Selective BET Inhibition in Kidney Fibrosis

A substantial increase in the incidence of chronic kidney disease (CKD) associated with fibrosis has progressed over the last decades in first world countries including Austria with devastating medical and socio-economic problems. The overall demographic development towards ageing societies associated with medical comorbidities such as hypertension, diabetes, obesity and atherosclerosis are main risk factors for the development of CKD. Further epidemiological studies have shown strong and consistent associations between acute kidney injury and the progression towards chronic kidney disease. Up to now no specific therapies to treat or prevent the progression of CKD are available. Currently available best CKD therapy entails few arguably kidney-specific therapies like targeting of the Renin-Angiotensin-System (RAS), but otherwise consist of control of systemic hypertension by any type of hypertensive drug or diuretic. The research proposed in our application represents a new and substantive departure from the status quo by shifting focus to a new epigenetic target level. The role of epigenetic modulation of gene expression in pro-fibrotic complications have recently become attention of the scientific community. However, the impact of selective BET (bromodomain and extra terminal) inhibition in kidney fibrosis have not been studied before. The BET protein family was identified as a critical mediator of gene expression in health and disease. The goal of this application, which is a collaboration project between the Medical University of Vienna and Harvard Medical School, is to evaluate the therapeutic potential of selective BET inhibitors in progressive kidney disease. The objective of our aim is (1) to evaluate the translational potential of BET inhibitors in kidney disease with selective BET inhibitors currently used in research and in clinical trials, and to compare the results in two highly relevant kidney fibrosis models, UUO and AKI to CKD model, (2) to clarify the role of BET inhibition in proximal tubular cells after injury and (3) to identify pro- fibrotic enhancer elements in proximal tubular cells. Our preliminary data strongly suggest that selective BET inhibition is effective in the prevention of fibrosis after UUO, and therefore likely in the prevention of CKD progression. This is expected to open up new therapeutic horizons in the treatment of fibrosis and stimulate new research horizons, particularly in BET-dependent epigenetic pathways relevant to fibrosis and therefore in drug development. Highly- selective BET inhibitors are currently in clinical testing in the cancer field, which supports the need of pre-clinical studies in highly prevalent non-cancer diseases such as CKD to further evaluate potential benefits and negative side effects in these patient cohorts. Our approach will test the possibility of repurposing selective BET inhibitors used in cancer for the treatment of progressive kidney disease and further evaluate down-stream transcriptional programs as new therapeutical avenues.

The goal of this project, which is a collaboration project between the University of Veterinary Medicine and Harvard Medical School, was to evaluate the therapeutic potential of selective BET inhibitors in progressive kidney disease. We established the epigenetic (enhancer) landscape after acute kidney injury in uninjured and repairing kidneys. We identify key transcription factors, which show specific binding at epigenetic elements, revealing epigenetic dynamics and transcriptional changes during kidney repair. BET inhibition before kidney injury leads to impaired recovery after acute kidney injury and increased mortality. Later treatment after the repair phase leads to decreased fibrosis in two other kidney injury models. Our comprehensive analysis of epigenetic changes after kidney injury in vivo has the potential to identify targets for therapeutic intervention. Importantly, our data also call attention to potential caveats involved in use of BET inhibitors in patients at risk for acute kidney injury. https://www.nature.com/articles/s41467-020-17205-5 A substantial increase in the incidence of kidney disease has progressed over the last decades in first world countries including Austria with devastating medical and socio-economic problems. The overall demographic development towards ageing societies associated with medical comorbidities such as hypertension, diabetes, obesity, previous injury to the kidney and atherosclerosis are main risk factors for the development of kidney disease. Further epidemiological studies have shown strong and consistent associations between acute kidney injury and the progression towards chronic kidney disease. The research represents a new and substantive departure from the status quo by shifting focus to a new epigenetic target level. The role of epigenetic modulation of gene expression have recently become attention of the scientific community. However, the impact of selective BET inhibition normally used in cancer treatment have not been studied before in kidney disease.