Persistently elevated glycolysis in kidney has been demonstrated to promote chronic kidney disease (CKD). However, the underlying mechanism remains largely unclear. Here, we observed that 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key glycolytic enzyme, was remarkably induced in kidney proximal tubular cells (PTCs) following ischemia-reperfusion injury (IRI) in mice, as well as in multiple etiologies of patients with CKD. PFKFB3 expression was positively correlated with the severity of kidney fibrosis. Moreover, patients with CKD and mice exhibited increased urinary lactate/creatine levels and kidney lactate, respectively. PTC-specific deletion of PFKFB3 significantly reduced kidney lactate levels, mitigated inflammation and fibrosis, and preserved kidney function in the IRI mouse model. Similar protective effects were observed in mice with heterozygous deficiency of PFKFB3 or those treated with a PFKFB3 inhibitor. Mechanistically, lactate derived from PFKFB3-mediated tubular glycolytic reprogramming markedly enhanced histone lactylation, particularly H4K12la, which was enriched at the promoter of NF-κB signaling genes like Ikbkb, Rela, and Relb, activating their transcription and facilitating the inflammatory response. Further, PTC-specific deletion of PFKFB3 inhibited the activation of IKKβ, I κ B α, and p65 in the IRI kidneys. Moreover, increased H4K12la levels were positively correlated with kidney inflammation and fibrosis in patients with CKD. These findings suggest that tubular PFKFB3 may play a dual role in enhancing NF-κB signaling by promoting both H4K12la-mediated gene transcription and its activation. Thus, targeting the PFKFB3-mediated NF-κB signaling pathway in kidney tubular cells could be a novel strategy for CKD therapy.

Diabetic kidney disease (DKD) is becoming the leading cause of chronic kidney disease, especially in the industrialized world. Despite mounting evidence has demonstrated that immunity and inflammation are highly involved in the pathogenesis and progression of DKD, the underlying mechanisms remain incompletely understood. Substantial molecules, signaling pathways, and cell types participate in DKD inflammation, by integrating into a complex regulatory network. Most of the studies have focused on individual components, without presenting their importance in the global or system-based processes, which largely hinders clinical translation. Besides, conventional technologies failed to monitor the different behaviors of resident renal cells and immune cells, making it difficult to understand their contributions to inflammation in DKD. Recently, the advancement of omics technologies including genomics, epigenomics, transcriptomics, proteomics, and metabolomics has revolutionized biomedical research, which allows an unbiased global analysis of changes in DNA, RNA, proteins, and metabolites in disease settings, even at single-cell and spatial resolutions. They help us to identify critical regulators of inflammation processes and provide an overview of cell heterogeneity in DKD. This review aims to summarize the application of multiple omics in the field of DKD and emphasize the latest evidence on the interplay of inflammation and DKD revealed by these technologies, which will provide new insights into the role of inflammation in the pathogenesis of DKD and lead to the development of novel therapeutic approaches and diagnostic biomarkers.

Klotho is an anti-aging protein produced primarily by tubular epithelial cells (TECs). Down-regulated expression of Klotho in injured TECs plays a key pathogenic role in promoting acute kidney injury (AKI) to chronic kidney disease (CKD) transition, yet therapeutic approaches targeting the restoration of renal Klotho levels remain challenging for clinical application. Here, we synthesize polydopamine-polyethylenimine-l-serine-Klotho plasmid nanoparticles (PPSK NPs), which can safely and selectively deliver the Klotho gene to the injured TECs through binding kidney injury molecule-1 and maintain the expression of Klotho protein. In vitro, PPSK NPs effectively reduce the hypoxia-reoxygenation-induced reactive oxygen species production and fibrotic gene expression. In the unilateral ischemia-reperfusion injury- and folic acid-induced AKI-CKD transition mouse models, a single low-dose injection of PPSK NPs is sufficient to preserve the normal kidney architecture and prevent renal fibrosis. Mechanismly, the protective effect of PPSK NPs relies on upregulating a key molecule peroxisome proliferator-activated receptor alpha (PPARα) via the inhibition of p38 and JNK phosphorylation, which in turn improves tubular fatty acid beta-oxidation and reduces renal lipid accumulation, thereby protecting against kidney fibrosis. In conclusion, our results highlight the translational potential of nanoparticle-based Klotho gene therapy in preventing the AKI-CKD transition.

