Robin L. Maser, PhD
Maser Laboratory: Scientific background
Autosomal dominant (AD) PKD is the most common genetic cause of end-stage renal failure. ADPKD is primarily characterized by the development and enlargement of hundreds of fluid-filled cysts that arise from epithelia-lined tubules within both kidneys. Cystic epithelial cells exhibit abnormal phenotypes that include increased proliferation, transepithelial fluid secretion, extracellular matrix deposition, and apoptosis. ADPKD is a systemic disease associated with cysts in the liver, cerebral aneurysms, hypertension, cardiac valve abnormalites, left ventricle hypertrophy, and endothelial dysfunction. Read more on the background.
Mutations within the PKD1 gene, encoding polycystin-1 (PC-1) protein, account for 85% of ADPKD cases, while the remainder are due to mutations within the PKD2 gene encoding polycystin-2 (PC-2). Although ADPKD is inherited in a dominant fashion, it is thought to have a recessive mechanism at the cellular level, requiring a second somatic mutation within either gene to lead to cyst initiation. PC1 activates multiple signaling pathways, while PC-2 is a non-selective cation channel.
Together, PC-1 and PC-2 form a receptor/ion channel signaling complex within the primary cilium and mediate fluid shear stress-induced intracellular calcium signaling, that is thought to be involved in maintaining renal cell differentiation. Recent studies suggest that PKD can arise from abnormalities in either the structure or function of the primary cilium.
Cellular antioxidant protection is provided by xenobiotic- and oxidant-metabolizing enzymes, reducing agents, and antioxidant proteins. Cells need to maintain a balance of oxidants and reductants (redox homeostasis) to prevent oxidant damage to cellular macromolecules (DNA, lipids, proteins) and to maintain regulation of growth- and death-promoting signaling pathways. The antioxidant response element (ARE) is a cis-acting, regulatory DNA sequence found in the promoters of a family of genes that are induced by electrophilic xenobiotics, phenolic antioxidants, and endogenous oxidants. Members of the ARE gene family provide basic cellular defense against endogenous oxidants and exogenous toxicants. The key transcriptional activator of the ARE is the NF-E2-related factor-2, Nrf2. Transactivation of the ARE by Nrf2 is responsible for both basal and induced expression of this gene family.
Nrf2 knockout (KO) mouse models have allowed the identification of Nrf2/ARE-regulated genes in many organ systems and are beginning to uncover new roles for this large gene family. Interestingly, Nrf2 and ARE gene expression were recently shown to be activated by laminar fluid flow (shear stress) in endothelial cells.