Tao 2013

Effective Treatment Of Polycystic Kidney Disease By Inactivation Of GSK3β in a cpk/cpk Mouse Model

Shixin Tao, Erin Suderman and Reena Rao

Objective: Polycystic kidney disease (PKD) is characterized by the formation of multiple fluid filled cysts.  Elevated cAMP levels contribute to cystogenesis and cyst expansion and inhibition of vasopressin-mediated cAMP generation is known to ameliorate PKD. We previously found that inactivation of a serine/ threonine protein kinase called glycogen synthase kinase 3β (GSK3β) can reduce renal vasopressin-mediated cAMP generation. Hence, in the current study we examined if inhibition or gene deletion of GSK3 could ameliorate cyst development and progression in PKD.

Methods: For the studies we used cpk/cpk mice, a model for autosomal recessive PKD, characterized by rapid postnatal renal cyst expansion resulting in death around weaning. Mice were injected daily from postnatal day 4 till day 15 with vehicle or GSK3 inhibitor, (TDZD-8, 5mg/Kg). In a separate study, we generated cpk/cpk mice with renal collecting duct specific GSK3β gene knockout. Kidney structure and function as well as markers for fibrosis and cell proliferation were analyzed.

Results: TDZD-8 treatment as well as GSK3β gene deletion significantly retarded renal cysts development and disease progression in cpk/cpk mice as suggested by the reduced Kidney /Body weight ratio, cyst area, cyst number and Blood urea nitrogen levels when compared to vehicle treated cpk/cpk mice.  Renal cAMP concentrations, fibrosis and proliferation were also significantly reduced in in both TDZD-8 treated and GSK3β knockout mice when compared to controls.

Conclusion: These results implicate GSK3β in renal cyst growth and suggest that GSK3 inhibitors may hold therapeutic potential to reduce cyst growth in PKD.