Alternatively Spliced Landscape of PPARγ mRNA in Podocytes is Distinct from Adipose Tissue

Abstract

Podocytes are highly differentiated epithelial cells, and their structural and functional integrity is compromised in a majority of glomerular and renal diseases, leading to proteinuria, chronic kidney disease, and kidney failure. Traditional agonists (e.g., pioglitazone) and selective modulators (e.g., GQ-16) of peroxisome-proliferator-activated-receptor-{gamma} (PPAR{gamma}) reduce proteinuria in animal models of glomerular disease and protect podocytes from injury via PPAR{gamma} activation. This indicates a pivotal role for PPAR{gamma} in maintaining glomerular function through preservation of podocytes distinct from its well-understood role in driving insulin sensitivity and adipogenesis. While its transcriptional role in activating adipokines and adipogenic genes is well-established in adipose tissue, liver and muscle, understanding of podocyte PPAR{gamma} signaling remains limited. We performed a comprehensive analysis of PPAR{gamma} mRNA variants due to alternative splicing, in human podocytes and compared with adipose tissue. We found that podocytes express the ubiquitous PPAR{gamma} Var 1 (encoding {gamma}1) and not Var2 (encoding {gamma}2), which is mostly restricted to adipose tissue and liver. Additionally, we detected expression at very low level of Var4, and barely detectable levels of other variants, Var3, Var11, VartORF4 and Var9, in podocytes. Furthermore, a distinct podocyte vs adipocyte PPAR-promoter-response-element containing gene expression, enrichment and pathway signature was observed, suggesting differential regulation by podocyte specific PPAR{gamma}1 variant, distinct from the adipocyte-specific {gamma}2 variant. In summary, podocytes and glomeruli express several PPAR{gamma} variants, including Var1 ({gamma}1) and excluding adipocyte-specific Var2 ({gamma}2), which may have implications in podocyte specific signaling and pathophysiology. This suggests that new selective PPAR{gamma} modulators can be potentially developed that will be able to distinguish between the two forms, {gamma}1 and {gamma}2, thus forming a basis of novel targeted therapeutic avenues.