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Abstract: TH-PO946

Sex-Specific Renal Pathology Following 5/6 Nephrectomy Is Modulated by miR-146b

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Paterson, Mark, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Kriegel, Alison J., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
Background

Chronic kidney disease (CKD) presents a complex pathological landscape in both men and women. Many studies have shown miRNAs can be powerful mediators of pathology at the molecular level. Our work focuses on the role of miRNAs in CKD, utilizing the 5/6 nephrectomy (5/6Nx) rat model. We have reported a significant increase in the expression of miR-146b in kidney tissue following 5/6Nx. The present study investigates the contribution miR-146b to CKD, and the relative contribution of sex hormones in modulating the pathology of CKD.

Methods

Male and female Sprague Dawley (SD) rats underwent 5/6Nx or sham surgeries at 10 weeks of age. The 5/6Nx consists of surgical resection of 2/3 of the left kidney and the entire right kidney. Seven weeks later, urine and blood were collected, the rats were euthanized, and the kidneys harvested for downstream application. To study the contribution of miR-146b, wild-type SD rats (WT) were compared to miR-146b null mutants (KO). To study the contribution of sex hormones, intact rats were compared to gonadectomized rats. Histological examination of kidney tissue was performed to assess renal fibrosis. Metabolite and electrolyte levels were measured in blood and urine using a blood gas analyzer. Creatinine clearance (CrCl) and fractional excretion of sodium (FENa) were derived from plasma and urine concentrations and urine flow rate.

Results

Following 5/6Nx, male WT and KO rats exhibit impaired renal function without significant renal fibrosis; diminished CrCl (WT: 2.09 vs. 0.85 ml/min, KO: 3.28 vs. 0.82 ml/min; sham vs. 5/6Nx) and increased FENa (WT: 0.12 vs. 0.40%; KO: 0.09 vs. 0.40%). Female WT rats exhibited similar renal dysfunction without fibrosis; reduced CrCl (0.99 vs. 0.28 ml/min) and elevated FENa (0.17 vs. 0.72%). However, female KO rats exhibited an exacerbation of renal dysfunction and injury compared to WT after 5/6Nx; sharply reduced CrCl (0.28 vs. 0.08 ml/min, WT vs. KO 5/6Nx), elevated FENa (0.72 vs. 4.43%), and significant fibrosis in the renal cortex (3.30 vs. 13.1% fibrotic area). Ovariectomy ameliorated nearly all structural and functional pathologies.

Conclusion

Our study suggests an important protective role for miR-146b in CKD which may be, in part, via modulation of estrogen signaling in the kidney. Future studies will address specific pathways targeted by miR-146b to elucidate its mechanism of action in CKD.

Funding

  • Other NIH Support