Background/Purpose: Approximately 40% of SLE patients will develop Lupus Nephritis (LN), of which 10-30 % will progress to end-stage renal disease. To further understand LN pathogenesis, we conducted transcriptomic profiling of blood and kidney biopsy samples from LN patients, healthy control (HC), and from four other nephritides.

Methods: Blood and kidney biopsies from healthy subjects (n=28 and 20 respectively), LN (26,21), Diabetic Nephropathy (DN; 10,6), Hypertensive kidney disease (HT;8,3), Minimal change disease (MC; 7,4), and Membranous nephropathy (MB; 4,4) were collected under informed consent. Gene expression profiling was conducted using RNA-Sequencing (RNASeq). Genes differently expressed between any two conditions (FDR < 0.05) were identified and clustered into co-expressed signatures. 

Results: We detected 5 and 6 gene signatures in blood and kidney, respectively. The signatures were enriched in distinct biological pathways, including “Interferon Signaling,” “Natural killer cell-mediated cytotoxicity (NK_CMC),” and “Aquaporin-mediated transport (AMT).” When compared to HC, Gene Set Variation Analysis (GSVA) showed an increase of “Interferon Signaling” expression in LN (p = 2.8E-6) and DN (p= 0.0038) blood and in LN (p=8.7E-8), DN (p=3.8E-4), HT (p=0.018) and MB (p=0.018) kidney. In LN and HT blood, we observed a decreased enrichment of the NK_CMC signature (p =1E-13, p=6.3E-3). A bimodal enrichment was observed in DN and MC blood, and ~40% of those patients showed an expression level comparable to that of the LN population. Also, the NK_CMC signature was upregulated in LN (P=0.011) and DN (P=0.016) kidney. Finally, the AMT signature was downregulated in kidney in all indications compared to healthy (p< 0.05).

Conclusion: Co-expression clustering of dysregulated genes unveiled signatures enriched in distinct biological pathways in both blood and kidney of nephritides. IFN signature upregulation in blood was specific to LN and DN, with a more prominent signal observed in LN. The IFN signature was upregulated in the kidney in all indications except MC. An NK-mediated cytotoxicity gene signature was down-regulation in the blood of LN and HT and upregulated in the kidney of LN and DN, suggesting a possible role of NK mediated cytotoxicity in LN and DN pathogenesis.  A signature enriched in aquaporin-mediated transport genes was downregulated in the kidney and might reflect kidney damage. Although this analysis was adequately powered for LN, trends observed in other indications require further validation with larger cohorts.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/distinct-biological-pathways-in-both-blood-and-kidney-further-define-molecular-profiles-across-diverse-nephritides/