GDC-0879, a BRAFV600E Inhibitor, Protects Kidney Podocytes from Death

Sieber, Jonas; Wieder, Nicolas; Clark, Allison; Reitberger, Manuel; Matan, Sofia; Schoenfelder, Jeannine; Zhang, Jianming; Mandinova, Anna; Bittker, Joshua A.; Gutierrez, Juan; Aygün, Ozan; Udeshi, Namrata D.; Carr, Steven A.; Mündel, Peter; Jehle, Andreas W.; Greka, Anna

doi:10.1016/j.chembiol.2017.11.006

Cited by 21 publications

(20 citation statements)

References 51 publications

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“…This extends previous work showing that podocyte depletion through ectopic diphtheria toxin expression drives focal and segmental glomerulosclerosis (FSGS) progression in a dose-dependent manner (18). Our findings corroborate the growing understanding that podocytes are the target of choice for therapeutic interventions (9,(20)(21)(22)(23)(24), and that podocyte-preserving strategies may hold the greatest promise for CKD prevention or treatment. Second, our model offers a potentially novel approach in which the timing of events leading to biochemical abnormalities observed in human CKD-MBD, including hyperphosphatemia and hypocalcemia, and thus elevated FGF23 and PTH levels, is readily controlled (25,26).…”

Section: Discussionsupporting

confidence: 89%

Inducible podocyte-specific deletion of CTCF drives progressive kidney disease and bone abnormalities

Christov¹,

Clark²,

Corbin³

et al. 2018

JCI Insight

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Progressive chronic kidney diseases (CKDs) are on the rise worldwide. However, the sequence of events resulting in CKD progression remain poorly understood. Animal models of CKD exploring these issues are confounded by systemic toxicities or surgical interventions to acutely induce kidney injury. Here we report the generation of a CKD mouse model through the inducible podocyte-specific ablation of an essential endogenous molecule, the chromatin structure regulator CCCTC-binding factor (CTCF), which leads to rapid podocyte loss (iCTCFpod-/-). As a consequence, iCTCFpod-/- mice develop severe progressive albuminuria, hyperlipidemia, hypoalbuminemia, and impairment of renal function, and die within 8-10 weeks. CKD progression in iCTCFpod-/- mice leads to high serum phosphate and elevations in fibroblast growth factor 23 (FGF23) and parathyroid hormone that rapidly cause bone mineralization defects, increased bone resorption, and bone loss. Dissection of the timeline leading to glomerular pathology in this CKD model led to the surprising observation that podocyte ablation and the resulting glomerular filter destruction is sufficient to drive progressive CKD and osteodystrophy in the absence of interstitial fibrosis. This work introduces an animal model with significant advantages for the study of CKD progression, and it highlights the need for podocyte-protective strategies for future kidney therapeutics.

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Section: Discussionsupporting

confidence: 89%

Inducible podocyte-specific deletion of CTCF drives progressive kidney disease and bone abnormalities

Christov¹,

Clark²,

Corbin³

et al. 2018

JCI Insight

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“…Recent reports indicate that GluR3 promotes cell growth through activation of MAPK pathway [27]. Therefore, GluR3 may be a survival factor for podocytes through activation of the MAPK pathway [34, 35]. …”

Section: Discussionmentioning

confidence: 99%

Expression of Glutamate Receptor Subtype 3 Is Epigenetically Regulated in Podocytes under Diabetic Conditions

Li¹,

Chen²,

Zhong³

et al. 2018

Kidney Dis

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Background: Recent studies suggest a role of epigenetics in the pathogenesis of diabetic kidney disease. However, epigenetic changes occurring specifically in kidney cells is poorly understood. Methods: To examine the epigenetic regulation of genes in podocytes under diabetic conditions, we performed DNA methylation and transcriptomic profiling in podocytes exposed to high glucose conditions. Results: Comparative analysis of genes with DNA methylation changes and correspondingly altered mRNA expression identified 337 hypomethylated genes with increased mRNA expression and only 2 hypermethyated genes (ESX1 and GRIA3) with decreased mRNA expression. Glutamate ionotropic receptor AMPA type subunit 3 (GRIA3) belongs to the ionotropic class of glutamate receptors that mediate fast excitatory synaptic transmission in the central nervous system. As podocytes have glutamate-containing vesicles and various glutamate receptors mediate important biological effects in podocytes, we further examined GRIA3 expression and its function in podocytes. Real-time PCR and western blots confirmed the suppression of GRIA3 expression in podocytes under high glucose conditions, which were abolished in the presence of a DNA methyltransferase inhibitor. Sites of DNA hypermethylation were also confirmed by bisulfite sequencing of the GRIA3 promoter region. GRIA3 mRNA and protein expression was suppressed in diabetic kidneys of human and mouse models, and knockdown of GRIA3 exacerbated high glucose-induced apoptosis in cultured podocytes. Conclusion: These results indicate that decreased GRIA3 expression in podocytes in diabetic condition heightens podocyte apoptosis and loss.

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“…Targeting pathogenic actin polymerization ( 152 , 153 ), abnormal TRPC5 and TRPC6 channel activation ( 136 , 154 , 155 ), aberrant integrin activation ( 156 , 157 ), and depletion of laminin-521 in the GBM ( 158 ) remain other emerging prospective treatments, all of which have shown significant promise in animal models. GDC-0879, a B-RAF V600E inhibitor, was also recently identified in a high-throughput screen of approved drugs to promote podocyte cell survival ( 159 ). Although the utility of this compound as a treatment for renal disease in vivo has not yet been explored, GDC-0879 has successfully been used in mouse models to inhibit tumor growth ( 160 ), making it an exciting candidate for future investigations in the kidney.…”

Section: Frontiers In Podocyte Biology—toward Novel Treatments Targetmentioning

confidence: 99%

Nephrin Signaling in the Podocyte: An Updated View of Signal Regulation at the Slit Diaphragm and Beyond

2018

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Podocytes are a major component of the glomerular blood filtration barrier, and alterations to the morphology of their unique actin-based foot processes (FP) are a common feature of kidney disease. Adjacent FP are connected by a specialized intercellular junction known as the slit diaphragm (SD), which serves as the ultimate barrier to regulate passage of macromolecules from the blood. While the link between SD dysfunction and reduced filtration selectivity has been recognized for nearly 50 years, our understanding of the underlying molecular circuitry began only 20 years ago, sparked by the identification of NPHS1, encoding the transmembrane protein nephrin. Nephrin not only functions as the core component of the extracellular SD filtration network but also as a signaling scaffold via interactions at its short intracellular region. Phospho-regulation of several conserved tyrosine residues in this region influences signal transduction pathways which control podocyte cell adhesion, shape, and survival, and emerging studies highlight roles for nephrin phospho-dynamics in mechanotransduction and endocytosis. The following review aims to summarize the last 5 years of advancement in our knowledge of how signaling centered at nephrin directs SD barrier formation and function. We further provide insight on promising frontiers in podocyte biology, which have implications for SD signaling in the healthy and diseased kidney.

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GDC-0879, a BRAFV600E Inhibitor, Protects Kidney Podocytes from Death

Cited by 21 publications

References 51 publications

Inducible podocyte-specific deletion of CTCF drives progressive kidney disease and bone abnormalities

Inducible podocyte-specific deletion of CTCF drives progressive kidney disease and bone abnormalities

Expression of Glutamate Receptor Subtype 3 Is Epigenetically Regulated in Podocytes under Diabetic Conditions

Nephrin Signaling in the Podocyte: An Updated View of Signal Regulation at the Slit Diaphragm and Beyond

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