Nrp-1 Mediated Plasmatic Ago2 Binding miR-21a-3p Internalization: A Novel Mechanism for miR-21a-3p Accumulation in Renal Tubular Epithelial Cells during Sepsis

Abstract

The mechanism underlying sepsis-associated acute kidney injury (SAKI), which is an independent risk factor for sepsis-associated death, is unclear. A previous study indicates that during sepsis miR-21a-3p accumulates in renal tubular epithelial cells (TECs) as the mediator of inflammation and mediates TEC malfunction by manipulating its metabolism. However, the specific mechanism responsible for the accumulation of miR-21a-3p in TECs during sepsis is unrevealed. In this study, a cecal ligation and puncture- (CLP-) induced sepsis rat model and rat TEC line were used to elucidate the mechanism. Firstly, miR-21a-3p and Ago2 levels were found out to increase in both plasma and TECs during sepsis, and the increase of intracellular Ago2 and miR-21a-3p could be mitigated when Ago2 was either inactivated or downregulated in septic plasma. Moreover, membrane Nrp-1 expression of TECs was increased significantly during sepsis and Nrp-1 knockdown also mitigated the rise of both the intracellular Ago2 and miR-21a-3p levels in TECs incubated with septic plasma. Furthermore, it was revealed that Ago2 can be internalized by TECs mediated with Nrp-1 and this process had no effect on the intracellular content of miR-21a-3p. Both Ago2 and miR-21a-3p could bind to TECs derived Nrp-1 directly. Finally, it was determined that miR-21a-3p was internalized by TECs via Nrp-1 and Ago2 facilitated this process. Taken together, it can be concluded from our results that Ago2 binding miR-21a-3p from septic plasma can be actively internalized by TECs via Nrp-1 mediated cell internalization, and this mechanism is crucial for the rise of intracellular miR-21a-3p content of TECs during sepsis. These findings will improve our understanding of the mechanisms underlying SAKI and aid in developing novel therapeutic strategies.

Expression of MicroRNAs in Sepsis-Related Organ Dysfunction: A Systematic Review

“…Zhiqiang Zou et al attempted to elucidate this mechanism by analyzing septic rats and the TEC line. They showed that miR-21a-3p levels in plasma and TECs increased during sepsis by the internalization of plasmatic Ago2, which binds miR-21a-3p mediated by membrane Nrp-1 [ 259 ].…”

Soluble Neuropilin-1 Is Elevated in Sepsis and Correlates with Organ Dysfunction and Long-Term Mortality in Critical Illness

“…Previously, NRP-1 has been associated with liver pathologies [39,41] and kidney disease [42][43][44][45]50,52,53]. Urinary NRP-1 has been proposed as a biomarker for lupus nephritis [42] due to its high expression in mesangial cells.…”

“…Other diseases that have been studied include kidney injury [42][43][44][45], autoimmune disease [46,47], and neurological disorders [48,49]. However, there is a lack of data on NRP-1 in human sepsis, despite efforts to understand its role in sepsis and its connection to kidney failure [50][51][52][53][54][55][56]. Given the involvement of NRP-1 in the immune system and regulation of vascular permeability [22,32,57,58], this study aims to investigate the role of its antagonist, sNRP-1, in critical illness and sepsis and assess its potential as a biomarker in this setting.…”

The semaphorin 4A–neuropilin 1 axis alleviates kidney ischemia reperfusion injury by promoting the stability and function of regulatory T cells

“…Nrp1 is a specific murine Treg surface marker that has been recognized as a coreceptor for a wide range of extracellular ligands, which are represented by Sema3A and Sema4A [25][26][27]34 . A series of studies have shown that Nrp1 is closely related to the suppressive capacity of Tregs, particularly Tregs in J o u r n a l P r e -p r o o f inflammatory microenvironments 21,25,35,36 promotes miR-21a-3p internalization by renal tubular epithelial cells, which aggravates SAKI 39 . In the current study, in the absence of Sema4A administration, the specific depletion of Nrp1 had no significant effect on kidney Tregs or IRI.…”