Extracellular Matrix Abnormalities in Polycystic Kidney Disease

Polycystic kidneys diseases (PKD) are a group of monogenic kidney disorders that lead to cyst development in the kidneys. Polycystic kidney diseases are a common indication for renal transplantation and dialysis and a leading cause of end-stage renal disease (ESRD). There are two types of PKD, the autosomal dominant type called ADPKD with an estimated prevalence rate of 1:400-1:1000 worldwide (Torres & Harris, 2009) and autosomal recessive PKD (ARPKD) with an estimated prevalence rate of 1:10,000-1:20,000. ADPKD is the most common form of PKD, whereas ARPKD is the most lethal form and affects newborns. ADPKD is attributed to several mutations in one or both of the two genes PKD1 and PKD2, whereas ARPKD is attributed to mutations in the PKHD1 gene. The protein products of PKD1 and PKD2 are transmembrane proteins called polycystin 1 and polycystin 2 respectively, whereas the protein product of PKHD1, also a transmembrane protein is termed as fibrocystin. In ADPKD, the cysts arise throughout the nephron segments, whereas in ARPKD, cysts arise from the collecting duct as fusiform dilatations. In addition to kidney cysts, PKD patients generally also exhibit liver disease. Abnormalities in electrolyte secretion (Yamaguchi et al., 1997), EGF and cAMP dependent cell proliferation (Hanaoka and Guggino (2000); Richards et al., 1998), cell-matrix interaction (Ramasubbu et al., 1998; Wilson et al., 1992) and planar cell polarity (Fisher et al., 2006; Patel et al., 2008) have all been attributed to the disease mechanism of PKD. However, the exact cause of cystogenesis is yet unknown. Following Dr. Grantham’s seminal work showing abnormal fluid secretion in ADPKD (Grantham, 1993), considerable progress has been done in that area (Magenheimer et al., 2006). Our understanding of the role of cAMP in cystogenesis has led to the development of high potency antagonists to vasopressin V2 receptors as therapeutic agents for ADPKD, which are currently undergoing clinical trials. There has been a great interest in understanding the role of primary cilia in PKD cystogenesis since several of the PKD associated proteins have been reported be localized to primary cilia in addition to other locations in the kidney epithelia (Yoder at al., 2002; Wang et al., 2007). However, the role of abnormal extracellular matrix in cystogenesis has not been pursued rigorously. This review will explore the current and past work that has been undertaken in this area.