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The progression path of diabetic kidney disease (DKD), the leading cause of kidney failure worldwide, is very complex. Knowledge of mechanisms by which circulating pro-inflammatory factors activate intrarenal signaling and contribute to DKD progression is limited. Our aim was to retrospectively identify circulating inflammatory factors that are associated with progression to kidney failure in a cohort of individuals with diabetes and early DKD.
Micro-dissected kidney biopsy tissue transcriptomics (n=74) and SOMASCAN plasma proteomics (n=162) profiles were generated from a cohort of Native Americans with type 2 diabetes . Histologic measurements were obtained from these biopsies and also in tissue from a second kidney biopsy an average of 7 years after the first. Differentially expressed genes (DEGs) and proteins (DEPs) were identified by comparing individuals who progressed to kidney failure versus those who did not. Ingenuity Pathway Analysis of kidney failure-associated DEGs was used to identify potential upstream regulators (URs); the DEP list was then used to further filter statistically significant in silico-predicted URs. For the top UR candidate, a literature-curated downstream signaling cascade was compiled and an transcriptional level activation score representing kidney tissue transcript expression of this cascade (KScore) was computed. The KScore was evaluated for association with DKD progression with Kaplan-Meier survival models and correlation with GFR slope and histologic DKD lesions. Further investigation of the UR signaling cascade was performed with 24h UR -stimulated kidney organoids generated from human pluripotent stem cells and two DKD mouse models (DBA/2 podocyte-JAK2 transgenic and uninephrectomized BKS Renin AAV db/db mice) treated with UR signaling pathway inhibitorsinhibitors.
Transcriptomic differential analysis resulted in 259 and 863 DEGs in the glomerular and tubulointerstitial profiles respectively. From 44 predicted URs (growth factors/cytokines) of both glomerular and tubulointerstitial DEGs, Interferon gamma (IFN-γ) was the top candidate with higher circulating levels in the plasma profiles of individuals progressing to kidney failure. Single cell transcriptional profiling revealed ubiquitous kidney cell expression of IFN- γ receptors (R1/R2). Early T2D kidney tissue IFN-γ KScores (summarizing expression of 72 downstream signaling mediators) correlated with DKD progression (GFR slope and kidney failure) over a median of 10 years (Figure 1) as well as increased mesangial volume, a histologic marker of DKD, measured after 7 years (r= 0.38, p= 0.04). Increased KScores of IFN-γ -stimulated kidney organoids were significantly suppressed by co-treatment with JAK1/2 inhibitor (major IFN-γ signaling mediators) (p=0.0007). Similar suppression of increased IFN-γ KScores by Jak1/Jak2 inhibitors were observed in DKD mouse models.
Our integrative multiscalar approach revealed that increased circulating IFN-γ levels and IFN-γ pathway activation in early DKD are associated with DKD progression to kidney failure. Our research supports further evaluation of the IFN-γ signaling pathway as a potential target for early DKD intervention
This abstract was also submitted for the (ASN 2023) congress. By submitting the abstract to WCN’24, abstract authors declare that re-submitting the abstract is permitted by the organizers of the previous meeting.