Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease

Author(s)

Bastos, A. P. ; Onuchic, L. F. ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Med, Dept Clin Med, Disciplina Nefrol, BR-01246903 Sao Paulo - Brazil

• Document type: Journal article
• Source: Brazilian Journal of Medical and Biological Research; v. 44, n. 7, p. 606-617, JUL 2011.
• Web of Science Citations: 11

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common human life-threatening monogenic disorders. The disease is characterized by bilateral, progressive renal cystogenesis and cyst and kidney enlargement, often leading to end-stage renal disease, and may include extrarenal manifestations. ADPKD is caused by mutation in one of two genes, PKD1 and PKD2, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC2 is a non-selective cation channel permeable to Ca(2+), while PC1 is thought to function as a membrane receptor. The cyst cell phenotype includes increased proliferation and apoptosis, dedifferentiation, defective planar polarity, and a secretory pattern associated with extracellular matrix remodeling. The two-hit model for cyst formation has been recently extended by the demonstration that early gene inactivation leads to rapid and diffuse development of renal cysts, while inactivation in adult life is followed by focal and late cyst formation. Renal ischemia/reperfusion, however, can function as a third hit, triggering rapid cyst development in kidneys with Pkd1 inactivation induced in adult life. The PC1-PC2 complex behaves as a sensor in the primary cilium, mediating signal transduction via Ca(2+) signaling. The intracellular Ca(2+) homeostasis is impaired in ADPKD, being apparently responsible for the cAMP accumulation and abnormal cell proliferative response to cAMP. Activated mammalian target for rapamycin ( mTOR) and cell cycle dysregulation are also significant features of PKD. Based on the identification of pathways altered in PKD, a large number of preclinical studies have been performed and are underway, providing a basis for clinical trials in ADPKD and helping the design of future trials. (AU)

• FAPESP's process: 09/13926-3 - Effects of Administration of Stem Cells with and without Pkd1 Expression on Renal Injury Induced by Ischemia/Reperfusion and the Renal Cystogenic Potential
• Grantee: Luiz Fernando Onuchic
• Support Opportunities: Regular Research Grants
• FAPESP's process: 10/10425-0 - Effects of Pkd1 Gene Expression in Exogenous Mesenchymal Stem Cells on Renal Ischemia/Reperfusion Injury and Regeneration
• Grantee: Ana Paula Almeida Bastos
• Support Opportunities: Scholarships in Brazil - Post-Doctoral