The Centers for Disease Control and Prevention estimates more than 10% of adults in the United States, over 20 million Americans have chronic kidney disease (CKD). Furthermore, the prevalence rate of CKD in the Veteran population is a third higher than in the general population. Podocytes are terminally differentiated epithelial cells in the glomerulus whose major function is the maintenance of this renal filtration barrier to prevent CKD. Podocyte injury is implicated in many glomerular diseases including Minimal Change Disease (MCD), Focal Segmental Glomerular Sclerosis (FSGS), and HIV-associated nephropathy (HIVAN). In many of these diseased conditions, the podocyte loses characteristic morphologic features and the functional capacity to maintain the glomerular filtration barrier. We recently demonstrated the role of Krppel-Like Factor 15 (KLF15), a kidney-enriched transcription factor, in mediating podocyte function. Specifically, a global loss of Klf15 increased the susceptibility to glomerular injury in two murine models of podocyte injury. Finally, we demonstrated 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 primary glomerulopathies, but their mechanism of action remains unclear. Although GCs are presumed to attenuate injury via their immunomodulatory effects, recent studies demonstrate that GCs may exert their therapeutic benefits by direct action on podocytes. We recently reported that KLF15 is an early inducible gene. We also determined that GCs transcriptionally regulate KLF15 expression. In addition, the podocyte-specific loss of Klf15 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 of hKLF15 attenuated glomerulosclerosis, kidney fibrosis, renal failure, and overall mortality in HIV-1 transgenic mice (a murine model of FSGS). Interestingly, promoter analysis revealed that many genes that harbor binding sites for KLF15 are directed at inhibiting Wnt signaling. We also demonstrated that the podocyte-specific expression of KLF15 is reduced in kidney biopsies from GC-nonresponders as compared to GC-responders and 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 KLF15 promoter activity and prevent podocyte injury under cell stress. Based on these findings we hypothesize that the restoration of KLF15 expression is essential for podocyte recovery as well as GC responsiveness in primary glomerulopathies. To address the hypothesis we will first determine the mechanism(s) by which podocyte-specific induction of KLF15 attenuates kidney injury in proteinuric murine models. We will also investigate whether GR-KLF15 binding is required for GC-responsive glomerular disease in cultured human podocytes and human kidney biopsies. Finally, we plan to identify novel small molecules that upregulate KLF15 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 shed new light on the identification and management of primary glomerulopathies. The long-term goal of our project is to identify small molecules that induce KLF15 expression and attenuate glomerular injury, while minimizing the systemic toxicity associated with GCs. The potential impact of this proposed research is that the identification of novel targets for the treatment of primary glomerulopathies is of major interest to the Veterans Health Administration, given the high prevalence of CKD among U.S. Veterans. Furthermore, therapeutic strategies that minimize the long-term use of GCs will have a tremendous impact on the complications associated with GCs in U.S. Veterans.
More than 200,000 U.S. Veterans across 150 medical centers have been diagnosed with chronic kidney disease (CKD). In fact, due to the rising prevalence of CKD among the U.S. Veterans, the Department of Veterans Affairs released clinical practice guidelines to underscore the importance of early management of CKD. CKD is predominantly a result of initial dysfunction in the glomerulus, the filtration system in the kidney, which results in proteinuria and subsequent kidney failure. Injury to podocytes, epithelial cells in the glomerulus that help maintain this filtration barrier, have been implicated in many glomerular diseases and therapies targeting podocyte dysfunction have been limited. We hypothesize that Krppel-like Factor 15, a novel regulator of podocyte-specific genes, mediates the renoprotective effects of glucocorticoids in glomerular disease and can serve as a novel target for therapy. Therefore, the studies we propose are highly significant and clinically relevant to the Department of Veterans Affairs.
|Estrada, Chelsea C; Paladugu, Praharshasai; Guo, Yiqing et al. (2018) Krüppel-like factor 4 is a negative regulator of STAT3-induced glomerular epithelial cell proliferation. JCI Insight 3:|
|Guo, Yiqing; Pace, Jesse; Li, Zhengzhe et al. (2018) Podocyte-Specific Induction of Krüppel-Like Factor 15 Restores Differentiation Markers and Attenuates Kidney Injury in Proteinuric Kidney Disease. J Am Soc Nephrol 29:2529-2545|
|Horne, Sylvia J; Vasquez, Jessica M; Guo, Yiqing et al. (2018) Podocyte-Specific Loss of Krüppel-Like Factor 6 Increases Mitochondrial Injury in Diabetic Kidney Disease. Diabetes 67:2420-2433|