MicroRNA-23b-3p Deletion Induces an IgA Nephropathy-like Disease Associated with Dysregulated Mucosal IgA Synthesis
Copyright © 2021 by the American Society of Nephrology..
BACKGROUND: IgA nephropathy (IgAN) is the most common primary GN worldwide. Circulating immune complexes form that are prone to deposition in the mesangium, where they trigger glomerular inflammation. A growing body of evidence suggests that dysregulated expression of microRNAs in IgAN may play a significant role in establishing the disease phenotype.
METHODS: We generated single miR-23b-3p(miR-23b) knockout mice using CRISPR-Cas9.
RESULTS: In humans, miR-23b levels are downregulated in kidney biopsies and sera of patients with IgAN, and serum miR-23b levels are negatively correlated with serum IgA1 levels. We show that miR-23b-/- mice develop an IgAN-like phenotype of mesangial IgA and C3 deposition associated with development of albuminuria, hypertension, an elevated serum creatinine, and dysregulated mucosal IgA synthesis. Dysregulation of IgA production is likely mediated by the loss of miR-23b-mediated suppression of activation-induced cytidine deaminase in mucosal B cells. In addition, we show that loss of miR-23b increases the susceptibility of the kidney to progressive fibrosis through loss of regulation of expression of gremlin 2 and IgA accumulation through downregulation of the transferrin receptor.
CONCLUSIONS: Our findings suggest an indispensable role for miR-23b in kidney disease, and in particular, IgAN. miR-23b may in the future offer a novel therapeutic target for the treatment of IgAN.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:32 |
|---|---|
| Enthalten in: |
Journal of the American Society of Nephrology : JASN - 32(2021), 10 vom: 15. Okt., Seite 2561-2578 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Li, Hongzhi [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 06.12.2021 Date Revised 03.02.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1681/ASN.2021010133 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM330224158 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM330224158 | ||
| 003 | DE-627 | ||
| 005 | 20231225210826.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1681/ASN.2021010133 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1100.xml |
| 035 | |a (DE-627)NLM330224158 | ||
| 035 | |a (NLM)34479967 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Li, Hongzhi |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a MicroRNA-23b-3p Deletion Induces an IgA Nephropathy-like Disease Associated with Dysregulated Mucosal IgA Synthesis |
| 264 | 1 | |c 2021 | |
| 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 Completed 06.12.2021 | ||
| 500 | |a Date Revised 03.02.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 by the American Society of Nephrology. | ||
| 520 | |a BACKGROUND: IgA nephropathy (IgAN) is the most common primary GN worldwide. Circulating immune complexes form that are prone to deposition in the mesangium, where they trigger glomerular inflammation. A growing body of evidence suggests that dysregulated expression of microRNAs in IgAN may play a significant role in establishing the disease phenotype | ||
| 520 | |a METHODS: We generated single miR-23b-3p(miR-23b) knockout mice using CRISPR-Cas9 | ||
| 520 | |a RESULTS: In humans, miR-23b levels are downregulated in kidney biopsies and sera of patients with IgAN, and serum miR-23b levels are negatively correlated with serum IgA1 levels. We show that miR-23b-/- mice develop an IgAN-like phenotype of mesangial IgA and C3 deposition associated with development of albuminuria, hypertension, an elevated serum creatinine, and dysregulated mucosal IgA synthesis. Dysregulation of IgA production is likely mediated by the loss of miR-23b-mediated suppression of activation-induced cytidine deaminase in mucosal B cells. In addition, we show that loss of miR-23b increases the susceptibility of the kidney to progressive fibrosis through loss of regulation of expression of gremlin 2 and IgA accumulation through downregulation of the transferrin receptor | ||
| 520 | |a CONCLUSIONS: Our findings suggest an indispensable role for miR-23b in kidney disease, and in particular, IgAN. miR-23b may in the future offer a novel therapeutic target for the treatment of IgAN | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a IgA | |
| 650 | 4 | |a chronic kidney disease | |
| 650 | 4 | |a immunology | |
| 650 | 7 | |a Bone Morphogenetic Proteins |2 NLM | |
| 650 | 7 | |a Complement C3 |2 NLM | |
| 650 | 7 | |a Cytokines |2 NLM | |
| 650 | 7 | |a GREM2 protein, human |2 NLM | |
| 650 | 7 | |a Grem2 protein, mouse |2 NLM | |
| 650 | 7 | |a Immunoglobulin A |2 NLM | |
| 650 | 7 | |a MIRN23b microRNA, human |2 NLM | |
| 650 | 7 | |a MicroRNAs |2 NLM | |
| 650 | 7 | |a Mirn23b microRNA, mouse |2 NLM | |
| 650 | 7 | |a Receptors, Transferrin |2 NLM | |
| 650 | 7 | |a Cytidine Deaminase |2 NLM | |
| 650 | 7 | |a EC 3.5.4.5 |2 NLM | |
| 700 | 1 | |a Chen, Zhichao |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Weitian |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Jingyi |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yunshuang |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Hongchuang |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Mingming |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Xuelian |e verfasserin |4 aut | |
| 700 | 1 | |a Yao, Xiusong |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zhijun |e verfasserin |4 aut | |
| 700 | 1 | |a Pawluczyk, Izabella Z A |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Shuchen |e verfasserin |4 aut | |
| 700 | 1 | |a Barratt, Jonathan |e verfasserin |4 aut | |
| 700 | 1 | |a Lv, Jicheng |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Kai |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Binghai |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of the American Society of Nephrology : JASN |d 1990 |g 32(2021), 10 vom: 15. Okt., Seite 2561-2578 |w (DE-627)NLM012606502 |x 1533-3450 |7 nnns |
| 773 | 1 | 8 | |g volume:32 |g year:2021 |g number:10 |g day:15 |g month:10 |g pages:2561-2578 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1681/ASN.2021010133 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 32 |j 2021 |e 10 |b 15 |c 10 |h 2561-2578 | ||