Grant: Project Grant

Polycystic kidney disease (PKD) is the most common inherited disorder of the kidney, affecting 1 in every 500 people. The vast majority of PKD cases are caused by a mutation or loss of one of two proteins, polycytsin 1 or 2. These proteins are located in the mechanical and chemical antenna of the cells, the so called primary cilium. The loss of polycystin function leads to the formation of large fluid-filled cysts, because it disturbs normal cell division in the renal tubules, the system responsible for resorbing nutrients and secreting waste products. Beside cyst formation, the other major feature of PKD is progressive organ scarring or fibrosis. This is a key problem because fibrosis completely disrupts the normal tissue architecture and leads to end-stage renal disease. The mechanism of how PKD leads to fibrosis is not understood, and currently there is no cure for the disease. Our previous studies showed that tubular cells play a major role in fibrosis because they can secrete scar-inducing chemical mediators (cytokines). We showed that myocardin-related transcription factor (MRTF), a protein regulating gene expression, is a central inducer of this process. Our preliminary data show that the level of MRTF is highly increased in mouse and human PKD tissue samples, and MRTF relocates into the nuclei of tubular cells. Based on these intriguing findings we surmise that MRTF is a key mediator in PKD, and a major contributor to the ensuing fibrosis. We will test this hypothesis by using a variety of cellular models, stem cell-derived kidney tissue (organoids), animal models and human samples. Utilizing a set of sophisticated molecular approaches we will examine whether genetic or pharmacological inhibition of MRTF ameliorates PKD. These studies may lead to completely new therapeutic approaches to treat this common and incurable kidney disease.