Acute kidney injury (AKI) is a leading cause of distant organ dysfunction among critically ill patients. Mitochondrial dysfunction is considered a key factor driving the damage after renal ischemia–reperfusion (IR) injury. Damaged mitochondria release mitochondrial damage-associated molecular patterns (mtDAMPs) into the cytosol, which initiate a systemic inflammatory response. To better understand the underlying mechanism, mice were challenged with 30 min of bilateral renal ischemia followed by 24 h of reperfusion. The cytokine profiling in mouse lung tissues revealed that TREM-1 was significantly increased. Western Blot (WB) analysis demonstrated that the cGAS and STING pathway was increased in AKI mice. Transmission electron microscopy (TEM) images indicated that the mtDAMPs were released from damaged kidney mitochondria. Injection of mtDAMPs into mice induced an inflammatory response in the lungs similar to that induced by AKI. Mouse macrophages and lung epithelial cells were utilized to verify if inhibition of the TREM-1 and cGAS-STING pathways reduces mtDAMP-induced lung injury. Electric Cell-substrate Impedance Sensing (ECIS) results demonstrated that inhibiting the TREM-1 and cGAS-STING pathways significantly increased cell proliferation and migration while reducing mtDAMP-induced cytotoxicity. In conclusion, our findings suggest that targeting TREM-1 and cGAS-STING has the potential to attenuate acute lung injury in IR-AKI.

Acute limb ischemia (ALI) is a sudden lack of blood flow to a limb, primarily caused by arterial embolism and thrombosis. Various experimental animal models, including non-invasive and invasive methods, have been developed and successfully used to induce limb ischemia-reperfusion injuries (L-IRI). However, there is no consensus on the methodologies used in animal models for L-IRI, particularly regarding the assessment of functional recovery. The present study aims to compare different approaches that induce L-IRI and determine the optimal animal model to study functional limb recovery. In this study, we applied a pneumatic cuff as a non-invasive method and ligated the aorta, iliac, or femoral artery as invasive methods to induce L-IRI. We have measured grip strength, motor function, creatine kinase level, inflammatory markers such as nuclear factor NF-κB, interleukin-6 (IL-6), hypoxia markers such as hypoxia-induced factor-1$\mathsf{\alpha }$ (HIF-1$\mathsf{\alpha }$), and evaluated the muscle injury with hematoxylin and eosin (H&E) staining in Sprague Dawley rats after inducing L-IRI. The pneumatic pressure cuff method significantly decreased the muscle strength of the rats, causing the loss of ability to hold the grid and inducing significant limb function impairment, while artery ligations did not. We conclude from this study that the tourniquet cuff method could be ideal for studying functional recovery after L-IRI in the rat model.

Background: Lupus nephritis remains a major cause of chronic kidney disease and kidney failure in systemic lupus erythematosus. Glucocorticoids are central to treatment but are limited by systemic toxicity. We evaluated whether a previously characterized collagen IV α3-targeted liposomal nanoparticle formulation carrying low-dose prednisolone could attenuate established lupus nephritis in MRL/lpr mice. Methods: Female MRL/lpr mice with disease present at treatment initiation and C57BL/6J control mice received saline or collagen IV α3-targeted prednisolone-loaded nanoparticles (Col4-α3-Pred-NPs). Renal outcomes were assessed by longitudinal proteinuria, glomerular filtration rate (GFR), survival, kidney histopathology, renal IgG and C3d deposition, dUTP/TUNEL-associated injury staining, and renal cytokine/chemokine profiling. Body weight, food and water intake, and blood glucose were monitored as measures of general condition and preliminary tolerability. Results: Col4-α3-Pred-NPs improved survival in MRL/lpr mice, reduced cumulative proteinuria burden, and attenuated terminal GFR decline compared with saline-treated MRL/lpr controls. Treatment reduced glomerular and tubulointerstitial injury, lowered composite EGTI histopathology scores, decreased terminal kidney enlargement, reduced glomerular IgG deposition and renal dUTP-positive injury signals, and reduced renal signals for IL-28A/B, IL-7, PD-ECGF, IL-11, CCL6/C10, and IL-15. C3d deposition was not significantly altered. Nanoparticle treatment was not associated with sustained treatment-related increases in blood glucose or body-weight loss during the measured study period. Conclusions: Collagen IV α3-targeted liposomal delivery of low-dose prednisolone attenuated established lupus nephritis in MRL/lpr mice and improved renal structural, functional, inflammatory, and survival outcomes. These findings support further evaluation of glomerulus-targeted nanotherapy as a potential strategy to improve the precision and therapeutic index of glucocorticoid treatment in lupus nephritis.

This study links Necrostatin-1 (Nec-1)-sensitive receptor-interacting protein kinase 1 (RIPK1)/mixed lineage kinase domain-like protein (MLKL)-associated signaling with biochemical, histological, inflammatory, and functional outcomes after rat hindlimb ischemia-reperfusion injury. Nec-1 reduced RIPK1 and MLKL phosphorylation, muscle injury, and early functional impairment. These findings extend prior skeletal-muscle studies by integrating molecular pathway activation with longitudinal functional recovery while supporting a contribution of RIPK1-associated necroptotic signaling.