Glycogen Synthase Kinase‐3 Inhibition Reduces Renal Cystogenesis in Polycystic Kidney Disease

Abstract

ObjectivePolycystic kidney diseases (PKD) are characterized by disregulated vasopressin (AVP) signaling in renal collecting ducts and elevated cAMP levels that contribute to progressive cyst enlargement. We previously found that inactivation of glycogen synthase kinase 3β (GSK3β) reduces AVP‐mediated increase in renal cAMP levels. Hence, we examined if inhibition of GSK3 could ameliorate cyst formation and growth in PKD.Methodscpk/cpk mouse model for autosomal recessive PKD show rapid postnatal renal cyst progression resulting in death by weaning. Wild type (WT) or cpk/cpk mice were injected daily with vehicle or GSK3 inhibitor, (TDZD‐8, 5mg/Kg BWt, IP) between postnatal days 3 to 14.ResultsGSK3β levels were elevated and detected in cyst‐lining epithelia of cpk/cpk mice. Renal cyst volume, kidney weight/ body weight ratio, blood urea nitrogen levels and interstitial fibrosis were significantly reduced in TDZD‐8 treated versus vehicle treated cpk/cpk mice. Renal cAMP levels were significantly reduced in TDZD‐8 treated cpk/cpk mice compared to vehicle treated cpk/cpk mice. In vitro cAMP induced cystogenesis assays revealed that GSK3 inhibitors like TDZD‐8 SB216763 and LiCl significantly reduces cyst formation by M1 cells.ConclusionThese studies show that inhibition of GSK3, a crucial kinase in AVP signaling preserves renal function in cpk/cpk mice by reducing renal cAMP levels and cystogenesis.