Molecular Mechanisms of Epigenetic Regulation, Inflammation, and Cell Death in ADPKD

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder, which is caused by mutations in thePKD1andPKD2genes, characterizing by progressive growth of multiple cysts in the kidneys, eventually leading to end-stage kidney disease (ESKD) and requiring renal replacement therapy. In addition, studies indicate that disease progression is as a result of a combination of factors. Understanding the molecular mechanisms, therefore, should facilitate the development of precise therapeutic strategies for ADPKD treatment. The roles of epigenetic modulation, interstitial inflammation, and regulated cell death have recently become the focuses in ADPKD. Different epigenetic regulators, and the presence of inflammatory markers detectable even before cyst growth, have been linked to cyst progression. Moreover, the infiltration of inflammatory cells, such as macrophages and T cells, have been associated with cyst growth and deteriorating renal function in humans and PKD animal models. There is evidence supporting a direct role of the PKD gene mutations to the regulation of epigenetic mechanisms and inflammatory response in ADPKD. In addition, the role of regulated cell death, including apoptosis, autophagy and ferroptosis, have been investigated in ADPKD. However, there is no consensus whether cell death promotes or delays cyst growth in ADPKD. It is therefore necessary to develop an interactive picture between PKD gene mutations, the epigenome, inflammation, and cell death to understand why inherited PKD gene mutations in patients may result in the dysregulation of these processes that increase the progression of renal cyst formation.

A synthetic agent ameliorates polycystic kidney disease by promoting apoptosis of cystic cells through increased oxidative stress

“…Cyst cell apoptosis has been investigated in many ADPKD models, with no clear consensus emerging regarding its involvement in disease progression ( 37 , 38 ). We have not observed significant apoptosis in any Pkd1 cystic model irrespective of timing of inactivation or tubule segment ( 26 , 27 ).…”

The Mechanisms of Regulated Cell Death: Structural and Functional Proteomic Pathways Induced or Inhibited by a Specific Protein—A Narrative Review

“…RCD means that the steps for cell degeneration are established, but that does not mean that the cell is predetermined to die; that is, there will be no apoptosis if there is no signal to initiate it. The role of apoptosis is important in many physiological and pathological processes of multicellular organisms, such as the morphogenesis of organs and tissues during embryonic development, in the maintenance and regeneration of tissues in the adult animal, in response to pathogens, or as a response to cellular stress and pathologies such as cancer [ 31 ]. The number of cells that die by apoptosis is enormous, both during embryonic development and in the adult state, associated with caspases, that not only control apoptosis, but also proliferation, differentiation, cell form and cell migration [ 4 ].…”

Broadening horizons: the multifaceted functions of ferroptosis in kidney diseases

“…Oxidative stress, inflammation, hypoxia and cell death play key roles in cyst formation and progression in ADPKD. Interestingly, several studies strongly supported that ferroptosis was involved in ADPKD development 141 . TMEM16A is a chloride bicarbonate transmembrane channel that is closely associated with renal cyst growth in ADPKD.…”