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8.02.2016

Kidney Cholesterol Identified as Major Contributor to Chronic Kidney Disease Development

A team of University of Miami Miller School of Medicine researchers has found a key mechanism linking inflammation in the kidney and lipid-dependent toxicity of podocytes, which are kidney cells that filter waste products from the blood into the urine.

An elevated level of tumor necrosis factor alpha (TNF) within the kidney can lead to chronic kidney disease (CKD), according to Alessia Fornoni, M.D., Ph.D., professor of medicine and Director of the Peggy and Harold Katz Family Drug Discovery Center.

“Our research indicates that an increased level of locally produced TNF in the kidney causes accumulation of cholesterol in key kidney cells,” she said. “It also demonstrated that therapeutic agents that can sequester those lipids from kidney cells may be sufficient to protect against the progression of CKD of metabolic and non-metabolic origin.”

Fornoni, an internationally recognized nephrologist who holds the Peggy and Harold Katz Family Chair, was lead author of the study, “Local TNF Causes NFATc1-Dependent Cholesterol-Mediated Podocyte Injury,” published recently in the Journal of Clinical Investigation. The study was conducted in collaboration with Sandra Merscher, Ph.D., co-corresponding author, a research associate professor who contributed to dissecting the mechanisms linking renal TNF to cholesterol accumulation. Other collaborating research groups that were instrumental to the generation of clinically relevant supporting data were led by Fornoni’s long-term collaborators Per-Henrik Groop, M.D., in Finland; GianMarco Ghiggeri, M.D., in Italy; and Matthias Kretzler, M.D., of the University of Michigan.

Other Miller School faculty members contributing to the study were Christian Faul, Ph.D., who helped develop new tools for the study, and George W. Burke III, M.D., who has helped the team exercise “bedside to bench and back” approaches to experimental research. The first author of the study is Christopher E. Pedigo, Ph.D., a University of Miami graduate student who is currently a post-doctoral fellow at Yale University. Besides Pedigo, this study represented a training ground for several other students (Gloria Michelle Ducasa, Farah Leclercq, Mengyuan Ge, and Tahreem Hashmi), post-docs (Alexis Sloan, Ph.D., and Alla Mitrofanova, Ph.D.) and scientists (Judith Molina-David Ph.D.).

Chronic kidney disease is a growing epidemic. Prior studies in Fornoni’s laboratory have demonstrated that in diabetes, which is the leading cause of chronic kidney disease, there is an accumulation of cholesterol in podocytes — cells that are a key component of the kidney filter. These studies, which were published in the journal Diabetes in 2013, also demonstrated that the accumulation of cholesterol was due to the podocytes’ inability to efflux cholesterol from the intracellular to the extracellular compartment.

Pharmacological reduction of kidney cholesterol content by a drug named cyclodextrin was sufficient to protect diabetic animals from the development of kidney disease. This discovery is now successfully moving toward clinical drug development thanks to the continuous help and support of Marc Golden, Fornoni’s long-term business partner.

Meanwhile, several scientific questions remained to be addressed, including: 1.) What are the specific mechanisms responsible for cholesterol accumulation in podocytes? 2.) Is this unique to diabetic kidney disease?

The major findings of the new study are: 1.) Cholesterol accumulation in podocytes is the result of impaired cholesterol efflux due to locally produced tumor necrosis factor. 2.) Locally produced TNF causes podocyte injury irrespectively of the circulating levels of this very well-known mediator of innate immunity. 3.) Cholesterol-dependent damage in podocytes is not specific for diabetes but also occurs in focal segmental glomerulosclerosis (FSGS), a rare kidney disease that affects children and minorities. 4.) Pharmacological or genetic induction of cholesterol efflux is sufficient to protect from experimental diabetic kidney disease and FSGS. Fornoni’s new data identifies a novel pathway linking key clinical and experimental findings that support targeting cholesterol metabolism in patients with kidney disease.

“This study reflects the strategy driving discovery at the Peggy and Harold Katz Family Center, where clinical observation and experimental mechanistic research are combined to fast track drug development for the millions of patients affected by kidney disease worldwide,” said Fornoni. “Discoveries like this can arise only from team science approaches, in which the participation of patients, philanthropists, clinicians and scientists from different disciplines is a collaboration focused on finding a cure. Special thanks for their support goes to the National Institutes of Health, the Katz Family, the NephCure Kidney International Foundation, and the Division of Nephrology and the Department of Medicine at the Miller School of Medicine.”

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