Objectives The current work aimed to provide a comprehensive single-cell landscape of lupus nephritis (LN) kidneys, including immune and non-immune cells, identify disease-associated cell populations and unravel their participation within the kidney microenvironment. Methods Single-cell RNA and T cell receptor sequencing were performed on renal biopsy tissues from 40 patients with LN and 6 healthy donors as controls. Matched peripheral blood samples from seven LN patients were also sequenced. Multiplex immunohistochemical analysis was performed on an independent cohort of 60 patients and validated using flow cytometric characterisation of human kidney tissues and in vitro assays. Results We uncovered a notable enrichment of CD163⁺ dendritic cells (DC3s) in LN kidneys, which exhibited a positive correlation with the severity of LN. In contrast to their counterparts in blood, DC3s in LN kidney displayed activated and highly proinflammatory phenotype. DC3s showed strong interactions with CD4⁺ T cells, contributing to intrarenal T cell clonal expansion, activation of CD4⁺ effector T cell and polarisation towards Th1/Th17. Injured proximal tubular epithelial cells (iPTECs) may orchestrate DC3 activation, adhesion and recruitment within the LN kidneys. In cultures, blood DC3s treated with iPTECs acquired distinct capabilities to polarise Th1/Th17 cells. Remarkably, the enumeration of kidney DC3s might be a potential biomarker for induction treatment response in LN patients. Conclusion The intricate interplay involving DC3s, T cells and tubular epithelial cells within kidneys may substantially contribute to LN pathogenesis. The enumeration of renal DC3 holds potential as a valuable stratification feature for guiding LN patient treatment decisions in clinical practice.

Renal tubule cells act as a primary site of injury in diabetic kidney disease (DKD), with dysfunctional mitochondrial quality control (MQC) closely associated with progressive kidney dysfunction in this context. Our investigation delves into the observed inactivation of yes-associated protein 1 (YAP1) and consequential dysregulation of MQC within renal tubule cells among DKD subjects through bioinformatic analysis of transcriptomics data from the Gene Expression Omnibus (GEO) dataset. Receiver operating characteristic curve analysis unequivocally underscores the robust diagnostic accuracy of YAP1 and MQC-related genes for DKD. Furthermore, we observed YAP1 inactivation, accompanied by perturbed MQC, within cultured tubule cells exposed to high glucose (HG) and palmitic acid (PA). This pattern was also evident in the tubulointerstitial compartment of kidney sections from biopsy-approved DKD patients. Additionally, renal tubule cell-specific Yap1 deletion exacerbated kidney injury in diabetic mice. Mechanistically, Yap1 deletion disrupted MQC, leading to mitochondrial aberrations in mitobiogenesis and mitophagy within tubule cells, ultimately culminating in histologic tubular injury. Notably, Yap1 deletion-induced renal tubule injury promoted the secretion of C-X-C motif chemokine ligand 1 (CXCL1), potentially augmenting M1 macrophage infiltration within the renal microenvironment. These multifaceted events were significantly ameliorated by administrating the YAP1 activator XMU-MP-1 in DKD mice. Consistently, bioinformatic analysis of transcriptomics data from the GEO dataset revealed a noteworthy upregulation of tubule cells-derived chemokine CXCL1 associated with macrophage infiltration among DKD patients. Crucially, overexpression of YAP1 via adenovirus transfection sustained mitochondrial membrane potential, mtDNA copy number, oxygen consumption rate, and activity of mitochondrial respiratory chain complex, but attenuated mitochondrial ROS production, thereby maintaining MQC and subsequently suppressing CXCL1 generation within cultured tubule cells exposed to HG and PA. Collectively, our study establishes a pivotal role of tubule YAP1 inactivation-mediated MQC dysfunction in driving DKD progression, at least in part, facilitated by promoting M1 macrophage polarization through a paracrine-dependent mechanism.