Research Finding Offers Hope for Treating or Preventing Progression of Chronic Kidney Disease

A University of Miami Miller School of Medicine researcher has found that inhibiting or reducing oxidative stress on podocytes, key cells of the kidney filter, can prevent their damage, suggesting a potential new target for treating patients and reducing progression of chronic kidney disease.

“Currently, clinicians rely on ACE (angiotensin-converting enzyme) inhibitors that reduce hypertension and slow the progression of kidney disease,” said Leopoldo Raij, M.D., professor of medicine, Director of Hypertension in the Department of Medicine’s Division of Nephrology and Hypertension, and Director of the Program for International Research Scholars at the Miller School’s International Medicine Institute. “But we need to find complementary ways to arrest both primary and indirect damage to the kidney.”

Raij was lead author of a study, “Podocyte Injury: The Role of Proteinuria, Urinary Plasminogen and Oxidative Stress,” published recently in the American Journal of Physiology – Renal Physiology. Runxia Tian, M.D., of the Research Section of the Miami Veterans Affairs Medical Center, was a co-author of the study. Jenny S. Wong, Ph.D., John C. He, M.D., Ph.D., and Kirk N. Campbell, M.D., of the Nephrology Division of the Icahn School of Medicine at Mount Sinai in New York were collaborators.

Normal urine is protein-free because special cells and structures work in partnership to prevent protein from leaking from the blood, a condition called proteinuria. Podocytes are critical for maintaining the integrity of the filter but are susceptible to damage and are limited in reproducing (undergoing cell division) to compensate for podocyte loss. When the loss exceeds 30 percent, the result is an irreversible “scar” called focal segmental glomerular sclerosis that is often progressive and leads to renal failure. Clinically, proteinuria accompanied by continued podocyte loss is a hallmark of kidney diseases, regardless of the original cause, which may include hypertension and diabetes, said Raij.

Human and animal data documented large amounts of biologically active plasminogen and its conversion product, the protease plasmin, in urine of subjects with chronic proteinuria. Raij hypothesized and proved that persistent exposure of podocytes — a molecule to which they are not normally exposed — may result in plasminogen binding and conversion to plasmin, leading to damage of these cells.

In these novel studies, Raij showed that plasmin-activated oxidative stress pathways directly induced podocyte damage and promoted synthesis of the powerful vasoconstrictor Endothelin1 and of CD36, a receptor that binds oxidized lipoproteins that promote inflammation and podocyte death.

“This study suggests that chronic exposure to plasminogen could serve as a ‘second hit’ in glomerular disease, making plasminogen a potentially attractive target for therapeutic intervention,” Raij said. “It may be possible to intervene to prevent plasminogen from being activated by the podocytes.”

Raij has focused his research and educational efforts on hypertension in relation to atherosclerosis, diabetes and kidney disease.

“My major focus has been to investigate the mechanisms that participate in vascular and renal injury in hypertension,” said Raij, who received the Irvine Page-Alva Bradley Lifetime Achievement Award in Hypertension, sponsored by the American Heart Association’s Council for High Blood Pressure Research — an award given for “outstanding contributions to combating hypertension through research, education, and service.”

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