Drug Treatment Approaches for HNF1B-Related Cystic Kidney Disease in a Mouse Model

Background: Heterozygous variants in the hepatocyte nuclear factor 1ß (HNF1B) constitute the most prevalent identified monogenic cause of developmental kidney disease. To date, treatment remains primarily symptomatic, and the overall prognosis is largely dependent on the renal outcome. In mouse models, Hnf1b has been demonstrated to regulate transcription of multiple cystic disease genes implicated in signaling pathways of autosomal dominant polycystic kidney disease (ADPKD). Recent reports also indicate the role of dysregulated glutamatergic signaling in the pathogenesis of kidney dysplasia associated with HNF1B. The pharmacological potential of regulators that influence ADPKD downstream and glutamate signaling suggests that these drugs may also be repurposed to address HNF1B-associated kidney phenotypes. Methods: Several repurposed substances, i.e. ADPKD drugs from preclinical studies and N-methyl-D-Aspartate (NMDA) regulators, were tested in a previously established Hnf1b knockout mouse model. To assess their potential therapeutic effect, the impact on cyst size alongside of renal retention parameters was quantified, including blood urea nitrogen and creatinine. Results: Inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, regulating secretion of cyst fluid, induced a significant decrease of the cystic index in the Hnf1b mouse model. The remaining repurposed drugs for ADPKD or NMDA regulators did not cause any significant changes in cystic indexes or laboratory parameters indicative of impaired kidney function. Conclusion: Our results suggest a potential therapeutic application of CFTR inhibitors in the context of dysplastic kidney disease caused by HNF1B, potentially due to the prominent role described for CFTR during neonatal and embryonic tubular development.