Kidney Week

Abstract: FR-PO0067

Unraveling Netrin-1: A Key Mediator of Sex-Based Differences in ADPKD Progression

Session Information

• ADPKD and Cystic Kidney Disease - 2
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)

Authors

• Witherington, Lily, Lily, Augusta University Medical College of Georgia, Augusta, Georgia, United States

Lily Witherington, Lily

• Elmarakby, Ahmed A., Augusta University Medical College of Georgia, Augusta, Georgia, United States

Ahmed A. Elmarakby, PharmD, PhD

• Sullivan, Jennifer C., Augusta University Medical College of Georgia, Augusta, Georgia, United States

Jennifer C. Sullivan, PhD

• Mohamed, Riyaz, Augusta University Medical College of Georgia, Augusta, Georgia, United States

Riyaz Mohamed, PhD

Background

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of ESRD, characterized by excessive cellular proliferation and fluid-filled cyst formation in the kidneys, ultimately leading to kidney failure. Notably, a sex difference has been observed in PKD, with males exhibiting larger cysts and faster disease progression in both clinical cases and rodent PKD models. However, underlying mechanisms driving these differences remain poorly understood. Netrin-1, a secreted protein that is upregulated following kidney injury, is known to play roles in cell proliferation, migration, and tumor growth. However, its involvement in PKD and potential sex-specific differences has not been explored. We hypothesize that greater upregulation of netrin-1 in male mice contributes to accelerated cyst growth compared to females.

Methods

To test this, we disrupted netrin-1 signaling in PKD by genetically deleting netrin-1 in renal tubules of Pkd1^RC/RC (RC/RC), a mouse model of ADPKD. In parallel, 10-week-old wild-type (WT) and RC/RC male and female mice were randomized to receive either vehicle or a netrin-1–specific neutralizing monoclonal antibody (10mg/kg/ip/48hr, n=4–5/group) for 4-weeks. At 14 weeks, all mice were euthanized, and blood and kidney samples were collected. Renal netrin-1 levels were quantified using Western blot and ELISA, renal function was evaluated via measurement of blood urea nitrogen (BUN), and cell proliferation was via ki67 staining.

Results

Our results showed that renal netrin-1 was significantly greater (P<0.001) in Pkd1^RC/RC mice, accompanied by elevated BUN (P<0.0001), cell proliferation (P<0.001) and cyst growth (P<0.0001) compared to respective WT. Moreover, netrin-1 expression, cyst growth, and kidney dysfunction were significantly higher in male versus female RC/RC mice (P_sex*TxT<0.002). Tubular netrin-1 overexpression induces cyst growth only in males (P_sex*TxT<0.0001). Importantly, genetic deletion or neutralization of netrin-1 significantly reduced cell proliferation (P_TxT<0.001) and cyst growth (P_TxT<0.01) and improved kidney function (P_TxT<0.01) in both sexes, however the effect was more pronounced in males (P_TxT<0.002).

Conclusion

These findings suggest that netrin-1 contributes to sex-specific differences in cyst progression in Pkd1^RC/RC mice. Future studies will aim to elucidate the underlying mechanisms by which netrin-1 mediates cyst growth in both sexes.

Acknowledgment

This work was supported by Augusta university SCORE pilot grant award and PKD foundation research award (1372452) and NIDDK (1R01DK142863-01A1) to RM.

Funding

• NIDDK Support