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Author Interview: THOMAS WEIMBS, PhD
Associate Professor
Department of Molecular, Cellular & Developmental Biology
And Neuroscience Research Institute
University of California Santa Barbara
Santa Barbara, California 93106-9610

Publication:
Dr. Thomas Weimbs, PhD

Signal transducer and activator of transcription-6 (STAT6) inhibition suppresses renal cyst growth in polycystic kidney disease
Erin E. Olsan, Sambuddho Mukherjee, Beatrix Wulkersdorfer, Jonathan M. Shillingford, Adrian J. Giovannone, Gueorgui Todorov, Xuewen Song, York Pei, and Thomas Weimbs
PNAS 2011 : 1111966108v1-201111966.

What are the main findings of the study?

We found that the transcription factor STAT6 is aberrantly activated in renal cyst-lining cells in polycystic kidney disease (PKD). Inhibition of STAT6 in a mouse model of PKD by gene knock-out resulted in reduced renal cyst growth and preservation of renal function indicating that STAT6 is a driving force of cyst growth.

The drug leflunomide has previously been shown to inhibit STAT6 activity. We found that treatment of PKD mice with leflunomide had similar beneficial effects as gene-knock-out of STAT6.

Were any of the findings unexpected?

STAT6 has previously mainly been characterized in cells of the immune system. Finding a major role for STAT6 in renal epithelial cells was unexpected.

What should clinicians and patients take away from this study?

It is too early to base clinical therapies on these findings. However, our findings suggest that STAT6 is a promising drug target for therapy of PKD. This is exciting because several drugs are available or under develop that target the STAT6 pathway.

What recommendations do you have for nephrology health care providers as a result of your study?

Additional approaches to inhibit the STAT6 pathway should be tested. Also, the efficacy of STAT6 inhibition should be tested in other animal models of PKD.

Abstract:

Autosomal-dominant (AD) polycystic kidney disease (PKD) is a leading cause of renal failure in the United States, and currently lacks available treatment options to slow disease progression. Mutations in the gene coding for polycystin-1 (PC1) underlie the majority of cases but the function of PC1 has remained poorly understood.

We have previously shown that PC1 regulates the transcriptional activity of signal transducer and activator of transcription-6 (STAT6). Here we show that STAT6 is aberrantly activated in cyst-lining cells in PKD mouse models. Activation of the STAT6 pathway leads to a positive feedback loop involving auto/paracrine signaling by IL13 and the IL4/13 receptor. The presence of IL13 in cyst fluid and the overexpression of IL4/13 receptor chains suggests a mechanism of sustained STAT6 activation in cysts. Genetic inactivation of STAT6 in a PKD mouse model leads to significant inhibition of proliferation and cyst growth and preservation of renal function.

We show that the active metabolite of leflunomide, a drug approved for treatment of arthritis, inhibits STAT6 in renal epithelial cells.

Treatment of PKD mice with this drug leads to amelioration of the renal cystic disease similar to genetic STAT6 inactivation. These results suggest STAT6 as a promising drug target for treatment of ADPKD.

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