Abstract
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by the progressive growth of cysts but it is also accompanied by diffuse tissue scarring or fibrosis. A number of recent studies have been published in this area, yet the role of fibrosis in ADPKD remains controversial. Here, we will discuss the stages of fibrosis progression in ADPKD, and how these compare with other common kidney diseases. We will also provide a detailed overview of some key mechanistic pathways to fibrosis in the polycystic kidney. Specifically, the role of the ‘chronic hypoxia hypothesis’, persistent inflammation, Transforming Growth Factor beta (TGFβ), Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) and microRNAs will be examined. Evidence for and against a pathogenic role of extracellular matrix during ADPKD disease progression will be provided.
Highlights
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by the progressive growth of cysts but it is accompanied by diffuse tissue scarring or fibrosis
A key contributory event in the initiation of fibrosis in ADPKD, is the inheritance of germline mutations in the PKD1 [9,10,11,12] or PKD2 [13] genes, which encode for the two polycystin proteins which co-localise in the primary cilia and other compartments [14] and interact with each other [15]
Indirect evidence that fibrosis may protect the polycystic kidney comes from cell signalling studies, where master regulators of the fibrogenesis processes, such as TGFβ, have either protective or neutral roles in the development of cystic disease, suggesting that fibrosis in ADPKD may have some protective roles
Summary
Fibrosis is defined as the excessive accumulation of extracellular matrix proteins (ECM), which is a direct outcome of dysregulation of a number of processes (and related pathways) in response to tissue injury [5]. Fibrosis progression is divided into three stages: (i) initiation, followed by (ii) persistent inflammation, and lastly (iii) established fibrosis. In humans, it is only in the embryo where tissue can be repaired without inflammation, scarring or fibrosis [7,8], with the embryonic mechanisms of scar-free healing remaining elusive. Established fibrosis is defined as tissue overgrowth, hardening and often scarring (Figure 1), characterized by excessive deposition of matrix proteins, such as collagen fibers.
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