Autosomal dominant polycystic kidney disease: recent advances in pathogenesis and potential therapies
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REVIEW ARTICLE
Autosomal dominant polycystic kidney disease: recent advances in pathogenesis and potential therapies Toshio Mochizuki • Ken Tsuchiya • Kosaku Nitta
Received: 19 July 2012 / Accepted: 11 November 2012 Ó Japanese Society of Nephrology 2012
Abstract Autosomal dominant polycystic kidney disease (ADPKD) is the most common progressive hereditary kidney disease. In 85–90 % of cases, ADPKD results from a mutation in the PKD1 gene, and the other 10–15 % of the cases are accounted for by mutations in PKD2. PKD1 and PKD2 encode polycystin-1 and polycystin-2. Polycystin-1 may be a receptor that controls the channel activity of polycystin-2 as part of the polycystin signaling complex. ADPKD is characterized by the progressive development of fluid-filled cysts derived from renal tubular epithelial cells that gradually compress the parenchyma and compromise renal function. In recent years, considerable interest has developed in the primary cilia as a site of the proteins that are involved in renal cystogenesis. The pathological processes that facilitate cyst enlargement are hypothesized to result from two specific cellular abnormalities: (1) increased fluid secretion into the cyst lumen and (2) inappropriately increased cell division by the epithelium lining the cyst. Since there is no clinically approved specific or targeted therapy, current practice focuses on blood pressure control and statin therapy to reduce the cardiac mortality associated with chronic kidney disease. However, recent advances in our understanding of the pathways that govern renal cystogenesis have led to a number of intriguing possibilities in regard to therapeutic interventions. The purpose of this article is to review the pathogenesis of renal cyst formation and to review novel targets for the treatment of ADPKD.
T. Mochizuki (&) K. Tsuchiya K. Nitta Department of Medicine, Kidney Center, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan e-mail: [email protected]
Keywords Autosomal dominant polycystic kidney disease Polycystin Cilium Fluid secretion Therapeutics
Introduction Autosomal dominant polycystic kidney disease (ADPKD) is the most common progressive hereditary kidney disease, and its incidence is 1 per 500–1000 persons in the general population [1]. It is caused by a germline mutation in PKD1 (85–90 %) or PKD2 (10–15 %) [2]. ADPKD is characterized by the slow development over a period of decades of large fluid-filled cysts in the kidneys [3]. The cysts result in dramatic enlargement of the kidneys, and, more importantly, they severely compromise the functional integrity of the remaining normal parenchyma. Cyst initiation and expansion is a complex process characterized by abnormalities in tubular cell proliferation, fluid secretion, extracellular matrix formation, and cell polarity [4]. Clinically significant impairments of renal function in ADPKD usually occur by late middle-age, and end-stage kidney disease (ESKD) requiring renal replacement therapy occurs in approximately 50 % of pa
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