Fine-tuning of NFκB by glycogen synthase kinase 3β directs the fate of glomerular podocytes upon injury

Abstract

NFκB is regulated by a myriad of signaling cascades including glycogen synthase kinase (GSK) 3β and plays a Janus role in podocyte injury. In vitro, lipopolysaccharide or adriamycin elicited podocyte injury and cytoskeletal disruption, associated with NFκB activation and induced expression of NFκB target molecules, including pro-survival Bcl-xL and podocytopathic mediators like MCP-1, cathepsin L and B7-1. Broad range inhibition of NFκB diminished the expression of all NFκB target genes, restored cytoskeleton integrity, but potentiated apoptosis. In contrast, blockade of GSK3β by lithium or TDZD-8, mitigated the expression of podocytopathic mediators, ameliorated podocyte injury, but barely affected Bcl-xL expression or sensitized apoptosis. Mechanistically, GSK3β was sufficient and essential for RelA/p65 phosphorylation specifically at serine 467, which specifies the expression of selective NFκB target molecules, including podocytopathic mediators, but not Bcl-xL. In vivo, lithium or TDZD-8 therapy improved podocyte injury and proteinuria in mice treated with lipopolysaccharide or adriamycin, concomitant with suppression of podocytopathic mediators but retained Bcl-xL in glomerulus. Broad range inhibition of NFκB conferred similar but much weakened antiproteinuric and podoprotective effects accompanied with a blunted glomerular expression of Bcl-xL and marked podocyte apoptosis. Thus, the GSK3β dictated fine-tuning of NFκB may serve as a novel therapeutic target for podocytopathy.

Genetic and Pharmacologic Targeting of Glycogen Synthase Kinase 3β Reinforces the Nrf2 Antioxidant Defense against Podocytopathy

“…Indeed, other mechanisms, such as suppression of proinflammatory NFkB activation and desensitization of mitochondria permeability transition, have been implicated, at least in part, in the podocyte protective effect following GSK3b inhibition. 32,51 In summary, targeted inhibition of GSK3b in podocytes via conditional KO or pharmacologic blockade reinforced the Nrf2 antioxidant response after doxorubicin or NTS insult, alleviated podocytopathy and glomerular injury and attenuated proteinuria. Our study suggests that the GSK3b-regulated Nrf2 cell defense pathway in glomerular podocytes might serve as a novel and feasible therapeutic target for proteinuric glomerulopathies.…”

“…To this end, we adopted the murine model of doxorubicin nephropathy, which recapitulates key features of podocytopathy in humans, including podocyte injury, massive proteinuria, and progressive glomerulosclerosis. 32,33 After a single tail-vein injection of doxorubicin, albuminuria started to develop in control mice on day 5 and peaked on day 7, as estimated by urine electrophoresis and Coomassie brilliant blue staining ( Figure 5A) and quantitated by measuring the urine albumin-to-creatinine ratios ( Figure 5B). This was associated with typical renal lesions of nephrotic glomerulopathy, featured by large protein casts in tubules, podocytic swelling and vacuolization, glomerular synechiae, glomerular capillary congestion, collapse and/or obliteration accompanied by hyaline material deposition, mesangial extracellular matrix accumulation, and mild glomerulosclerosis, shown by periodic acid-Schiff (PAS) staining ( Figure 5C) and assessed by glomerular damage scores ( Figure 5D).…”

“…32 In brief, mice were anesthetized and perfused by infusing the abdominal artery with 5 ml of PBS containing 8310…”

ABIN1 in the pathogenesis of Glomerulonephritis and the novel polocyte-neutrophil proinflammatory axis.

“…As highlighted previously, NF-κB activation is associated with GN and is important to podocyte response to proinflammatory stimulation [35][36][37]. Inhibition of NF-κB signaling protects against development of disease, at least in part, through reduced expression of cytokines that are transcriptional targets of NF-κB [30,33,34,38].…”

“…Dysregulation of NF-κB activity is associated with many human diseases, especially those involving chronic inflammation, and recent studies suggest that NF-κB plays a role in the incidence and severity of GN as well [30][31][32][33][34]. In particular, both mesangial cells and podocytes demonstrate NF-κB activation and cytokine production in response to proinflammatory mediators [35][36][37].…”