KRÜPPEL-LIKE FACTOR 15 IS A NOVEL MEDIATOR OF GLUCOCORTICOID-RESPONSIVE GLOMERULAR DISEASE

  • Mallipattu, Sandeep (PI)

Project Details

Description

The Centers for Disease Control and Prevention estimates more than 10% of adults in the UnitedStates, over 20 million Americans have chronic kidney disease (CKD). Furthermore, the prevalence rate ofCKD in the Veteran population is a third higher than in the general population. Podocytes are terminallydifferentiated epithelial cells in the glomerulus whose major function is the maintenance of this renal filtrationbarrier to prevent CKD. Podocyte injury is implicated in many glomerular diseases including Minimal ChangeDisease (MCD), Focal Segmental Glomerular Sclerosis (FSGS), and HIV-associated nephropathy (HIVAN). Inmany of these diseased conditions, the podocyte loses characteristic morphologic features and the functionalcapacity to maintain the glomerular filtration barrier. We recently demonstrated the role of Krüppel-Like Factor15 (KLF15), a kidney-enriched transcription factor, in mediating podocyte function. Specifically, a global loss ofKlf15 increased the susceptibility to glomerular injury in two murine models of podocyte injury. Finally, wedemonstrated that the local kidney expression of KLF15 is reduced in human FSGS and HIVAN. Glucocorticoids (GCs) are the first line of immunosuppressive therapy in the treatment of many primaryglomerulopathies, but their mechanism of action remains unclear. Although GCs are presumed to attenuateinjury via their immunomodulatory effects, recent studies demonstrate that GCs may exert their therapeuticbenefits by direct action on podocytes. We recently reported that KLF15 is an early inducible gene. We alsodetermined that GCs transcriptionally regulate KLF15 expression. In addition, the podocyte-specific loss ofKlf15 abrogated GC-mediated podocyte recovery in three independent proteinuric murine models. Conversely,the overexpression of KLF15 rescued actin derangement under cell stress. Furthermore, the induction ofhKLF15 attenuated glomerulosclerosis, kidney fibrosis, renal failure, and overall mortality in HIV-1 transgenicmice (a murine model of FSGS). Interestingly, promoter analysis revealed that many genes that harbor bindingsites for KLF15 are directed at inhibiting Wnt signaling. We also demonstrated that the podocyte-specificexpression of KLF15 is reduced in kidney biopsies from GC-nonresponders as compared to GC-respondersand healthy control subjects. Finally, we generated a luciferase-KLF15 promoter assay and validated it for cell-based high-throughput screening (HTS) in order to identify novel small molecules that increase KLF15promoter activity and prevent podocyte injury under cell stress. Based on these findings we hypothesize thatthe restoration of KLF15 expression is essential for podocyte recovery as well as GC responsiveness inprimary glomerulopathies. To address the hypothesis we will first determine the mechanism(s) by whichpodocyte-specific induction of KLF15 attenuates kidney injury in proteinuric murine models. We will alsoinvestigate whether GR-KLF15 binding is required for GC-responsive glomerular disease in cultured humanpodocytes and human kidney biopsies. Finally, we plan to identify novel small molecules that upregulateKLF15 expression and restore podocyte structure and differentiation markers under cell stress. This proposal will address a current gap in the field by generating an integrated model that will shednew light on the identification and management of primary glomerulopathies. The long-term goal of our projectis to identify small molecules that induce KLF15 expression and attenuate glomerular injury, while minimizingthe systemic toxicity associated with GCs. The potential impact of this proposed research is that theidentification of novel targets for the treatment of primary glomerulopathies is of major interest to the VeteransHealth Administration, given the high prevalence of CKD among U.S. Veterans. Furthermore, therapeuticstrategies that minimize the long-term use of GCs will have a tremendous impact on the complicationsassociated with GCs in U.S. Veterans.

StatusFinished
Effective start/end date1/01/1831/12/21

Funding

  • U.S. Department of Veterans Affairs: $200,000.00

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