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Project description:Macrophages (MФs) play an important role in the repairment of acute kidney injury (AKI). The heterogeneity of renal MФ subsets during pathogenesis of AKI are still remain elusive. We used single cell RNA sequencing (scRNA-seq) to analyze the heterogeneity of renal MФs
2025-08-21 | GSE220675 | GEO
Project description:Kidney Single-Cell Atlas Reveals Macrophage Heterogeneity in Progression and Regression of Cisplatin Induced AKI.
| PRJNA911169 | ENA
Project description:Kidney Single-Cell Atlas Reveals Macrophage Heterogeneity in Progression and Regression of Cisplatin Induced AKI [scRNA-seq]
| PRJNA910961 | ENA
Project description:BackgroundLittle is known about the roles of myeloid cell subsets in kidney injury and in the limited ability of the organ to repair itself. Characterizing these cells based only on surface markers using flow cytometry might not provide a full phenotypic picture. Defining these cells at the single-cell, transcriptomic level could reveal myeloid heterogeneity in the progression and regression of kidney disease.MethodsIntegrated droplet- and plate-based single-cell RNA sequencing were used in the murine, reversible, unilateral ureteric obstruction model to dissect the transcriptomic landscape at the single-cell level during renal injury and the resolution of fibrosis. Paired blood exchange tracked the fate of monocytes recruited to the injured kidney.ResultsA single-cell atlas of the kidney generated using transcriptomics revealed marked changes in the proportion and gene expression of renal cell types during injury and repair. Conventional flow cytometry markers would not have identified the 12 myeloid cell subsets. Monocytes recruited to the kidney early after injury rapidly adopt a proinflammatory, profibrotic phenotype that expresses Arg1, before transitioning to become Ccr2+ macrophages that accumulate in late injury. Conversely, a novel Mmp12+ macrophage subset acts during repair.ConclusionsComplementary technologies identified novel myeloid subtypes, based on transcriptomics in single cells, that represent therapeutic targets to inhibit progression or promote regression of kidney disease.
| S-EPMC7790206 | biostudies-literature
Project description:Inner ear macrophages play a vital role in cochlear homeostasis. Recent studies have demonstrated the existence of macrophages at different sites of the cochlea, with increased cochlear infiltration as an inflammatory response mechanism to injury. However, current methods, such as conventional immunohistochemistry and flow cytometry, provide limited information about the diversity of cochlear macrophages. Recently, multiplex immunohistochemistry (mIHC) successfully identified the heterogeneity of immune cells in cancer tissue and thereby improved our understanding of the disease prognosis. In this study, we modified the mIHC technique for cochlear tissue and utilized it to investigate cochlear macrophage behavior and heterogeneity before and after exposure to ototoxic drugs such as cisplatin. Four-week-old C57BL/6N female mice were intraperitoneally injected with cisplatin at 5 mg/kg/day consecutively for 6 days. Their hearing levels were assessed before and after the injection. Their cochleae were harvested before (day 0) and on days 8 and 15 after the cisplatin injection. Paraffin-embedded sections were sequentially immunostained using macrophage surface markers to identify the different categories of macrophages. Each immunostaining cycle included incubation with primary antibody, incubation with secondary antibody, chromogenic staining, and image scanning. Thereafter, all antibodies were stripped out, and antigen retrieval was performed to prepare the tissue for the next cycle. The results revealed that activated cochlear macrophages were not entirely differentiated into M1 or M2 categories but into multi-marker M1/M2 mixed macrophages. Furthermore, the ratio of these mixed (M1/M2) macrophages to Iba1+ macrophages increased in the auditory nerve after cisplatin exposure, suggesting local auditory nerve inflammation. The increase in the population of activated macrophages in the auditory nerve region was concomitant with the temporary shift of hearing threshold on day 8 post-cisplatin injection. The findings of this study indicate the effectiveness of mIHC in identifying cochlear macrophage heterogeneity both in the resting state and after cisplatin exposure. Therefore, mIHC could be a powerful tool in cochlear immunology research. Our findings may provide new insights into the co-relation between the cochlear macrophage and cisplatin exposure.
