Transcriptional and spatial profiling of the kidney allograft unravels a central role for FcyRIII+ innate immune cells in rejection

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 19, 2023

Abstract Rejection remains the main cause of premature graft loss after kidney transplantation, despite use potent immunosuppression. This highlights need to better understand composition and cell-to-cell interactions alloreactive inflammatory infiltrate. Here, we performed droplet-based single-cell RNA sequencing 35,152 transcriptomes from 16 transplant biopsies with varying phenotypes severities rejection without rejection, identified cell-type specific gene expression signatures for deconvolution bulk tissue. A association was between recipient-derived FCGR3A+ monocytes, FCGR3A + NK cells severity intragraft inflammation. Activated monocytes overexpressed CD47 LILR genes increased paracrine signaling pathways promoting T cell infiltration. FCRL3 , suggesting that antibody-dependent cytotoxicity is a central mechanism NK-cell mediated injury. Multiplexed immunofluorescence using 38 markers on 18 independent biopsy slides confirmed this role FcγRIII+ nonclassical in antibody-mediated specificity glomerular area. These results highlight involvement innate immune pathogenesis allograft identify several potential therapeutic targets might improve longevity.

Язык: Английский

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The Road from AKI to CKD: Molecular Mechanisms and Therapeutic Targets of Ferroptosis

Cell Death and Disease, Год журнала: 2023, Номер 14(7)

Опубликована: Июль 13, 2023

Abstract Acute kidney injury (AKI) is a prevalent pathological condition that characterized by precipitous decline in renal function. In recent years, growing body of studies have demonstrated maladaptation following AKI results chronic disease (CKD). Therefore, targeting the transition to CKD displays excellent therapeutic potential. However, mechanism mediated multifactor, and there still lack effective treatments. Ferroptosis, novel nonapoptotic form cell death, believed role progression. this study, we retrospectively examined history characteristics ferroptosis, summarized ferroptosis’s research progress CKD, discussed how ferroptosis participates regulating progression CKD. Furthermore, highlighted limitations present projected future evolution ferroptosis. We hope work will provide clues for further contribute study targets prevent diseases.

Язык: Английский

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The key role of altered tubule cell lipid metabolism in kidney disease development

Kidney International, Год журнала: 2024, Номер 106(1), С. 24 - 34

Опубликована: Апрель 16, 2024

Kidney epithelial cells have very high energy requirements, which are largely met by fatty acid oxidation. Complex changes in lipid metabolism observed patients with kidney disease. Defects oxidation and increased uptake, especially the context of hyperlipidemia proteinuria, contribute to this excess build-up exacerbate disease development. Recent studies also highlighted role de novo lipogenesis fibrosis. The defect causes starvation. Increased synthesis, lower can cause toxic build-up, reactive oxygen species generation, mitochondrial damage. A better understanding these metabolic processes may open new treatment avenues for diseases targeting metabolism.

Язык: Английский

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Autophagy activates EGR1 via MAPK/ERK to induce FGF2 in renal tubular cells for fibroblast activation and fibrosis during maladaptive kidney repair

Autophagy, Год журнала: 2023, Номер 20(5), С. 1032 - 1053

Опубликована: Ноя. 18, 2023

Macroautophagy/autophagy contributes to maladaptive kidney repair by inducing pro-fibrotic factors such as FGF2 (fibroblast growth factor 2), but the underlying mechanism remains elusive. Here, we show that EGR1 (early response 1) was induced in injured proximal tubules after ischemic acute injury (AKI) and this induction suppressed autophagy deficiency inducible, renal tubule-specific atg7 (autophagy related 7) knockout (iRT-atg7 KO) mice. In cultured tubular cells, TGFB1 (transforming beta also dependent. Egr1 knockdown cells reduced expression during treatment, leading less secretion decreased paracrine effects on fibroblasts. ChIP assay detected an increased binding of Fgf2 gene promoter TGFB1-treated cells. Both transcription inhibited neutralizing antibody, suggesting a positive feedback for EGR1-mediated autoregulation. This confirmed using fgf2-deficient Upstream EGR1, mice MAPK/ERK (mitogen-activated protein kinase) activation post-ischemic tubules. inhibition correlated with SQSTM1/p62 (sequestosome aggregation its sequestration MAPK/ERK. interacted blocked treatment autophagy-deficient Inhibition tubules, amelioration fibrosis improvement function. These results suggest activates which induces transactivate FGF2. is then secreted into interstitium stimulate fibroblasts fibrogenesis.

