511 - Investigating Cadherin 12 as a modifier of kidney injury in a mouse model of obstructive uropathy

Publication Number: 2496.511

Mayke A.C.. ten Hoor, Leiden University Medical Center, Tilburg, Noord-Brabant, Netherlands; Jaap Mulder, Erasmus MC / LUMC, Rotterdam, Zuid-Holland, Netherlands; Peter Hohenstein, Leiden University Medical Center, Leiden, Zuid-Holland, Netherlands

Background: Posterior urethral valves (PUV) are the most common cause of kidney failure in boys, affecting approximately 1 in 5,000 male births. The urinary tract obstruction characteristic of PUV leads to urinary pressure build-up, ultimately resulting in bladder dysfunction, hydroureteronephrosis, and progressive renal injury. Despite advances in early diagnosis and intervention, clinical outcomes remain highly variable. This variability highlights the need to identify disease-modifying factors that could enable risk assessment and inform personalized treatment strategies. Cadherin 12 (CDH12) was previously identified through a genome-wide association study as a plausible candidate gene for modulating kidney injury in patients with PUV, supported by its expression in fetal kidney tissue, its role in epithelial-mesenchymal transition (EMT) - a key process in renal fibrosis - and its association with genes known to be upregulated in obstructive uropathy.

Objective: To investigate the role of Cdh12 in modulating kidney injury in a mouse model of obstructive uropathy.

Design/Methods: Constitutive Cdh12 knockout mice were generated to assess whether loss of Cdh12 mitigates kidney damage in response to obstructive uropathy. Adult male wildtype and Cdh12 knockout mice underwent unilateral ureteral obstruction (UUO) for 10 days. Both the UUO and contralateral kidneys (CLKs), serving as controls, were harvested for gene expression analysis. Group comparisons were performed using two-way repeated measures ANOVA, followed by the Bonferroni post hoc test.

Results: As demonstrated in Figure 1, initial RT-qPCR results revealed significantly reduced expression of partial EMT markers in Cdh12 knockout kidneys compared to wildtype controls subjected to UUO: Snail family transcriptional repressor 1 (Snai1; -29%), Actin alpha 2 (Acta2; -28%), and Alpha-1 type I collagen (Col1a1; -19%) (all p < 0.05). No gene expression differences were found between the CLKs of wildtype and Cdh12 knockout mice (data not shown).

Conclusion(s): These findings indicate that loss of Cdh12 attenuated the partial EMT response in kidneys subjected to UUO, pointing to a role in fibrotic signaling and reinforcing its function as a potential modifier of kidney injury in obstructive uropathy. Further transcriptomic analysis via 3' mRNA sequencing is ongoing to refine the mechanistic understanding of CDH12 in renal injury.

Figure 1 - Relative mRNA expression levels of Snai1, Acta2, Col1a1 in the UUO kidneys from wildtype (Cdh12+/+) and Cdh12 knockout (Cdh12-/-) mice.
Data are represented as mean ± SEM; *p < 0.05.