Ying Maggie Chen, Assistant Professor of Medicine
A new study led by Ying Maggie Chen, MD, PhD, Division of Nephrology, found a new class of drugs that shows great promise in the treatment of nephrotic syndrome (NS) resulting from podocyte endoplasmic reticulum (ER) dysfunction.
NS is a leading cause of chronic kidney disease affecting over 500 million people worldwide. Damage to podocytes, the highly specialized epithelial cells that cover the glomerular capillaries in the kidney, is a characteristic feature of NS. While the importance of ER stress in the pathogenesis of NS is acknowledged, no treatment currently targets podocyte ER dysfunction.
Dr. Chen’s group investigated the molecular pathogenesis and treatment of podocyte ER stress-induced NS by using a mouse model of NS caused by LAMB2 C321R, a mutation identified in human patients. Their aim was to determine whether ER calcium homeostasis is dysregulated in podocytes undergoing ER stress and to discover novel therapeutic agents targeting the ER to inhibit podocyte injury and proteinuria in NS, including focal segmental glomerulosclerosis (FSGS).
They found that the podocyte ER calcium release channel, type 2 ryanodine receptor (RyR2), underwent a remodeling during ER stress, resulting in ER calcium leakage and cytosolic calcium elevation. The leaky RyR2 activated cytosolic protease calpain 2, which lead to podocyte injury. However, a chemical compound (K201) and a biotherapeutic protein (MANF) fixed the leaky RyR2 and inhibited podocyte injury. K201 also attenuated proteinuria in their NS mouse model.
The new class of drugs – podocyte ER calcium channel stabilizers – may have wide clinical implications in the treatment of NS, focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), minimal change disease (MCD), Alport syndrome and diabetic nephropathy. Dr. Chen, through the Office of Technology Management at Washington University, filed a U.S. nonprovisional patent (Serial No. 16/446073), June 19, 2019.
Modulation of podocyte ER calcium depletion-induced apoptosis and injury by K201 and MANF (Fig 8)
“We will continue to collaborate with the NIH-National Center for Advancing Translational Sciences to discover more ER stress modulators to treat ER stress-mediated glomerular and tubular diseases,” say Chen. “We are also eager to establish collaborations with pharmaceutical companies to move forward our therapeutic agents from preclinical mouse models to clinical trials.”
The article, “Discovery of endoplasmic reticulum calcium stabilizers to rescue ER-stressed podocytes in nephrotic syndrome,” was published in PNAS June 24, 2019. Read full article here. Authors:
The paper has been highlighted by Nature Reviews Nephrology (read the review here). and the June 26 edition of ASN In The Loop, the American Society of Nephrology’s daily e-news briefing that highlights exciting announcements and current research in the world of nephrology.
Read more about Dr. Chen and her research team, who have pioneered the development of urinary ER stress biomarkers research, on the Y. Maggie Chen Lab Web Site.