miR-181a Improved Renal Inflammation by Targeting TNF-α in a Diabetic Nephropathy Animal Model

Abstract

<b><i>Introduction:</i></b> Recent studies have elucidated that miR-181a plays a vital role in various inflammation-associated diseases; however, its role in the pathogenesis of diabetic nephropathy (DN) has not been elucidated clearly. Hence, we investigated the involvement of miR-181a in the pathogenesis of DN in patients and animal models. <b><i>Methods:</i></b> miR-181a levels were measured in the kidneys of DN patients and a DN mouse model (db/db mice) by RT-PCR. The interaction of miR-181a with the 3′-UTR of potential target transcripts was investigated using luciferase reporter assays. miR-181a-GFP-AAV and miR-181a inhibitor were used to overexpress or downregulate miR-181a in the kidney of db/db mice, respectively. The expression of inflammatory proteins and target genes was measured in the kidneys of the animals. <b><i>Results:</i></b> In DN patients and DN mouse models, expression analyses showed a significant decrease in miR-181a levels in the kidney. In addition, a negative linear correlation between miR-181a and proinflammatory gene (IL-1β and TNF-α) levels was observed in the kidneys of DN patients. Overexpression of miR-181a reduced IL-1β and TNF-α expression, whereas suppression of miR-181a worsened these changes, which was attenuated by combined treatment with TNF-α neutralizing antibody in db/db mice. Moreover, luciferase assays revealed that TNF-α is a direct target of miR-181a. <b><i>Conclusion:</i></b> Our data emphasized the anti-inflammatory actions of miR-181a by targeting TNF-α in the context of renal inflammation in DN. Hence, we concluded that miR-181a could be a potential therapeutic option for minimizing renal inflammation in DN.

Extracellular vesicles in chronic kidney disease: diagnostic and therapeutic roles

“…However, further investigation is needed to explore the correlation between miR-192 derived from EVs and other renal function indicators. Other studies showed that urinary EV miR-181a was significant reduced in CKD patients at all stages, as well as in DN patients ( Khurana et al, 2017 ; Zha et al, 2019 ; Liu et al, 2022 ). Furthermore, miR-181a overexpression could reduce glomerulosclerosis and tubular epithelial injury ( Liu et al, 2018d ).…”

Unveiling the crucial role of intercellular adhesion molecule‐1 in secondary diabetic complications

“…miR-181a overexpression in mesangial cells reduces IL-6 and IL-1β levels, attenuating DN-associated inflammation. 22 In vitro models simulating DN suggest that increased miR-485 expression mitigates inflammation and limits mesangial cell proliferation. Recent research has suggested that miR-141 suppresses DN partly through its inhibitory impact on ICAM-1, with empirical support from feedback verification studies.…”

“…The miRNA miR‐141, in particular, has been noted for its ability to inhibit ICAM‐1 and thereby exert a protective effect against DN. miR‐181a overexpression in mesangial cells reduces IL‐6 and IL‐1β levels, attenuating DN‐associated inflammation 22 . In vitro models simulating DN suggest that increased miR‐485 expression mitigates inflammation and limits mesangial cell proliferation.…”

The Role of microRNAs in Inflammation

“…miR-149 shows its anti-inflammatory response via targeting TAK1/NF-ĸB signaling in osteoarthritic chondrocytes [ 80 ]. miR-181a down-regulates TNF-α, thereby improving renal inflammation in the diabetic nephropathy animal model [ 81 ]. The down-regulation of miR-150 induces the LPS-mediated release of pro-inflammatory cytokines in THP-1 macrophages via STAT1 up-regulation [ 82 ].…”