Язык: Английский

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The metabolic pathway regulation in kidney injury and repair

Frontiers in Physiology, Год журнала: 2024, Номер 14

Опубликована: Янв. 12, 2024

Kidney injury and repair are accompanied by significant disruptions in metabolic pathways, leading to renal cell dysfunction further contributing the progression of pathology. This review outlines complex involvement various energy production pathways glucose, lipid, amino acid, ketone body metabolism within kidney. We provide a comprehensive summary aberrant regulation these kidney repair. After acute (AKI), there is notable mitochondrial damage oxygen/nutrient deprivation, reduced activity glycolysis bioenergetics. Additionally, occur pentose phosphate pathway (PPP), acid metabolism, supply bodies. The subsequent phase characterized shift toward glycolysis, along with decreased fatty β-oxidation continued disturbances metabolism. Furthermore, impact on injury, regeneration, development fibrosis analyzed. Finally, we discuss potential therapeutic strategies targeting ameliorate promote

Язык: Английский

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Spatiotemporal Landscape of Kidney Tubular Responses to Glomerular Proteinuria

Journal of the American Society of Nephrology, Год журнала: 2024, Номер unknown

Опубликована: Апрель 23, 2024

Key Points Glomerular proteinuria induces large-scale changes in gene expression along the nephron. Increased protein uptake proximal tubule results axial remodeling and injury. delivery to distal causes dedifferentiation of epithelium. Background Large increases glomerular filtration induce major body homeostasis are associated with a higher risk kidney functional decline cardiovascular disease. We investigated how elevated exposure modifies landscape tubular function entire nephron, understand cellular that mediate these important clinical phenomena. Methods conducted single-nucleus RNA sequencing, intravital imaging, antibody staining spatially map transport processes mouse tubule. then delineated were altered transgenic model inducible (POD-ATTAC) at 7 28 days. Results activated pleiotropic all nephron sections. Extension from early (S1) later (S2) parts initially triggered dramatic expansion hybrid S1/2 population, followed by injury failed repair, cumulative effect loss canonical S2 functions. Proteinuria also induced acute S3. Meanwhile, overflow luminal proteins caused transcriptional convergence between specialized regions generalized dedifferentiation. Conclusions modulated cell signaling epithelia distinct patterns segment-specific manner.

Язык: Английский

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ACSS2 gene variants determine kidney disease risk by controlling de novo lipogenesis in kidney tubules

Journal of Clinical Investigation, Год журнала: 2023, Номер 134(4)

Опубликована: Дек. 5, 2023

Worldwide, over 800 million people are affected by kidney disease, yet its pathogenesis remains elusive, hindering the development of novel therapeutics. In this study, we employed kidney-specific expression quantitative traits and single-nuclear open chromatin analysis to show that genetic variants linked dysfunction on chromosome 20 target acyl-CoA synthetase short-chain family 2 (ACSS2). By generating ACSS2 knock-out mice, demonstrated their protection from fibrosis in multiple disease models. Our primary tubular cells revealed regulates de novo lipogenesis (DNL), causing NADPH depletion increasing ROS levels, ultimately leading NLRP3-dependent pyroptosis. Additionally, discovered pharmacological inhibition or ablation fatty acid synthase safeguarded against profibrotic gene prevented mice. Lipid accumulation genes related DNL were elevated kidneys patients with fibrosis. findings pinpoint as a critical reveal role disease.

