Sparsentan ameliorates glomerular hypercellularity and inflammatory-gene networks induced by IgA1-IgG immune complexes in a mouse model of IgA nephropathy
IgA nephropathy (IgAN), is characterized by glomerular deposition of immune complexes (IC) consisting of IgA1 with O-glycans deficient in galactose (Gd-IgA1) and Gd-IgA1-specific IgG autoantibodies. These ICs induce kidney injury, and in the absence of disease-specific therapy, up to 40% of IgAN patients progress to kidney failure. IgA1 with its clustered O-glycans is unique to humans, which hampered development of small-animal models of IgAN. Here, we used a model wherein engineered IC (EIC) formed from human Gd-IgA1 and recombinant human IgG autoantibody are injected into nude mice to induce glomerular injury mimicking human IgAN. In this model, we assessed the protective effects of sparsentan, a single-molecule dual endothelin angiotensin receptor antagonist (DEARA) vs. vehicle on EIC-induced glomerular proliferation and dysregulation of gene expression in kidney. Oral administration of sparsentan (60 or 120 mg/kg daily) to mice intravenously injected with EIC attenuated the EIC-induced glomerular hypercellularity. Furthermore, the analysis of changes in the whole kidney transcriptome revealed that key inflammatory and proliferative biological genes and pathways that are upregulated in this EIC model of IgA nephropathy were markedly reduced by sparsentan, including complement genes, integrin components, members of the MAP kinase family, and Fc receptor elements. Partial overlap between mouse and human differentially expressed genes in IgAN further support the translational aspect of the immune and inflammatory component from our transcriptional findings. In conclusion, our data indicate that in the mouse model of IgAN, sparsentan targets immune and inflammatory processes leading to protection from mesangial hypercellularity.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
|---|---|
| Enthalten in: |
American journal of physiology. Renal physiology - (2024) vom: 21. März |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Reily, Colin [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Angiotensin |
|---|
| Anmerkungen: |
Date Revised 21.03.2024 published: Print-Electronic Citation Status Publisher |
|---|
| doi: |
10.1152/ajprenal.00253.2023 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM370008049 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM370008049 | ||
| 003 | DE-627 | ||
| 005 | 20240322001800.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240322s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1152/ajprenal.00253.2023 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1339.xml |
| 035 | |a (DE-627)NLM370008049 | ||
| 035 | |a (NLM)38511222 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Reily, Colin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Sparsentan ameliorates glomerular hypercellularity and inflammatory-gene networks induced by IgA1-IgG immune complexes in a mouse model of IgA nephropathy |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 21.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status Publisher | ||
| 520 | |a IgA nephropathy (IgAN), is characterized by glomerular deposition of immune complexes (IC) consisting of IgA1 with O-glycans deficient in galactose (Gd-IgA1) and Gd-IgA1-specific IgG autoantibodies. These ICs induce kidney injury, and in the absence of disease-specific therapy, up to 40% of IgAN patients progress to kidney failure. IgA1 with its clustered O-glycans is unique to humans, which hampered development of small-animal models of IgAN. Here, we used a model wherein engineered IC (EIC) formed from human Gd-IgA1 and recombinant human IgG autoantibody are injected into nude mice to induce glomerular injury mimicking human IgAN. In this model, we assessed the protective effects of sparsentan, a single-molecule dual endothelin angiotensin receptor antagonist (DEARA) vs. vehicle on EIC-induced glomerular proliferation and dysregulation of gene expression in kidney. Oral administration of sparsentan (60 or 120 mg/kg daily) to mice intravenously injected with EIC attenuated the EIC-induced glomerular hypercellularity. Furthermore, the analysis of changes in the whole kidney transcriptome revealed that key inflammatory and proliferative biological genes and pathways that are upregulated in this EIC model of IgA nephropathy were markedly reduced by sparsentan, including complement genes, integrin components, members of the MAP kinase family, and Fc receptor elements. Partial overlap between mouse and human differentially expressed genes in IgAN further support the translational aspect of the immune and inflammatory component from our transcriptional findings. In conclusion, our data indicate that in the mouse model of IgAN, sparsentan targets immune and inflammatory processes leading to protection from mesangial hypercellularity | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Angiotensin | |
| 650 | 4 | |a Gene expression | |
| 650 | 4 | |a Glomerulus | |
| 650 | 4 | |a IgA nephropathy | |
| 650 | 4 | |a Inflammation | |
| 700 | 1 | |a Moldoveanu, Zina |e verfasserin |4 aut | |
| 700 | 1 | |a Pramparo, Tiziano |e verfasserin |4 aut | |
| 700 | 1 | |a Hall, Stacy |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Zhi-Qiang |e verfasserin |4 aut | |
| 700 | 1 | |a Rice, Terri |e verfasserin |4 aut | |
| 700 | 1 | |a Novak, Lea |e verfasserin |4 aut | |
| 700 | 1 | |a Komers, Radko |e verfasserin |4 aut | |
| 700 | 1 | |a Jenkinson, Celia P |e verfasserin |4 aut | |
| 700 | 1 | |a Novak, Jan |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t American journal of physiology. Renal physiology |d 2000 |g (2024) vom: 21. März |w (DE-627)NLM105736171 |x 1522-1466 |7 nnns |
| 773 | 1 | 8 | |g year:2024 |g day:21 |g month:03 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1152/ajprenal.00253.2023 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |j 2024 |b 21 |c 03 | ||