MicroRNA-23b-3p Deletion Induces an IgA Nephropathy-like Disease Associated with Dysregulated Mucosal IgA Synthesis

Significance Statement Accumulating evidence implicates microRNAs in IgA nephropathy (IgAN), which is a common primary GN in which aberrant IgA aggregated with complement 3, with or without IgG/IgM is deposited in glomerular mesangium. We showed, in a mouse model, that miR-23b deficiency induced an IgA nephropathy-like disease, marked by mesangial IgA and C3 deposition, increased proteinuria, elevated serum IgA levels, and development of high blood pressure. Elevations in serum IgA levels and mesangial IgA deposition were associated with dysregulated mucosal IgA synthesis through targeting the activation-induced cytidine deaminase gene in the gut. miR-23b deficiency-induced dysfunctional kidney effects were likely mediated through regulation of expression of gremlin 2 (Grem2) and the transferrin receptor (Tfrc), which weexamined in human mesangial cells. 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.