Mechanisms and Selective Modulation of PPARy for the Treatment of Podocytopathies

ABSTRACT / PROJECT SUMMARY
Glomerular disease manifests as nephrotic syndrome with high-grade proteinuria with co-morbidities, and is characterized by podocyte injury and loss, which are critical determinants of disease progression. Glomerular disease can unfortunately be frequently refractory to current treatments, leading to progression to chronic kidney disease and end-stage kidney disease. Thus, there is an unmet medical need to identify more effective and less toxic podocyte-targeted treatments for glomerular disease. We have previously demonstrated that PPARγ agonists and thiazolidinediones such as pioglitazone, protect podocytes from injury, reduce proteinuria and glomerular injury in an animal model of glomerular disease, and improve clinical outcomes in nephrotic syndrome. Despite these advances, lack of their podocyte-specific mechanistic understanding and unwanted side effects has impeded their robust clinical application. Their widespread use as anti-diabetic drugs has also been under scrutiny, which has however led to the emergence of more selective modulators of PPARγ which have shown promise in recent clinical trials (NCT02638038). Motivated by these developments and to enable the clinical application of PPARγ modulation, here we seek to move away from traditional agonists and toward selective modulation of PPARγ for the treatment of nephrotic syndrome. Our recent data reveals that GQ-16, a more selective modulator of PPARγ, that binds to PPARγ distinctly from traditional agonist pioglitazone, reduces proteinuria and nephrotic syndrome-associated comorbidities in a rat model of minimal change disease with high efficacy, while resulting in reduced adipogenesis and lipid accumulation, compared to pioglitazone. Transcriptomic analyses revealed that pioglitazone and GQ-16 activate or restore common and distinct glomerular genes and pathways. These downstream effects in podocytes are likely directed by the PPARγ1 splice variant, distinct from the adipocyte-γ2 variant. Based on these findings, our central hypothesis is that PPARγ can be selectively modulated for better targeted therapeutic treatment for nephrotic syndrome with reduced side effects and that its podocyte-protective effects are regulated transcriptionally. To test our central hypothesis, we propose two Specific Aims: 1) Determine podocyte-specific direct transcriptional targets of PPARγ, and 2) Determine the beneficial role of selective modulation of PPARγ in treating nephrotic syndrome. Successful completion of these studies will advance the understanding of podocyte-specific PPARγ signaling and identify a potential therapeutic strategy to treat podocytopathies by a next generation PPARγ-modulator.

Grant Number: 5R01DK133440-03
NIH Institute/Center: NIH
Principal Investigator: Shipra Agrawal