| S-EPMC9633043 | biostudies-literature
Project description:The effectiveness of cisplatin, a mainstay in the treatment of many solid organ cancers, is hindered by dose-limiting nephrotoxicity. Cisplatin causes AKI in 30% of patients. Patients who do not develop AKI by clinical standards during treatment are still at risk for long-term decline in kidney function and the development of CKD. The connection between AKI and CKD has become increasingly studied, with renal fibrosis a hallmark of CKD development. To prevent both the short- and long-term effects of cisplatin, researchers must use models that reflect both types of pathology. Although a lot is known about cisplatin-induced AKI, very little is known about the mechanisms by which repeated low levels of cisplatin lead to fibrosis development. In this review, strategies used in various rodent models to prevent kidney injury, its progression to fibrosis, or both, are examined to gain mechanistic insights and identify potential therapeutic targets for cisplatin-induced kidney pathologies. Reviewing the results from these models highlights the diverse and highly complex role of cell death, cell senescence, endoplasmic reticulum stress, autophagy, and immune cell activation in acute and chronic kidney injuries. The use of several models of kidney injury is needed for development of agents that will prevent all aspects of cisplatin-induced kidney injury.
| S-EPMC8425641 | biostudies-literature
Project description:In a clinically-relevant model of 4 week, low-dose cisplatin-induced AKI, mice were injected subcutaneously with non small cell lung cancer (NSCLC) cells that harbor an activating Kirsten rat sarcoma viral oncogene homolog (KRAS)G12V mutation. Phospho extracellular signal-regulated kinase1/2 (pERK1/2) expression in kidney and tumors was decreased by the MEK1/2 inhibitors, U0126 and trametinib, that potently inhibit pERK1/2. U0126 resulted in a significant improvement in kidney function, acute tubular necrosis (ATN) and tubular cell apoptosis in mice with AKI. Genes that were significantly decreased by U0126 were heat shock protein 1, cyclin-dependent kinase 4 (CDK4) and stratifin (14-3-3σ). U0126 resulted in a significant decrease in tumor weight and volume and significantly increased the chemotherapeutic effect of cisplatin. Trametinib, a MEK1/2 inhibitor that is FDA-approved for the treatment of cancer, did not result in functional protection against AKI or worse AKI, but dramatically decreased tumor growth more than cisplatin. Smaller tumors in cisplatin or MEK1/2 inhibitor-treated mice were not related to changes in microtubule-associated proteins 1A/1B light chain 3B (LC3-II), p62, cleaved caspase-3, granzyme B, or programmed death-ligand 1 (PD-L1). In summary, despite ERK inhibition by both U0126 and trametinib, only U0126 protected against AKI suggesting that the protection against AKI by U0126 was due to an off-target effect independent of ERK inhibition. The effect of U0126 to decrease AKI may be mediated by inhibition of heat shock protein 1, CDK4 or stratifin (14-3-3σ). Trametinib was more effective than cisplatin in decreasing tumor growth, but unlike cisplatin, trametinib did not cause AKI.
| S-EPMC7592388 | biostudies-literature
Project description:Homogeneity and heterogeneity of the cytopathological mechanisms in different etiology-induced acute kidney injury (AKI) are poorly understood. Here, we performed single-cell sequencing (scRNA) on mouse kidneys with five common AKI etiologies (CP-Cisplatin, IRI-Ischemia-reperfusion injury, UUO-Unilateral ureteral obstruction, FA-Folic acid, and SO-Sodium oxalate). We constructed a potent multi-model AKI scRNA atlas containing 20 celltypes with 80,689 high-quality cells. The data suggest that compared to IRI and CP-AKI, FA- and SO-AKI exhibit injury characteristics more similar to UUO-AKI, which may due to tiny crystal-induced intrarenal obstruction. Through scRNA atlas, 7 different functional proximal tubular cell (PTC) subtypes were identified, we found that Maladaptive PTCs and classical Havcr1 PTCs but not novel Krt20 PTCs affect the pro-inflammatory and pro-fibrotic levels in different AKI models. And cell death and cytoskeletal remodeling events are widespread patterns of injury in PTCs. Moreover, we found that programmed cell death predominated in PTCs, whereas apoptosis and autophagy prevailed in the remaining renal tubules. We also identified S100a6 as a novel AKI-endothelial injury biomarker. Furthermore, we revealed that the dynamic and active immune (especially Arg1 Macro_2 cells) -parenchymal cell interactions are important features of AKI. Taken together, our study provides a potent resource for understanding the pathogenesis of AKI and early intervention in AKI progression at single-cell resolution.