Язык: Английский

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Dyslipidemia-induced renal fibrosis related to ferroptosis and endoplasmic reticulum stress

Journal of Lipid Research, Год журнала: 2024, Номер 65(9), С. 100610 - 100610

Опубликована: Июль 31, 2024

Dyslipidemia may induce chronic kidney disease and trigger both ferroptosis endoplasmic reticulum (ER) stress, but the instigating factors are incompletely understood. We tested hypothesis that different models of dyslipidemia engage distinct injury mechanisms. Wild-type (WT) or proprotein-convertase subtilisin/kexin type-9 (PCSK9)-gain-of-function (GOF) Ossabaw pigs were fed with a 6-month normal diet (ND) high-fat (HFD) (n = 5-6 each). Renal function fat deposition studied in vivo using CT, blood tissue ex-vivo for lipid profile, systemic renal vein FFAs levels, mechanisms including peroxidation, ferroptosis, ER stress. Compared WT-ND pigs, HFD PCSK9-GOF elevated triglyceride which highest WT-HFD, whereas total LDL cholesterol levels rose only particularly PCSK9-GOF/HFD. The groups had worse than ND groups. WT-HFD kidneys retained more FFA other groups, all developed fibrosis. Furthermore, HFD-induced indicated by increased free iron, decreased glutathione peroxidase-4 mRNA expression, while induced stress upregulated GRP94 CHOP protein expression. In vitro, pig epithelial cells treated palmitic acid oxidized to mimic showed similar trends those observed vivo. Taken together, hypertriglyceridemia promotes retention PCSK9-GOF-induced hypercholesterolemia elicits resulting These observations suggest targets preventing treating fibrosis subjects specific types dyslipidemia.

Язык: Английский

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The Role of Mitochondrial Sirtuins (SIRT3, SIRT4 and SIRT5) in Renal Cell Metabolism: Implication for Kidney Diseases

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(13), С. 6936 - 6936

Опубликована: Июнь 25, 2024

Kidney diseases, including chronic kidney disease (CKD), diabetic nephropathy, and acute injury (AKI), represent a significant global health burden. The kidneys are metabolically very active organs demanding large amount of ATP. They composed highly specialized cell types in the glomerulus subsequent tubular compartments which fine-tune metabolism to meet their numerous diverse functions. Defective renal metabolism, altered fatty acid oxidation or glycolysis, has been linked both AKI CKD. Mitochondria play vital role emerging research identified mitochondrial sirtuins (SIRT3, SIRT4 SIRT5) as key regulators metabolic adaptation, especially SIRT3. Sirtuins belong an evolutionarily conserved family mainly NAD

Язык: Английский

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The Intersection of Genetic Factors, Aberrant Nutrient Metabolism and Oxidative Stress in the Progression of Cardiometabolic Disease

Antioxidants, Год журнала: 2024, Номер 13(1), С. 87 - 87

Опубликована: Янв. 10, 2024

Cardiometabolic disease (CMD), which encompasses metabolic-associated fatty liver (MAFLD), chronic kidney (CKD) and cardiovascular (CVD), has been increasing considerably in the past 50 years. CMD is a complex that can be influenced by genetics environmental factors such as diet. With increased reliance on processed foods containing saturated fats, fructose cholesterol, mechanistic understanding of how these molecules cause metabolic required. A major pathway excessive nutrients contribute to through oxidative stress. In this review, we discuss stress drive role aberrant nutrient metabolism genetic risk they potentially interact promote progression MAFLD, CVD CKD. This review will focus mutations are known alter metabolism. We for include Patatin-like phospholipase domain-containing protein 3 (PNPLA3), Membrane Bound O-Acyltransferase Domain Containing 7 (MBOAT7) Transmembrane 6 Superfamily Member 2 (TM6SF2). addition, prevent uptake hypercholesterolemia contributes CVD. also mechanisms CKD mutually associated with one another. some MAFLD CKD, while seem dissociate from other. Through better causative effect intersects our genetics, novel therapies precision approaches developed treating CMD.

Язык: Английский

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