Kidney Week

Abstract: TH-PO1126

Sex-Dependent Effects of Whole-Life Arsenic Exposure and High-Fat Diet on the Kidney Proteome

Session Information

• CKD: Mechanisms - 1
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Cummins, Timothy, University of Louisville School of Medicine, Louisville, Kentucky, United States

Timothy Cummins, PhD

• Carty, Joshua Shane, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Joshua Shane Carty, MD

• Barati, Michelle T., University of Louisville School of Medicine, Louisville, Kentucky, United States

Michelle T. Barati, PhD

• Gaweda, Adam E., University of Louisville School of Medicine, Louisville, Kentucky, United States

Adam E. Gaweda, PhD

• Wilkey, Daniel Wade, University of Louisville School of Medicine, Louisville, Kentucky, United States

Daniel Wade Wilkey

• States, J. Christopher, University of Louisville School of Medicine, Louisville, Kentucky, United States

J. Christopher States, PhD

• Klein, Jon B., University of Louisville School of Medicine, Louisville, Kentucky, United States

Jon B. Klein, MD, PhD, FASN

• Merchant, Michael, University of Louisville School of Medicine, Louisville, Kentucky, United States

Michael Merchant, PhD

Background

The Agency for Toxic Substances and Disease Registry (ATSDR) Substance Priority List ranks Arsenic (As) the number one priority. Environmental exposure to As as well as western high fat diets are global concerns for developed and developing nations. High-fat diet co-morbidities including diabetes, kidney disease, hypertension and cardiovascular disease likely modify pathologic mechanisms of As renal toxicity. We addressed the hypothesis that a proteomic approach to study whole life exposure to sodium arsenite (As_i) in male and female mice fed a high fat diet could reveal proteins and mechanistic pathways important to understanding As_i toxicity.

Methods

Cortical kidney lysates from four groups of male and female mice (n=3/group) were compared using a proteomic approach. Groups included (A) mice exposed to 0 or (B) 100 ppb As_i in drinking water from conception, and fed (C) normal or (D) high-fat chow diet for 21 weeks post weaning at 3 weeks. Univariate and multivariate methods were used to compare protein abundances (q<0.05) and identify As_i, sex-based or diet-induced effects on the kidney. Immunohistochemistry and immunoblot confirmation assays indicated potential proteins associated with kidney dysregulation as a function of As_i exposure, sex-based differences and diet.

Results

2931 kidney proteins were identified, 107 were increased and 94 were decreased (log2FC1) in females vs males after multiple testing correction. Multivariate PLSDA and clustering methods defined differences dominated by sex>diet>>As_i. 2-way ANOVA identified As-exposure regulation of glomerular proteins important for podocyte function, and proximal and distal tubular proteins including As_i up-regulation of aquaporin-3 in females only. Histologic analysis identified arsenic-associated focal degenerative tubule cell toxicity in males and female. Overall, informatics analyses indicated sex, diet, and As_i proteome differences appear to impact multiple biological components such as RNA binding, mitochondria function, and energy metabolism.

Conclusion

Renal proteome studies of sexual dimorphic responses in As_i and high-fat diet exposures indicate potential for sex- and As_i-dependent markers of diet induced kidney damage.

Funding

• NIDDK Support