Functional role of microRNA‐500a‐3P‐loaded liposomes in the treatment of cisplatin‐induced AKI

Abstract

Cisplatin treatment results in acute kidney injury (AKI) by the phosphorylation of mixed lineage kinase domain-like protein (MLKL). The knockout of MLKL, which is a principle mediator of necroptosis, is believed to alleviate the AKI symptoms. The present study was aimed to improve the therapeutic efficacy in AKI. For this purpose, miR-500a-3P was identified as appropriate miRNA therapeutics and loaded in liposome delivery carrier. The authors have showed that the miR-LIP directly controls the expression of RIPK3 and MLKL-a modulator of necroptosis and thereby reduces the severity of kidney injury. The miR-LIP significantly controlled the phosphorylation of MLKL compared to that of CDDP-treated HK2 cells. Similar results are observed with RIPK3. The miR-LIP has also been demonstrated to control the inflammatory response in tubular cells. Western blot analysis further revealed that the phosphorylation of P-65 was mainly responsible for the inflammatory response and miR-LIP significantly decreased the CDDP-induced NF-kB phosphorylation. Overall, the present study explored the molecular mechanism behind the necroptosis in AKI and potential of miRNA in targeting MLKL pathways. Study further highlights the potential advantage of liposome as a delivery carrier for miRNA therapeutics.

Dysregulated MicroRNAs as Biomarkers or Therapeutic Targets in Cisplatin-Induced Nephrotoxicity: A Systematic Review

“…All studies were published in English, between 2010 and 2021. Most of these studies were conducted in China [24,25,31,32,[36][37][38][39][40][41][42][43][44][47][48][49][50] and the United States of America (USA) [26,27,34,38,46]. The main differences among the 30 included studies were related All studies were published in English, between 2010 and 2021.…”

“…Of the remaining 432 articles, 393 were excluded by reviewing their titles and abstracts. The full text of the remaining 39 articles underwent a review, and 30 studies [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ] that met the eligibility criteria were included. Figure 1 shows a flowchart of the literature search and Supplementary Table S1 .…”

“…All studies were published in English, between 2010 and 2021. Most of these studies were conducted in China [ 24 , 25 , 31 , 32 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 47 , 48 , 49 , 50 ] and the United States of America (USA) [ 26 , 27 , 34 , 38 , 46 ]. The main differences among the 30 included studies were related to population, cisplatin dose, nephrotoxicity assessment, and time of analysis of the miRNAs.…”

Identification of hub genes and networks in cisplatin-induced acute kidney injury

“…In addition, it has been found that miR-449 is highly expressed in CI-AKI, and abnormal expression of miR-449 regulates apoptosis of kidney tubular epithelial cells through deacetylase 1/P53/Bcl2 associated X protein pathway [43]. The synthetic miR-500a-3p liposome could signi cantly reduce kidney injury [44]. The expression of miRNA is regulated in many ways, of which transcriptional regulation is the most common.…”

Epigenetic Mechanisms Involved in Cisplatin-Induced Nephrotoxicity: An Update

“…Once RIPK1 is activated, its interaction with RIPK3 occurs, forming complex IIb/necrosome, which mediates the phosphorylation of MLKL, whose translocation to the plasma membrane promotes necroptosis by disrupting plasma membrane integrity [ 97 ]. Some studies in renal tubular cells have demonstrated the involvement of miR-500a-3p in RIPK1, RIPK3, and MLKL regulation when these cells are treated with CDDP [ 98 , 99 ]. On the other hand, RIPK1 ubiquitination results in NF-κB activation, mediating the survival and production of multiple inflammatory cytokines, which are also regulated by several miRs when these cells are exposed to CDDP.…”