Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a devastating systemic disorder, resulting in approximately $3.3 billion cost per year to the US health care system. It is characterized by progressive development and enlargement of bilateral renal cysts leading to renal failure. Early nephron-protective strategies may alter the course of the disease, but the mechanisms contributing to disease severity and progression remain to be fully elucidated, limiting the development of new therapies. Furthermore, the follow up and evaluation of a treatment response in patients represents a major challenge due to the large phenotypic variability, the natural course of the disease and limitations in currently available biomarkers. It has been proposed that loss of functional polycystin-1 and polycystin-2 (main ADPKD protein products) result in reduced intracellular Ca+2, cAMP accumulation and activation of protein kinase A (PKA) signaling. In addition, ADPKD has been associated with increased renal reactive oxygen species (ROS), mitochondrial abnormalities and metabolic dysregulations early on the disease, likely influencing disease progression. The connection between these processes remains unresolved. Intracellular signaling, organelles, and metabolic pathways are influenced by the redox environment, which is determined by the production and removal of ROS, due to ROS's ability to activate or deactivate a variety of enzymes and signaling molecules. Our preliminary data in Pkd1RC/RC mice shows an early upregulation in renal ROS producer NADPH oxidase 4 (NOX4), associated with mitochondrial abnormalities and metabolic dysregulations that correlates with disease severity and progression. NOX4 upregulation and metabolic abnormalities were more pronounced in a Pkd1RC/RC model with constitutive upregulation of PKA, consistent with previous studies in endothelial cells showing upregulation of NOX4 via cAMP/PKA/CREB-dependent pathway. How NOX4 affects the cellular redox environment and its influence in mitochondrial function and metabolic pathways, and whether activation of PKA signaling leads to NOX4 upregulation are not known. Our central hypothesis is that PKA-mediated NOX4 upregulation, dynamically regulates the cellular redox environment inducing mitochondrial abnormalities and metabolic dysregulations, and contributes to disease severity and progression. Three specific aims will be pursued: Aim 1: will determine the impact of NOX4 in cellular redox environment, mitochondria structure and function and metabolic pathways in ADPKD and the contribution to disease severity and progression. Aim 2: will test whether activation of PKA signaling induces early NOX4 upregulation in ADPKD. Aim 3: will determine whether urine NOX4, surrogate markers of mitochondria injury and oxidative stress may be useful real-time biomarkers to assess disease severity and progression in patients with early ADPKD. Successful studies will have important clinical implications by advancing the understanding of the role of ROS in ADPKD, providing potentially modifiable therapeutic target and identifying novel early biomarkers in ADPKD.
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