Awardees
 

Supervisor: Darren Yuen
Award: KRESCENT Post-Doctoral Fellowship
Institution: St Michael's Hospital, Toronto
Year: 2021-2023

Study title: Prolyl hydroxylase (PHD) inhibition to treat kidney fibrosis

Biography
Dr. Santosh Kumar Goru received his PhD from the Department of Pharmacy at Birla institute of technology and science, Pilani, India in 2018. During his PhD, his work was focused on novel molecular mechanisms and treatments to treat the scarring of kidneys in diabetic animals. In 2018 Dr. Goru moved to Toronto for his postdoctoral studies and will complete his post-doctoral fellowship under the supervision of Dr. Darren Yuen at the keenan Research centre for Biomedical Science and Li Ka Shing knowledge Institute of St.michael’s hospital, Toronto. Dr. Goru’s project is focused on discovering a new treatment for kidney scarring. During his KRESCENT post-doctoral fellowship, Dr. Goru will explore the possible novel therapies to treat kidney scarring. 

General Audience Summary
Kidney failure is an increasingly common, costly, and life-threatening condition requiring dialysis or transplantation for survival. A major reason why kidneys fail is that nearly all forms of kidney disease lead to scarring, a process that can progressively destroy normal functioning kidney tissue. Unfortunately, no safe and effective anti-scarring treatments exist. We and others have recently shown that YAP and TAZ are two closely related proteins that are critical for scar production by fibroblasts, the main sources of scar tissue in the kidney. A common complication of chronic kidney disease is anemia (low blood levels). Recently, drugs have been developed which inhibit enzymes called prolyl hydroxylases (PHDs), which can raise blood levels by stabilizing a protein called HIF1-a. PHD inhibitors are now in phase 3 clinical trials as a potential treatment for renal anemia. HIF1-a has been shown to promote scarring in the kidney, raising concerns that PHDs may actually increase the risk of kidney failure in patients with kidney disease. To explore this possibility, we treated scar producing cells called fibroblasts with PHD inhibitors. Surprisingly, we found that PHD inhibitors reduced fibroblast scar production. Further investigation showed that PHD inhibitors also decreased YAP and TAZ levels, suggesting that these drugs may block scarring through inhibiting YAP and TAZ. Using cutting edge lab techniques, we will systematically test whether PHDs activate YAP and TAZ in fibroblasts to start the scarring process in the injured kidney, and whether PHD inhibition reduces scar production in cells and animals. These studies are the first to potentially link YAP/TAZ activation with PHD activity and subsequent scarring. Given that scarring is such an important cause of chronic kidney injury, and because PHD inhibitors are already being tested in phase III clinical trials, our hope is that this research may rapidly lead to a new treatment for chronic kidney disease, and thus better outcomes for patients.