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Kidney Week

Abstract: PO0421

Proteogenomic Effects of Environmental and Uremic Toxin Acrolein on Mouse Kidneys

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Rane, Sanjana, University of Louisville, Louisville, Kentucky, United States
  • Jin, Shunying, University of Louisville, Louisville, Kentucky, United States
  • Isaacs, Susan M., University of Louisville, Louisville, Kentucky, United States
  • Barati, Michelle T., University of Louisville, Louisville, Kentucky, United States
  • Merchant, Michael, University of Louisville, Louisville, Kentucky, United States
  • Pan, Jianmin, University of Louisville, Louisville, Kentucky, United States
  • Rai, Shesh, University of Louisville, Louisville, Kentucky, United States
  • Srivastava, Sanjay, University of Louisville, Louisville, Kentucky, United States
  • Rane, Madhavi J., University of Louisville, Louisville, Kentucky, United States
Background

Acrolein is present in the environment, water, food and is a uremic toxin endogenously produced through lipid peroxidation and polyamine oxidation. Its mechanism of action involves cellular thiol reactivity and glutathione depletion-induced oxidative stress. However, direct effects of acrolein on kidneys are not known. The current study conducted RNA-seq and proteomic analysis on mouse kidneys exposed to acrolein.

Methods

C57BL/6 mice were subjected to filtered-air (control) or inhaled-acrolein (1.0 ppm), 6h/day, 5 days/week for 12 weeks. Total-RNA and kidney homogenates from all mice were subjected to RNA-seq and proteomic analysis. Immunoblotting, H&E and Sirius-Red staining of kidneys was performed.

Results


RNA-seq analysis detected activation of profibrotic pathways including TGFb/TGFbR/SMAD3/TEAD4/Autotaxin and down-regulation of anti-fibrotic pathways including STAT5A/FGF21/PPARb/IL-22. Proteomic analysis identified fibrotic pathways, activation of oxidative stress, mitochondrial dysfunction, proteasomal degradation, apoptosis, and inflammatory pathways. Proteomic analysis demonstrated acrolein-decreased expression of antioxidant proteins, non-erythroid hemoglobin and glutathione synthetase (GSS), targets of transcription factor Nuclear Factor-Erythroid derived-2 (NF-E2). Accordingly, acrolein decreased renal NF-E2 expression and increased cleaved caspase-3 and profibrotic connective tissue growth factor (CTGF) expression. H&E staining demonstrated damaged tubules while Sirius-Red staining demonstrated increased collagen deposition in kidneys of acrolein exposed mice. Over-expression of NF-E2 in immortalized human renal proximal tubule (HK-11) cells, inhibited acrolein-induced CTGF expression and caspase-3 cleavage.

Conclusion

Our studies demonstrate activation of oxidative stress, apoptotic and profibrotic pathways in acrolein treated kidneys. Chronic exposures of acrolein may lead to progressive fibrosis-induced End Stage Renal Disease (ESRD). In vivo modulation of NF-E2 expression may slow-down progressive fibrosis-induced ESRD.

Funding

  • Other NIH Support