Frank Park, PhD, investigates the role of heterotrimeric G-proteins and its regulation in polycystic kidney disease
Polycystic kidney disease (PKD) is the most common genetic disease of the kidney, with over 12 million individuals currently affected worldwide resulting in significant morbidity and mortality. This disease accounts for ~45% of patients with end-stage renal failure in Europe and the United States. The vast majority of patients (~85%) suffer from autosomal dominant polycystic kidney disease (ADPKD), with the remaining 10-15% suffering from the autosomal recessive form of this disease (ARPKD). In normal adult kidneys, the renal epithelia are predominantly in a low mitotic state. In PKD, genetic mutations drive the reversion of these adult epithelial cells towards a dedifferentiated embryological state with elevated levels of cell proliferation. In fact, this abnormal increase in epithelial cell proliferation is the major phenotypic hallmark exhibited in kidneys affected by PKD. Two distinct genes, PKD1 and PKD2, have been positionally cloned over the past 15 years and are believed to be solely responsible for most, if not all cases of ADPKD. Unfortunately, there are no currently available modalities to therapeutically replace the loss of polycystin function. Instead, therapies are targeted to downstream signaling pathways that facilitate the initiation and progression of cysts in ADPKD.
The most promising pharmacologic therapies to treat ADPKD, including vasopressin V2 receptor antagonists and somatostatin receptor agonists are focused on controlling the activity of heterotrimeric G proteins (or G proteins). These G proteins are an ancient, evolutionarily conserved protein family, which are composed of three main subunits: , , and . Over the past several decades, multiple isoforms of each G protein subunit have been identified. This enables G proteins to act as master molecular switches and control a diverse number of intracellular pathways, including those involved in modifying epithelial cell structure, proliferation, growth, survival and polarity. For many decades until the late 1990’s, it was long believed that the activation/inactivation cycle of heterotrimeric G proteins was controlled exclusively at the cell surface by the stimulation of G-protein coupled receptors (GPCR). Since then, there has been a slow shift in this dogmatic thought process due to the identification of two groups of accessory proteins, Regulator of G protein Signaling (RGS) and Activator of G protein Signaling (AGS), which can regulate G protein function in an atypical GPCR-independent mechanism to control signaling intensity i.e., act as a “brake” or “accelerator” of the system.
Little was known about this type of G protein regulation in the context of PKD, until a recent study published in the Journal of American Society of Nephrology by Dr. Frank Park (Division of Nephrology) and colleagues in which they documented the abnormal expression of G-protein signaling modulator 1 (Gpsm1) also known as Activator of G protein Signaling 3 (AGS3) in the kidneys from rodent models of ARPKD and ADPKD compared to the near undetectable expression of this protein in non-cystic kidneys. Similarly high levels of Gpsm1 protein was detected in human ADPKD kidneys compared to normal kidneys. The interesting aspect of this protein is that it has been shown to play a critical role in regulating mitotic spindle orientation, cell polarity and adenylyl cyclase activity, which are biological phenomena are either emerging or already well established as important pathogenic mechanisms in PKD. The Park lab has now shown that direct genetic knockdown of endogenous Gpsm1 in renal epithelial cells is associated with reduced cell numbers, likely through changes in the activation of proliferative as well as apoptotic pathways, which is a current area of focus within the Park lab. The Park lab is currently working with multiple collaborators from within MCW and abroad (Johns Hopkins University) to dissect out the genetic role of Gpsm1 in the development of renal cysts by studying multiple murine models of ADPKD.
In summary, the long-term goal of the Park lab is to continue elucidating the signal transduction pathways involved in the remodeling of epithelial cells to form cysts in the context of PKD. The novel findings by the Park lab are expected to have a positive impact to the field of PKD in two ways: 1) determine the fundamental importance of G protein regulation on epithelial cell proliferation in the absence of extrinsic cues; and 2) provide new therapeutic targets for pharmaceutical intervention in PKD by directly targeting either Gpsm1, its associated G protein subunits and/or downstream signaling molecules.
Article written by Frank Park, PhD, Division of Nephrology