MicroRNA-10 negatively regulates inflammation in diabetic kidney via targeting activation of the NLRP3 inflammasome

• Published in: Molecular therapy 2021-07, Vol.29 (7), p.2308-2320
• Main Authors: Ding, Hanying, Li, Jinxiang, Li, Yang, Yang, Minliang, Nie, Sheng, Zhou, Miaomiao, Zhou, Zhanmei, Yang, Xiaobing, Liu, Youhua, Hou, Fan Fan
• Format: Article
• Language: English
• Subjects: Animals; Diabetes Mellitus, Experimental - complications; diabetic kidney disease; Diabetic Nephropathies - etiology; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Humans; Inflammasomes - genetics; Inflammasomes - metabolism; Inflammation - etiology; Inflammation - metabolism; Inflammation - pathology; kidney inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; microRNA; MicroRNAs - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 inflammasome; Original; Podocytes - metabolism; Podocytes - pathology
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2021.03.012

NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome activation has emerged as a central mediator of kidney inflammation in diabetic kidney disease (DKD). However, the mechanism underlying this activation in DKD remains poorly defined. In this study, we found that kidney-enriched microRNA-10a and -10b (miR-10a/b), predominantly expressed in podocytes and tubular epithelial cells, were downregulated in kidney from diabetic mice and patients with DKD. High glucose decreased miR-10a/b expression in vitro in an osmolarity-independent manner. miR-10a/b functioned as negative regulators of the NLRP3 inflammasome through targeting the 3′untranslated region of NLRP3 mRNA, inhibiting assembly of the NLRP3 inflammasome and decreasing caspase-1-dependent release of pro-inflammatory cytokines. Delivery of miR-10a/b into kidney prevented NLRP3 inflammasome activation and renal inflammation, and it reduced albuminuria in streptozotocin (STZ)-treated mice, whereas knocking down miR-10a/b increased NLRP3 inflammasome activation. Restoration of miR-10a/b expression in established DKD ameliorated kidney inflammation and mitigated albuminuria in both db/db and STZ-treated mice. These results suggest a novel intervention strategy for inhibiting kidney inflammation in DKD by targeting the NLRP3 inflammasome. [Display omitted] Kidney inflammation has emerged as a central mediator in diabetic kidney disease. This study found that a kidney-enriched noncoding RNA miR-10 inhibits inflammation by blocking the NLRP3 inflammasome and improves kidney damage in diabetic models, suggesting that targeting NLRP3 by miR-10 might be a key strategy for treatment of diabetic kidney disease.