| S-EPMC10175265 | biostudies-literature
Project description:The mechanisms that determine full recovery versus subsequent progressive CKD after AKI are largely unknown. Because macrophages regulate inflammation as well as epithelial recovery, we investigated whether macrophage activation influences AKI outcomes. IL-1 receptor-associated kinase-M (IRAK-M) is a macrophage-specific inhibitor of Toll-like receptor (TLR) and IL-1 receptor signaling that prevents polarization toward a proinflammatory phenotype. In postischemic kidneys of wild-type mice, IRAK-M expression increased for 3 weeks after AKI and declined thereafter. However, genetic depletion of IRAK-M did not affect immunopathology and renal dysfunction during early postischemic AKI. Regarding long-term outcomes, wild-type kidneys regenerated completely within 5 weeks after AKI. In contrast, IRAK-M(-/-) kidneys progressively lost up to two-thirds of their original mass due to tubule loss, leaving atubular glomeruli and interstitial scarring. Moreover, M1 macrophages accumulated in the renal interstitial compartment, coincident with increased expression of proinflammatory cytokines and chemokines. Injection of bacterial CpG DNA induced the same effects in wild-type mice, and TNF-? blockade with etanercept partially prevented renal atrophy in IRAK-M(-/-) mice. These results suggest that IRAK-M induction during the healing phase of AKI supports the resolution of M1 macrophage- and TNF-?-dependent renal inflammation, allowing structural regeneration and functional recovery of the injured kidney. Conversely, IRAK-M loss-of-function mutations or transient exposure to bacterial DNA may drive persistent inflammatory mononuclear phagocyte infiltrates, which impair kidney regeneration and promote CKD. Overall, these results support a novel role for IRAK-M in the regulation of wound healing and tissue regeneration.
| S-EPMC3904561 | biostudies-literature
Project description:Macrophage migration inhibitory factor (MIF) is elevated in patients with acute kidney injury (AKI) and is suggested as a potential predictor for renal replacement therapy in AKI. In this study, we found that MIF also plays a pathogenic role and is a therapeutic target for AKI. In a cisplatin-induced AKI mouse model, elevated plasma MIF correlated with increased serum creatinine and the severity of renal inflammation and tubular necrosis, whereas deletion of MIF protected the kidney from cisplatin-induced AKI by largely improving renal functional and histological injury, and suppressing renal inflammation including upregulation of cytokines such as interleukin (IL)-1β, tumor necrosis factor-alpha (TNF-α), IL-6, inducible nitric oxide synthase (iNOS), MCP-1, IL-8, and infiltration of macrophages, neutrophils, and T cells. We next developed a novel therapeutic strategy for AKI by blocking the endogenous MIF with an MIF inhibitor, ribosomal protein S19 (RPS19). Similar to the MIF-knockout mice, treatment with RPS19, but not the mutant RPS19, suppressed cisplatin-induced AKI. Mechanistically, we found that both genetic knockout and pharmacological inhibition of MIF protected against AKI by inactivating the CD74-nuclear factor κB (NF-κB) signaling. In conclusion, MIF is pathogenic in cisplatin-induced AKI. Targeting MIF with an MIF inhibitor RPS19 could be a promising therapeutic potential for AKI.
| S-EPMC6171075 | biostudies-literature