Abstract: FR-PO842
Sex-Based Differences in Proximal Tubule Recovery of Filtered Proteins
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
- Shipman, Katherine E., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
- Baty, Catherine J., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
- Youm, Elynna B., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
- Edwards, Aurelie, Boston University, Boston, Massachusetts, United States
- Weisz, Ora A., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
Background
The proximal tubule (PT) efficiently reclaims albumin and other proteins that escape the glomerular filtration barrier to maintain protein free urine. The recovery of filtered proteins occurs via receptor-mediated endocytosis facilitated by the multiligand receptors megalin and cubilin. PT health is impacted by excess albumin uptake that occurs when the glomerular barrier is breached and by nephrotoxic drugs that enter cells in a megalin/cubilin dependent manner. Transcriptomic and proteomic studies in male rodents have demonstrated differences in the expression of megalin and cubilin across the S1, S2, and S3 sub-segments that comprise the PT. Based on this, we previously developed an axial model of protein uptake in mice which predicts that most uptake under normal conditions occurs in S1, with S2 providing excess uptake capacity under nephrotic conditions. Multiple studies have shown that females are more protected from renal injury than males, however, the mechanisms underlying this difference in protection from renal injury are unknown.
Methods
To determine if there are sex-based differences in baseline PT recovery of filtered proteins, urine and kidneys were collected from five male and five female 13-week-old C57BL/6 mice. Urinary albumin was quantified by ELISA. Kidneys were processed for Western blotting and immunofluorescence staining. We used imaging-based approaches to quantify the expression and distribution of megalin and cubilin in SGLT2-positive S1 and SGLT2-negative S2 segments.
Results
Compared to males, female mice had lower levels of urinary albumin excretion when normalized to creatinine at baseline. Female mice had greater expression of total megalin and cubilin and decreased expression of NHE3 in the kidney cortex. Male and female mice had similar levels of megalin expression and surface localization in S1, however, female mice had greater expression and surface localization of megalin in S2. A greater fraction of total cubilin localized to the apical surface compared to megalin along the length of PT.
Conclusion
Our data suggest differences in the capacity of the PT to recover filtered proteins between male and female mice which could be especially relevant under nephrotic conditions. Current studies are focused on incorporating these sex-based differences into a mathematical model of protein uptake along the length of the PT.
Funding
- NIDDK Support