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Idiopathic membranous nephropathy and minimal change disease (MCD) transcriptome

ABSTRACT: Introduction: Minimal change disease (MCD) is a major cause of nephrotic syndrome. With a substantial number of patients requiring long-term immunosuppression leading to significant morbidity, the study aim was to determine MCD glomerular transcriptome to serve as a basis for biomarker discovery and novel drug target identification. Animal work showed podocyte injury induced by IL-7/IL-7R signaling (Zhai S, BBRC, 2018). Methods: Renal biopsies from adult patients representing the following groups were selected from the Norwegian Kidney Biopsy Registry: MCD (n=14), as well as normal tissue (n=8) and primary membranous nephropathy (MN; n=12) as the two reference groups. RNA for 75 base-pair paired-end RNASeq was obtained by dissecting glomeruli via laser capture microdissection (LCM) from FFPE cross-sections. Systematic delineation of condition-specific alteration in transcriptional landscapes was achieved by combining pathway-centered analyses with methodologies derived from network science and integrating multiple bioinformatics resources. Results: Compared to normal glomeruli, glomeuli from MCD displayed an inflammatory signature that appeared to be predominantly governed by the IL1 and IL7 systems. While enrichment of IL1 production and secretion was a shared feature of MCD and MN compared to normal tissue, responses involving IL7 pathway activation were unique to MCD. Indeed, IL7R expressed by glomeruli was the most up-regulated gene of to the interleukin-family in MCD vs normal controls. IL7 pathway activation was paralleled by significant enrichment in adaptive immune system processes and transcriptional regulation and depletion in pathways related to energy metabolism and transcription. Downregulation of these organ function-related themes again occurred predominately in MDC and were significantly less pronounced in MN. Conclusion: Our results demonstrate that archival FFPE-biopsies can be used to generate glomeruli-specific gene expression profiles suitable for systematic delineation of kidney-associated diseases. Here the latter provides a data-driven rationale to experimentally address these MCD-specific features as biomarkers and as novel drug targets. In this context inhibiting activation of the IL7 pathway may be particularly promising.

ORGANISM(S): Homo sapiens

PROVIDER: GSE216841 | GEO | 2023/01/25

REPOSITORIES: GEO

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Project description:Description Primary membranous nephropathy (MN) is an autoimmune kidney disease histomorphologically defined by subepithelial deposition of immune complexes in the glomeruli, and exhibits a high risk for end-stage kidney disease. Circulating antibodies against phospholipase A2 receptor 1 (PLA2R1) are detected in 70-80% of MN patients and correlate with treatment response and prognosis. Experimental proof that human PLA2R1-antibodies induce MN is still missing. Methods: In passive transfer experiments, minipigs received plasma or purified IgG from patients with PLA2R1-associated MN or from healthy controls. PLA2R1-antibodies and proteinuria were monitored using Western blot, ELISA and Coomassie staining. Kidney tissues were analyzed using immunohistochemistry, immunofluorescence, electron microscopy and proteomic analyses. Results: We show that minipigs, like humans, express PLA2R1 on podocytes. Human PLA2R1-antibodies bound to minipig PLA2R1 in-vitro and in-vivo. Passive transfer of human PLA2R1-antibodies, derived from patients with PLA2R1- associated MN, led to the development of histomorphologic characteristics of human early-stage MN in minipigs, activation of components of the complement cascade and induction of low levels of proteinuria. In the later phases of disease, development of an autologous phase of disease was observed. Conclusions: Applying a translational approach from humans to minipigs we show that human PLA2R1-antibodies are pathogenic, although in the heterologous phase of disease only low level proteinuria developed. Proteomic samples: Porcine glomeruli were isolated following previously published protocols known for human glomeruli, with slight modifications (Stahl et al., Kidney Int. 1984;26(1):30–34.). A total of six samples of sieved glomeruli from porcine kidney were used. 1. untreated_negative_control Experiment 1 (passive transfer of human PLA2R1 antibody from PLA2R1-antibody positive patient into minipigs) 2. exp_1_passive_antibody_rep1 Same experimental procedure in two animals (replicate 1) (treated with patient antibody) 3. exp_1_passive_antibody_rep2 Same experimental procedure in two animals (replicate 2) (treated with patient antibody) 4. exp_1_passive_antibody_control control animal for Pig A and B (treated with healthy antibody) Experiment 2 (passive transfer of human plasma from PLA2R1-antibody positive patient into minipigs) 5. exp_2_passive_plasma treated animal (treated with patient plasma) 6. exp_2_passive_plasma_control control animal (treated with healthy plasma)

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Idiopathic membranous nephropathy and minimal change disease (MCD) transcriptome

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