Abstract: FR-PO875
Targeting Interleukin-6/Glycoprotein130 Signaling Ameliorates Renal Injury in Polycystic Ovary Syndrome
Session Information
- Women's Health and Kidney Diseases
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Women's Health and Kidney Diseases
- 2200 Women's Health and Kidney Diseases
Authors
- Rezq, Samar, The University of Mississippi Medical Center, Jackson, United States
- Basnet, Jelina, The University of Mississippi Medical Center, Jackson, Mississippi, United States
- Huffman, Alexandra M., The University of Mississippi Medical Center, Jackson, Mississippi, United States
- Flaherty, Joseph R., The University of Mississippi Medical Center, Jackson, Mississippi, United States
- Abdelhameed, Ahmed, The University of Mississippi Medical Center, Jackson, Mississippi, United States
- Alsemeh, Amira Ebrahim, Zagazig University Faculty of Human Medicine, Zagazig, Egypt
- Asala, Tolulope Eyitayo, The University of Mississippi Medical Center, Jackson, Mississippi, United States
- Yanes Cardozo, Licy, The University of Mississippi Medical Center, Jackson, Mississippi, United States
- Romero, Damian G., The University of Mississippi Medical Center, Jackson, Mississippi, United States
Background
Polycystic ovary syndrome (PCOS) usually presents with hyperandrogenism, chronic low-grade systemic inflammation, and renal injury. The inflammatory cytokine Interleukin-6 (IL-6) is involved in the pathogenesis of several renal injury models by activating its soluble receptor (sIL-6R) and a membrane-bound glycoprotein130 (gp130); however, its role in PCOS-mediated renal damage is unknown. We aimed to test the hypothesis that the increases in systemic and renal IL-6 levels, mediate renal injury in PCOS via IL-6/gp130 signaling activation.
Methods
PCOS was induced in three-week-old female mice using dihydrotestosterone (DHT)-filled Silastic tubes (8 mg, SC) or vehicle for 12 weeks. Eight weeks post-induction, the animals were treated with the IL-6/gp130 signaling inhibitor SC144 (10 mg/kg, SC, 3x/week) or its vehicle for 4 weeks. Body weight, fat mass (EchoMRI), kidney weight, the glomerular filtration rate (GFR, transcutaneous fluorescence), as well as the renal injury markers urinary albumin to creatinine ratio (UACR, clinical chemistry analyzer) and NGAL (ELISA) were assessed. Renal gp130 protein and IL-6 mRNA expression were quantified by Western blot and RT-qPCR, respectively. H&E stained renal sections were used for histopathological analysis, whereas Masson trichrome staining was used to assess renal fibrosis.
Results
DHT significantly (p<0.05) increased body weight (26.2±0.9 vs. 22.23±0.4 g), fat mass (3.2±0.4 vs. 1.9±0.4 g), kidney weight (1.4-fold), UACR (1,227±420 vs. 404±169 μg albumin/mg creatinine), urinary NGAL (2-fold), and serum IL-6 levels (2.2-fold). DHT also increased the expression of renal gp130 and IL-6 (1.5-fold). The disturbance in the aforementioned parameters was associated with decreased GFR and a worsen renal histological structure with congested glomeruli, exfoliation of luminal epithelial lining, interstitial hemorrhage, and fibrotic changes. SC144 therapy had no significant effects on kidney weight, GFR, or NGAL, but it attenuated DHT-induced increases in fat mass and UACR while decreasing both glomerular and tubular injury and renal fibrosis.
Conclusion
IL-6/gp130 activation plays a significant role in renal outcomes in PCOS and could be targeted as a novel therapeutic approach to ameliorate renal injury in PCOS.
Funding
- Other NIH Support