Kidney Week

Abstract: FR-OR108

Temporal and Tissue-Specific Activation of AHR Signaling in Discrete Renal Diseases

Session Information

• Signaling in CKD Progression
  October 26, 2018 | Location: 23A, San Diego Convention Center
  Abstract Time: 05:42 PM - 05:54 PM

Category: CKD (Non-Dialysis)

• 1903 CKD (Non-Dialysis): Mechanisms

Authors

• Walker, Joshua A., Boston University, Boston, Massachusetts, United States

Joshua A. Walker, PhD

• Roth, Daniel M., Boston University, Boston, Massachusetts, United States

Daniel M. Roth,

• Belghasem, Mostafa, Boston University, Boston, Massachusetts, United States

Mostafa Belghasem,

• Tashjian, Joseph Y., Boston University, Boston, Massachusetts, United States

Joseph Y. Tashjian,

• Richards, Sean, Boston University, Boston, Massachusetts, United States

Sean Richards,

• Whelan, Stephen A., Boston University, Boston, Massachusetts, United States

Stephen A. Whelan,

• Arinze, Nkiruka, Boston University, Boston, Massachusetts, United States

Nkiruka Arinze,

• Lee, Norman, Boston University, Boston, Massachusetts, United States

Norman Lee,

• Kolachalama, Vijaya B., Boston University, Boston, Massachusetts, United States

Vijaya B. Kolachalama,

• Francis, Jean M., Boston University, Boston, Massachusetts, United States

Jean M. Francis,

• Chitalia, Vipul C., Boston University School of Medicine, Boston, Massachusetts, United States

Vipul C. Chitalia,

Background

Aryl hydrocarbon receptor (AHR) signaling is emerging as an important mediator of uremic toxicity regulating several manifestations of uremic solutes. While previous studies showed AHR activation in whole organs in response to uremia, no studies have examined cell- type specific AHR activation in vivo in uremic and non-uremic conditions in discrete models of kidney diseases.

Methods

Transgenic mice containing two dioxin-response elements upstream of a beta-galactosidase (β-gal) reporter gene were subjected torenalanischemia/areperfusioninjury(I/R),andanaAdenine-induced CKD,oranda recently developed Indoxylsolute specific animal modelss. TCDD, a canonicalAHRligand served as a positive control. β-gal protein expressionswaserecompared using a recently validatedquantitativecolor-based image segmentation quantitative image analytical techniqueanalysis. Double label immunofluorescence was used to analyze cell specific expression of β-gal. mRNA was analyzed with qRT-PCR. Plasma was analyzed for levels of blood-urea nitrogen (BUN), creatinine.

Results

In all the models, β-gal expression in kidneys predominated in both the proximal and distal renal tubules, but distinctly sparedwas absent fromthe glomeruli. In I/R model, β-gal expression significantly increased within 24 hours of injury (p<0.05) and decreased at both 48 and 96hrs post-surgery, while renal function continued to remains significantly altered at all these time points (p<0.01). Along with renal tubules, CKD and solute specific AHR models showed significant increase β-gal expression in endothelial, smooth muscle cells of the aorta and liver (p<0.05). A trend towards increased AHR activation in cardiomyocytes and neuron cells bodies was observed. Xxx Uremic solutes

Conclusion

The current study represents the first use of this reporter animal in disease-specific models.The model demonstrated a broad sensitivity in uremic kidney diseases and also in uremia-independent mechanisms such as hypoxia. While supportive of our previous observations in uremic thrombosis, AHR activation in some of the organs provide a hypothesis-generating insight. The model demonstrated a broad sensitivity in uremic kidney diseases and also in uremia-independent mechanisms such as hypoxia.

Funding

• Other NIH Support