Mechanisms and Selective Modulation of PPARy for the Treatment of Podocytopathies

摘要/项目总结 肾小球疾病表现为肾病综合征，伴有高级别蛋白尿和合并症，其特征在于足细胞损伤和丢失，这是疾病进展的关键决定因素。不幸的是，肾小球疾病通常对目前的治疗难以治疗，导致进展为慢性肾病和终末期肾病。因此，存在未满足的医学需求，以鉴定用于肾小球疾病的更有效且毒性更小的足细胞靶向治疗。我们之前已经证明，在肾小球疾病动物模型中，PPARγ激动剂和噻唑烷二酮类药物（如吡格列酮）可保护足细胞免受损伤，减少蛋白尿和肾小球损伤，并改善肾病综合征的临床结局。尽管取得了这些进展，但缺乏对足细胞特异性机制的理解和不必要的副作用阻碍了其稳健的临床应用。它们作为抗糖尿病药物的广泛使用也受到了严格审查，然而，这导致了更具选择性的PPARγ调节剂的出现，这些调节剂在最近的临床试验中显示出了希望（NCT 02638038）。受这些发展的启发，为了使PPARγ调节的临床应用成为可能，我们在这里寻求从传统的激动剂转向选择性调节PPARγ治疗肾病综合征。我们最近的数据显示，与传统激动剂吡格列酮不同，GQ-16是一种更具选择性的PPARγ调节剂，与PPARγ结合，在微小病变疾病大鼠模型中有效减少蛋白尿和肾病综合征相关的合并症，同时与吡格列酮相比，导致脂肪生成和脂质蓄积减少。转录组学分析显示，吡格列酮和GQ-16激活或恢复共同和不同的肾小球基因和途径。足细胞中的这些下游效应可能由与脂肪细胞-γ2变体不同的PPARγ1剪接变体指导。基于这些发现，我们的中心假设是，可以选择性地调节PPARγ，以更好地靶向治疗肾病综合征，减少副作用，其足细胞保护作用是转录调节。为了验证我们的中心假设，我们提出了两个特定的目的：1）确定足细胞特异性的直接转录靶点的过氧化物酶体增殖物激活受体γ，2）确定选择性调节过氧化物酶体增殖物激活受体γ在治疗肾病综合征中的有益作用。这些研究的成功完成将促进对足细胞特异性PPARγ信号传导的理解，并确定通过下一代PPARγ调节剂治疗足细胞病变的潜在治疗策略。

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.