JAK-STAT signaling is activated in the kidney and peripheral blood cells of patients with focal segmental glomerulosclerosis

Abstract

Focal segmental glomerular sclerosis (FSGS) is a devastating disease with limited treatment options and poor prognosis. Activated JAK-STAT signaling has been implicated in other kidney diseases. Since new technologies allow us to better evaluate changes in systemic and renal JAK-STAT activity as it relates to kidney function, we examined this in 106 patients with biopsy-proven FSGS compared to 47 healthy control individuals. Peripheral immune function was assessed in peripheral blood mononuclear cells by phosphoflow studies before and after cytokine stimulation. Kidney JAK-STAT activity was measured by immunofluorescence and by transcriptomics. A STAT1 activity score was calculated by evaluating message status of downstream targets of pSTAT 1. Peripheral blood mononuclear cells were found to be upregulated in terms of pSTAT production at baseline in FSGS and to have limited reserve to respond to various cytokines. Increased staining for components of the JAK-STAT system in FSGS by microscopy was found. Furthermore, we found transcriptomic evidence for activation of JAK-STAT that increased pSTAT 1 and pSTAT 3 in glomerular and tubulointerstitial sections of the kidney. Some of these changes were associated with the likelihood of remission of proteinuria and progression of disease. JAK-STAT signaling is altered in patients with FSGS as compared to healthy controls with activated peripheral immune cells, increased message in the kidney and increased activated proteins in the kidney. Thus, our findings support immune activation in this disease and point to the JAK-STAT pathway as a potential target for treatment of FSGS.

Organoid single-cell profiling identifies a transcriptional signature of glomerular disease

“…5A). These gene sets were used to generate "aggregate gene expression scores" in isolated glomerular tissue from a cohort of individuals with various etiologies of chronic kidney disease (European Renal cDNA Bank, ERCB) (28,29). Query of the subset of the identified genes available on the microarray platforms ( Fig.…”

Inflammatory and JAK-STAT Pathways as Shared Molecular Targets for ANCA-Associated Vasculitis and Nephrotic Syndrome

“…Because expression of a single gene is not necessarily indicative of network or pathway activity, a STAT1 score was generated, given that a similar approach yielded a JAK-STAT activation score that was associated with increased STAT1 and STAT3 phosphorylation in FSGS 13 . Using a data driven approach, a kidney-specific STAT1 network comprised of 17 genes was identified 14 , and further refined for genes functionally up-regulated by IFNγ stimulation by utilizing the Database of IFN Regulated Genes, Interferome 15 .…”

“…For the inflammatory-related pathways, evidence for their potential causal role in autoimmune or renal disease has been established, including TNF [28][29][30] , JAK-STAT 16 , NFκB 31 , proteasome signaling 32,33 , and reactivation of glucocorticoid signaling through the use of glucocorticoid agonists 34 . JAK-STAT pathway activation has already been implicated across other kidney diseases including diabetic kidney disease (DKD) [35][36][37][38] , and FSGS 13 . In addition to the inflammatory-related pathways, reduced HNF4 transcriptional activity could represent a state of de-differentiation as Hnf4a can induce mesenchymal to epithelial transition 39 .…”

“…Because transcription factor activation is driven by its ability to activate downstream transcription and not simply expression, we generated a STAT1 activation score. This approach was previously used to characterize JAK-STAT pathway activation and correlated with activated (phos-STAT) activation in FSGS 13 in the NEPTUNE cohort. The STAT1 score correlated across diseases on an individual patient level with CXCL10 (IP-10) mRNA, and urinary EGF.…”

Redefining Nephrotic Syndrome in Molecular Terms: Outcome-associated molecular clusters and patient stratification with noninvasive surrogate biomarkers

“…In upstream regulator analysis (an analysis that takes into account both enrichment of and underlying direction of differential gene expression changes using cause and effect relationships), the top predicted activated protein network was TNF (IPA Z-score=10.2, enrichment p-value=3.65E-84, Figure 3B). A mechanistic network centered on downstream effects of TNF activation explained 26% (660/2517) of the differentially expressed genes in the analysis and included multiple transcription factors previously implicated in chronic kidney diseases including activation of the NFκB complex (as well as activation of NFKB1 (p105/p50) and RELA (p65) subunits) (8-10), and STAT1 and STAT3 (11). Lastly, 11 of the genes in the TNF causal network (including TNF) were supported by multiple literature assertions in IPA ( Figure 3C), and were also profiled on a targeted proteomic profile panel.…”