Greater netrin-1 in male ADPKD mice drives enhanced cyst growth compared to females

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of end-stage renal disease (ESRD). ADPKD is characterized by excessive cellular proliferation and fluid-filled cyst formation in the kidneys, which ultimately contribute to the development of ESRD and kidney failure. Notably, a sex difference has been observed in ADPKD, with males exhibiting larger cyst growth and faster disease progression than females in both clinical cases and rodent ADPKD models. However, the underlying mechanisms driving these differences remain poorly understood. Netrin-1, a laminin-related secreted protein that is upregulated following kidney injury, is known to play roles in cell proliferation, migration, and tumor growth. However, its involvement in ADPKD 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. To test this, 10-week-old male and female wild-type (WT) and Pkd1RC/RC mice were randomized to receive either vehicle or a netrin-1–specific neutralizing monoclonal antibody (10 mg/kg/ip/48hr, n=4–5/group) for 4 weeks. At 14 weeks of age, all mice were euthanized, and blood and kidney samples were collected for histological, biochemical, and Western Blot analyses. Renal netrin-1 protein levels were quantified using both Western Blot and ELISA, renal function was evaluated via measurement of blood urea nitrogen (BUN), cell proliferation was measured via ki67 staining, and cyst growth was determined by measurement of the kidney to body weight ratio. Our results showed that renal netrin-1 was significantly greater in Pkd1RC/RC mice (PGenotype< 0.001), accompanied by elevated BUN (PGenotype< 0.0001), cell proliferation (PGenotype< 0.001), and cyst growth (PGenotype< 0.0001) when compared to same-sex respective WT mice. Moreover, netrin-1 levels (Psex< 0.0001; Psex*Genotype< 0.0001), cyst growth (Psex< 0.003; Psex*Genotype< 0.001), and kidney dysfunction (Psex< 0.001; Psex*genotype< 0.002) were significantly higher in male Pkd1RC/RC mice compared to their age matched female counterparts. Notably, the neutralization of netrin-1 significantly reduced cell proliferation (PTxT< 0.00;), cyst growth (PTxT< 0.01), and improved kidney function (PTxT< 0.01) in both sexes. However, the effect was more pronounced in males when compared to females (Ki67: Psex*TxT< 0.002; cyst growth: Psex*TxT< 0.002; BUN: Psex*TxT< 0.002). These findings suggest that netrin-1 contributes to sex-specific differences in the cyst progression of male and female Pkd1RC/RC mice. Future studies will aim to elucidate the impact of sex hormones and the underlying mechanisms by which netrin-1 mediates differences in cyst growth between both sexes. Table: see text This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.