ABSTRACT
The purpose of the present study was to determine the role of inositol 1,4,5-trisphosphate receptor 3 (IP3R3) in renal cyst development in autosomal dominant polycystic kidney disease (ADPKD). 2-aminoethoxy-diphenyl borate (2-APB) and shRNA were used to suppress the expression of IP3R3. The effect of IP3R3 on cyst growth was investigated in Madin-Darby canine kidney (MDCK) cyst model, embryonic kidney cyst model and kidney specific Pkd1 knockout (PKD) mouse model. The underlying mechanism of IP3R3 in promoting renal cyst development was investigated by Western blot and immunofluorescence staining. The results showed that the expression level of IP3R3 was significantly increased in the kidneys of PKD mice. Inhibiting IP3R3 by 2-APB or shRNA significantly retarded cyst expansion in MDCK cyst model and embryonic kidney cyst model. Western blot and immunofluorescence staining results showed that hyperactivated cAMP-PKA signaling pathway in the growth process of ADPKD cyst promoted the expression of IP3R3, which was accompanied by a subcellular redistribution process in which IP3R3 was translocated from endoplasmic reticulum to intercellular junction. The abnormal expression and subcellular localization of IP3R3 further promoted cyst epithelial cell proliferation by activating MAPK and mTOR signaling pathways and accelerating cell cycle. These results suggest that the expression and subcellular distribution of IP3R3 are involved in promoting renal cyst development, which implies IP3R3 as a potential therapeutic target of ADPKD.
Subject(s)
Animals , Dogs , Mice , Cysts/genetics , Inositol 1,4,5-Trisphosphate Receptors/pharmacology , Kidney/metabolism , Polycystic Kidney Diseases/metabolism , Polycystic Kidney, Autosomal Dominant/drug therapy , Madin Darby Canine Kidney CellsABSTRACT
Resumen: La poliquistosis renal autosómica dominante es la enfermedad renal hereditaria más frecuente. Se caracteriza por la progresiva aparición de quistes renales que suelen conducir a la enfermedad renal crónica extrema en la edad adulta. La aprobación del uso de tolvaptán (antagonista del receptor V2 de la vasopresina) ha marcado un cambio significativo en el tratamiento de esta enfermedad. En los últimos años apareció evidencia que demuestra el beneficio en iniciar tratamiento con tolvaptán en pacientes que presentan una enfermedad con rápida evolución. Se realiza una revisión descriptiva de los principales estudios clínicos publicados en el periodo 2012-2022 y se sugiere un esquema de utilidad para seleccionar aquellos pacientes que pueden beneficiarse del inicio de tratamiento.
Abstract: Autosomal dominant polycystic kidney disease is the most common hereditary kidney disease. It is characterized by the progressive appearance of renal cysts that usually lead to extreme chronic kidney disease in adulthood. The approval of the use of tolvaptán (V2 vasopressin receptor antagonist) has meant a significant change in the treatment of this disease. In recent years, evidence has proved the benefits of initiating treatment with tolvaptán in patients with a rapidly evolving disease. A descriptive review of the main clinical studies published in 2012-2022 period is carried out and a useful scheme is suggested to select those patients who can benefit from the start of treatment.
Resumo: A doença renal policística autossômica dominante é a doença renal hereditária mais comum. Caracteriza-se pelo aparecimento progressivo de cistos renais que geralmente levam à doença renal crônica extrema na idade adulta. A aprovação do uso do tolvaptano (antagonista do receptor de vasopressina V2) marcou uma mudança significativa no tratamento dessa doença. Nos últimos anos, surgiram evidências que demonstram o benefício de iniciar o tratamento com tolvaptano em pacientes com doença de evolução rápida. Faz-se uma revisão descritiva dos principais estudos clínicos publicados no período 2012-2022 e sugere-se um esquema útil para selecionar aqueles pacientes que podem se beneficiar do início do tratamento.