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Proteinuria Reduction in Nephrotic Syndrome Without Suppressing the Immune System

Proteinuria Reduction in Nephrotic Syndrome Without Suppressing the Immune System 375 280 Mary Bates, PhD

Study suggests a distinct, non-immunosuppressive mechanism of action for drugs that ameliorate proteinuria in an NS model.

Nephrotic syndrome (NS) is a leading cause of chronic kidney disease in children and adults. NS is characterized by dysregulation of the kidneys’ glomerular filtering units, resulting in massive proteinuria, hypoalbuminemia, and edema.

Glucocorticoids are the primary treatment for NS but are often associated with significant side effects, says William E. Smoyer, MD, vice president and director for the Center for Clinical and Translational Research at the Abigail Wexner Research Institute at Nationwide Children’s Hospital. Dr. Smoyer and others recently reported that the PPARγ agonist pioglitazone (Pio) was able to reduce proteinuria in several patients with complicated forms of NS, some of whom had failed to respond to glucocorticoid treatment. Pio is a non-immunosuppressive drug that is FDA-approved for type 2 diabetes.

In a new study, Dr. Smoyer and colleagues investigated the mechanisms by which Pio reduces proteinuria. First, they demonstrated that glucocorticoids and Pio both effectively ameliorated proteinuria in a rat model of NS (PAN-induced NS). Next, the researchers compared the transcriptomes from glomeruli isolated from rats with NS treated with either glucocorticoids or Pio.

“We wanted to look at the different and common gene expression signatures between rats treated with glucocorticoids and rats treated with Pio,” says Julie Dougherty, PhD, a research scientist in the Smoyer Lab at Nationwide Children’s and co-author of the study. “Since both drugs reduced proteinuria, they likely use a common mechanism. But we know Pio is doing this without suppressing the immune system.”

Among the genes that were upregulated by NS and ameliorated by both treatments, the team identified 29 commonly regulated genes of interest. These genes were primarily involved in cell cycle regulation and extracellular matrix remodeling. According to Dr. Dougherty, these results were unexpected because the rat model of NS is mild and does not exhibit scarring, yet there were still changes in genes that encode proteins normally associated with scarring.

In addition, the researchers validated their results in rats by comparing them with gene expression data from humans with NS in a publicly available database. They found that the dysregulated genes identified in rats correlated with findings from humans with NS, both the milder form of disease as well as the more progressive form of the disease, in which scarring occurs.

Together, the results demonstrated that glucocorticoids and Pio both reduce proteinuria in an NS model, largely through ameliorating dysregulated glomerular extracellular matrix-associated genes. This suggests that targeting glomerular extracellular matrix dysregulation may be a promising non-immunosuppressive approach to treat proteinuria in NS.

“For the last 70 years, glucocorticoids have been the mainstay of treatment for NS,” says Dr. Smoyer, who is also a professor of pediatrics at The Ohio State University College of Medicine.

“Now, we are considering the possibility that reducing proteinuria in NS may not require suppressing the immune system. It may be that immune suppression is not a common mechanism of action of these drugs, but a common side effect.”

 

Reference:

Bhayana S, Dougherty JA, Kamigaki Y, Agrawal S, Wijeratne S, Fitch J, Waller AP, Wolfgang KJ, White P, Kerlin BA, Smoyer WE. Glucocorticoid- and pioglitazone-induced proteinuria reduction in experimental NS both correlate with glomerular ECM modulation. iScience. 2023 Dec 2;27(1):108631. doi: 10.1016/j.isci.2023.108631.

About the author

Mary a freelance science writer and blogger based in Boston. Her favorite topics include biology, psychology, neuroscience, ecology, and animal behavior. She has a BA in Biology-Psychology with a minor in English from Skidmore College in Saratoga Springs, NY, and a PhD from Brown University, where she researched bat echolocation and bullfrog chorusing.

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