Hongzhi Li1, Zhichao Chen2, Weitian Chen2, Jingyi Li3, Yunshuang Liu4, Hongchuang Ma5, Mingming Shi2, Xuelian Sun1, Xiusong Yao6, Zhijun Li1, Izabella Z A Pawluczyk7, Shuchen Zhang8, Jonathan Barratt7, Jicheng Lv9, Kai Wang10, Binghai Zhao5. 1. Nephrosis Precision Medicine Innovation Center, University of Beihua School of Medicine, Beihua University, Jilin 132011, Jilin, China. 2. College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. 3. Renal Division, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China zhaobinghai01@vip.163.com wangkai@hrbmu.edu.cn. 4. Department of Ultrasound, Affiliated Hong Qi Hospital, Mudanjiang Medical University, Mudanjiang 157011, China. 5. Nephrosis Precision Medicine Innovation Center, University of Beihua School of Medicine, Beihua University, Jilin 132011, Jilin, China zhaobinghai01@vip.163.com wangkai@hrbmu.edu.cn. 6. Nephrology Department of Jinlin Central Hospital, Jinlin 132011, Jilin, China. 7. Department of Cardiovascular Sciences, University of Leicester, Leicester LE1 7RH, UK. 8. Electron Microscopy Center, Basic Medical Science College, Harbin Medical University, Harbin, 150081, China. 9. Renal Division, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China. 10. Molecular Imaging Research Center, Harbin Medical University (MIRC), Harbin, Heilongjiang 150028, China zhaobinghai01@vip.163.com wangkai@hrbmu.edu.cn.
Abstract
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.
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.
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