Chandra Mohan has a theory about the development of lupus nephritis, the leading cause of lupus-related deaths. If he’s right, there may already be a treatment.
Lupus is an autoimmune disease that can attack practically any part of the body. In lupus nephritis, it causes severe kidney inflammation, leading to hundreds of deaths and tens of thousands of hospitalizations per year in the United State alone.
In cases of kidney disease caused by something other than lupus, there are high levels of three specific molecules that work together to cause the disease. An enzyme known as kallikrein leads to the production of bradykinin, a peptide that helps regulate blood pressure and inflammation.
At the same time, the kidneys have elevated levels of the two bradykinin receptors, proteins that chemically bond with bradykinin to set certain biological processes in motion.
“If bradykinin binds to receptor two, good things happen in the kidneys,” said Mohan, Hugh Roy and Lillie Cranz Cullen Endowed Professor of biomedical engineering with the University of Houston Cullen College of Engineering. “But if bradykinin binds to receptor one, bad things happen. The kidneys become inflamed and there’s more renal disease.”
While this is the established “pathogenic cascade” of other kidney diseases, recent studies have shown that people with lupus nephritis have elevated levels of these same three molecules – kallikreins, bradykinin and bradykinin receptor one. Thanks to a $200,000 grant from the Alliance for Lupus Research, Mohan will study whether the interaction of these molecules is the cause of lupus nephritis.
Fortunately, he’s got a head start in this process. A drug for other kidney diseases is currently in clinical trials. This drug acts as an inhibitor that attaches to bradykinin receptor one and physically blocks it from bonding with bradykinin. No bond means no kidney inflammation.
Using animal models, Mohan and his research team, including Research Assistant Professor Yong Du, will study how subjects with lupus nephritis respond to the inhibitor drug. If these subjects show significant improvement, he will have established the link between lupus nephritis and the kallikrein/ bradykinin/bradykinin receptor one pathogenic cascade.
More than that, though, Mohan will have shown that the inhibitor is also an excellent candidate for treating lupus nephritis, one that could, hopefully, come to market relatively quickly.
“There’s a high chance this will work,” said Mohan. “The company that developed the drug has already gone through many libraries of molecules and selected this inhibitor and it seems to be working in clinical trails with other renal diseases. The safety of the inhibitor has already been established. So if our experiments go well, the trials can quickly move to human lupus nephritis in just a few years.”