Podocyte injury resulting from a loss of podocyte differentiation has been implicated in many kidney diseases such as Focal Segmental Glomerular Sclerosis (FSGS) and HIV Associated Nephropathy (HIVAN). FSGS and HIVAN are among the most prominent causes of end stage renal disease in the United States, especially in African Americans. It has been previously shown that Retinoic Acid (RA) induces podocyte differentiation via stimulation of cAMP/PKA/CREB pathway. However, the transcription factors mediating the effects of RA on podocyte differentiation markers are not known. Microarray gene expression studies in human podocytes treated with RA were done to identify genes highly regulated by RA. Computational analysis revealed a CREB-targeted gene called Krupper-Like Factor 15 (KLF15) was highly upregulated by RA in podocytes. KLF15 is not only kidney enriched, but has been previously shown to mediate adipocyte differentiation. First, it was confirmed that RA stimulated a significant increase in KLF15 mRNA and protein expression in conditionally immortalized mouse and human podocytes. This finding was replicated in cultured HIV infected podocytes as well as in glomeruli isolated from HIV transgenic mice. Furthermore, the over- expression of KLF15 stimulated the expression of synaptopodin (podocyte differentiation marker) in wild-type and HIV-infected murine podocytes. Additionally, Chromatin Immunoprecipitation studies revealed that KLF15 binds to the promoter region of nephrin and podocin (slit diaphragm proteins) in RA treated mouse podocytes. Although, KLF15-/- mice at baseline had only a two-fold increase in proteinuria with minimal podocyte injury, KLF15-/- mice treated with lipopolysaccharide (LPS), a murine model of podocyte injury, showed a significant increase in proteinuria and podocyte effacement as compared to LPS treated wild-type mice. Based on these findings, the hypothesis is that KLF15 is a key regulator of podocyte differentiation.
The first aim i s to determine the role of KLF15 in RA-mediated podocyte differentiation by treating KLF15 deficient cells with or without RA. These findings will be validated in vivo.
The second aim i s to characterize the role of KLF15 in diseased states. Initially, the expression of KLF15 in kidney biopsies of healthy donors will be compared to patients with FSGS and HIVAN. Next, the role of KLF15 will be characterized in murine models of HIVAN (transgenic murine model) and FSGS (Adriamycin induced nephropathy). Finally, the mechanism mediating the regulation of KLF15 in these diseased states will be determined. By identifying that KLF15 is an important transcriptional regulator of podocyte differentiation, new insight will be gained in kidney physiology and disease as well as further evidence will be provided for the use of Retinoic Acid in the treatment of glomerular disease.
FSGS and HIVAN are among the most prominent causes of end stage renal disease in the United States, especially in African Americans. By identifying that KLF15 is an important transcriptional regulator of podocyte differentiation, new insight will be gained in kidney physiology and disease as well as further evidence will be provided for the use of Retinoic Acid in the treatment of glomerular disease.
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