PROPHYLACTIC nCMT-3 ATTENUATES SEPSIS-INDUCED ACUTE KIDNEY INJURY IN ASSOCIATION WITH NLRP3 INFLAMMASOME ACTIVATION AND APOPTOSIS

Abstract

Background: The kidney is the most common extrapulmonary organ injured in sepsis. The current study examines the ability of aerosolized nanochemically modified tetracycline 3 (nCMT-3), a pleiotropic anti-inflammatory agent, to attenuate acute kidney injury (AKI) caused by intratracheal LPS. Methods: C57BL/6 mice received aerosolized intratracheal nCMT-3 (1 mg/kg) or saline, followed by intratracheal LPS (2.5 mg/kg) to induce acute lung injury–induced AKI. Tissues were harvested at 24 h. The effects of nCMT-3 and LPS on AKI were assessed by plasma/tissue levels of serum urea nitrogen, creatinine, neutrophil gelatinase-associated lipocalin, kidney injury molecule 1, and renal histology. Renal matrix metalloproteinase (MMP) level/activity, cytochrome C, Bax, Bcl-2, caspase-3, p38 mitogen-activated protein kinase activation, NLRP3, and caspase-1 were also measured. Apoptotic cells in kidney were determined by TUNEL assay. Renal levels of IL-1β and IL-6 were measured to assess inflammation. Results: Acute lung injury–induced AKI was characterized by increased plasma blood urea nitrogen, creatinine, injury biomarkers (neutrophil gelatinase-associated lipocalin, kidney injury molecule 1), and histologic evidence of renal injury. Lipopolysaccharide-treated mice demonstrated renal injury with increased levels of inflammatory cytokines (IL-1β, IL-6), active MMP-2 and MMP-9, proapoptotic proteins (cytochrome C, Bax/Bcl-2 ratio, cleaved caspase-3), apoptotic cells, inflammasome activation (NLRP3, caspase-1), and p38 signaling. Intratracheal nCMT-3 significantly attenuated all the measured markers of renal injury, inflammation, and apoptosis. Conclusions: Pretreatment with aerosolized nCMT-3 attenuates LPS-induced AKI by inhibiting renal NLRP3 inflammasome activation, renal inflammation, and apoptosis.

Novel Ps-Ome Mirna130b-3p Reduces Inflammation and Injury and Improves Survival After Renal Ischemia-Reperfusion Injury

“…Given its acute onset and complex pathophysiology involving multiple cellular pathways and processes, it has posed a significant challenge for physicians (1)(2)(3)(4)(36)(37)(38). However, because of recent advances in elucidating the pathways involving inflammation, innate immunity and DAMPs, promising progress has been made in attenuating the initial injury (8,39,40). One such DAMP is eCIRP, which was initially discovered to be elevated in the circulation of critical care patients during hemorrhagic shock or septic shock (16).…”

“…Reperfusion exacerbates the initial injury by triggering an inflammatory response and via generation of reactive oxygen species, causing further damage in a compromised environment (5)(6)(7)(8). Regarding renal I/R injury, tubular epithelial tissue in the kidneys is severely affected, releasing cytokines and damage-associated molecular patterns (DAMPs), which engage the innate immune system and cause additional injury (5,(8)(9)(10)(11)(12). Understanding the molecular pathways in AKI pathogenesis and inflammation helps identify potential therapeutic targets.…”

“…During ischemia/reperfusion (I/R), the ischemic environment becomes increasingly acidic, leading to cellular dysfunction, disturbed ionic concentration homeostasis, osmotic dysregulation, cell death, and tissue swelling (5)(6)(7). Reperfusion exacerbates the initial injury by triggering an inflammatory response and via generation of reactive oxygen species, causing further damage in a compromised environment (5)(6)(7)(8). Regarding renal I/R injury, tubular epithelial tissue in the kidneys is severely affected, releasing cytokines and damage-associated molecular patterns (DAMPs), which engage the innate immune system and cause additional injury (5,(8)(9)(10)(11)(12).…”

Knockdown of Circ_0114428 Alleviates LPS-Induced Hk2 Cell Apoptosis and Inflammation Injury via Targeting Mir-215-5p/Traf6/Nf-Κb Axis in Septic Acute Kidney Injury

“…Sepsis was a disease that causes inflammation throughout the body and could lead to shock or death in severe cases, and AKI was the most common organ dysfunction caused by sepsis (5,29,30). Although more and more researchers were focusing on sepsis, its complex pathogenesis made the treatment of sepsis still difficult (31)(32)(33). Most of the current studies on AKI had been explored on the basis of AKI cell models constructed by LPS-induced cell damage (28,34,35).…”

Circusp42 Ameliorates LPS-Induced Human Renal Epithelial Cells in Vitro by Regulating the Mir-182-5p/Dusp1 Axis

“…Because of the complicated pathogenesis of AKI caused by sepsis, the exploration of potentially effective treatment options becomes particularly important. Studies have shown that intratracheal atomization of tetracycline 3 (nCMT-3) with nanochemical modification in 57BL/6 mice alleviated LPS-induced AKI by inhibiting renal NLRP3 inflammasome activation, renal inflammation, and cell apoptosis (7).…”