ZHX2-Deficient State

Session Information

• Glomerular Diseases: Podocyte Biology - I
  November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1204 Podocyte Biology

Authors

• Del Nogal Avila, Maria, Rush University Medical Center, Chicago, Illinois, United States

Maria Del Nogal Avila,

• Donoro blazquez, Hector, Rush University Medical Center, Chicago, Illinois, United States

Hector Donoro blazquez,

• Kharlyngdoh, Joubert Banjop, Rush University Medical Center, Chicago, Illinois, United States

Joubert Banjop Kharlyngdoh,

• Das, Ranjan, Rush University Medical Center, Chicago, Illinois, United States

Ranjan Das,

• Molina-Jijon, Eduardo, Rush University Medical Center, Chicago, Illinois, United States

Eduardo Molina-Jijon,

• Avila-Casado, Carmen, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada

Carmen Avila-Casado,

• Mace, Camille E., Rush University Medical Center, Chicago, Illinois, United States

Camille E. Mace,

• Clement, Lionel C., Rush University Medical Center, Chicago, Illinois, United States

Lionel C. Clement,

• Chugh, Sumant S., Rush University Medical Center, Chicago, Illinois, United States

Sumant S. Chugh,

Background

Relapse or worsening of glomerular diseases like MCD and FSGS is commonly found after a common cold.
Different cytokines and soluble receptors increase in circulation by or in response of the infection agent. We developed and tested a ‘cytokine cocktail’ composed of 7 of these cytokines and we assessed it in different animal models of Zhx2 deficiency or FSGS.

Methods

A common cold cytokine cocktail (dose X) containing IL-2, IL-4R, IL-6, IL-10, INF-γ, TNF-α and ICAM-1 was injected into control (BALB/c, n=-5) and Zhx2 deficient mice (BALB/cJ, n=5). Different doses of the cocktail and the effect of individual cytokines was assessed.
Podocyte specific Zhx2 deficient (Zhx2 ^flox/flox cre^+/+, n=3) and floxed control mice (Zhx2 ^flox/flox, n=3) (dose X/15); mice deficient in Ephrin B1 or both Zhx2 and Apa were also injected with the cytokine cocktail (dose X/5).
Buffalo Mna (B. Mna) rats were injected with the cytokine cocktail (X/50) to study relapse in FSGS (n=7).

Results

Common cold cytokines induced acute albuminuria in BALB/cJ mice (65.3±24.3 µg per 18h), but not in BALB/c (10.8±1.5 µg per 18h), compared with baseline (BALB/cJ 5.1±1.1 µg per 18h; BALB/c 6.5±1.1 µg per 18h) (p<0.05), having higher nuclear expression of Zhx1 but not Zhx3. Individually, none of these cytokines caused albuminuria in either strain.
Reducing 50% the dose X still induced significant albuminuria in BALB/cJ mice (15.3±0.6 µg per 18h) compared with baseline (2.8±0.9 µg per 18h) (p<0.05).
Eliminating individually from the cocktail 3 different cytokines against which antibodies are in clinical use (IL-4R, IL6, TNF-α) also eliminated albuminuria in BALB/cJ mice.
Cytokine induced albuminuria was also noted in Zhx2 ^flox/flox/cre⁺⁺, but not in control Zhx2 ^flox/flox mice. Mice deficient in APA also developed albuminuria, and it is higher when mice are deficient in both Zhx2 and APA. Mice lacking Ephrin B1 in podocytes did not develop albuminuria.
B. Mna rats had a significant increase in proteinuria (61.5±4.2) from baseline (47±4.1), using a much lower dose (X/50) of the rat “cytokine cocktail”.

Conclusion

These findings suggest that an altered Zhx2 expression and its transmembrane partners predispose to MCD and FSGS relapse following a common cold.

Funding

• NIDDK Support