{"doi":"10.3389/fphar.2025.1609100","title":"Editorial: Diabetic kidney disease: routes to drug development, pharmacology and underlying molecular mechanisms, volume II","abstract":"Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD), driven primarily by metabolic dysfunction, immune cell infiltration, and inflammation in the kidney. These changes lead to nephron loss, mesenchymal activation, and finally kidney fibrosis 1 . DKD accounts for almost half of all CKD cases, with around 40% of individuals with diabetes developing DKD 1,2 . Despite its prevalence, DKD progression varies among patients, and its underlying mechanism remains poorly understood. DKD often remains asymptomatic until it advances to kidney failure. Kidney fibrosis is the final pathological outcome of CKD in the diabetic kidney. Several theories have been proposed regarding the origin of myofibroblasts, which play crucial roles in the progression of kidney fibrosis. Myofibroblasts can derive from tubular epithelial cells via partial epithelial-to-mesenchymal transition (EMT), endothelial cells through endothelial-to-mesenchymal transition (EndMT), or profibrotic (M2-like)-macrophages via macrophage-to-mesenchymal transition (MMT) 3,4 . Additionally, myofibroblasts have also been proposed to originate from activated resident fibroblasts or bone marrow-derived cells 5,6 . In DKD, an increase in endothelial cell permeability, and a decrease in pericytes coverage contribute to tissue damage and the release of chemokines further exaggerate the infiltration of immune cells and inflammation. The excessive inflammation-mediated tissue injury results in the deposition of the components of extracellular matrix (ECM), such as collagens, fibronectin, desmin, and integrins. Ultimately, these pathological alterations disrupt kidney structure, function, and metabolism, resulting in kidney fibrosis and failure 7 . A recent study highlighted a comprehensive multimodal atlas of the human kidney 8 . Using single-cell assay for transposase-accessible chromatin and RNA sequencing (scATAC-seq) and spatially resolved metabolomics, this study has characterized region-specific metabolic signatures of different nephron segments, including endothelial cells and proximal tubular epithelial cells 8 . Spatial metabolomics further demonstrated suppressed fatty acid oxidation (FAO) along with an accumulation of long-chain acylcarnitines, a type of lipids that are key intermediates in FAO, in proximal tubular cells from patients with kidney disease 9,10 . Related research in type I diabetic (T1DM) patients identified that despite preserved kidney function and the absence of albuminuria at an early stage, metabolic disturbances can be present 11 . Utilizing single-cell RNA sequencing, spatial metabolomics, and positron emission tomography imaging to assess tricarboxylic acid cycle (TCA) cycle activity, they reported suppressed oxidative metabolism in the renal cortex and medulla of T1DM patients 11 . Overall, this study highlights that early metabolic impairments could serve as preclinical markers for DKD, suggesting a critical role of mitochondrial dysfunction in the progression of DKD. Elevated urinary lactate levels have emerged as a biomarker of mitochondrial dysfunction and correlate with a decline in kidney function in diabetic patients 12 . Mitophagy, the mitochondrial quality control program that recycles defective mitochondria is also impaired during DKD 4,13,14 . Mitochondrial proteome data profiling in healthy podocytes revealed that NADH:ubiquinone oxidoreductase subunit S4 (NDUFS4) stabilizes respiratory supercomplexes. In diabetic podocytes, suppressed NDUFS4 levels were also associated with reduced mitochondrial function, contributing to DKD progression 15 .Here, we discussed two sections:Deleted: end-stage kidney disease (ESKD) Suppressed FAO in diabetic renal tubules, endothelial cells, and podocytes is concomitantly associated with aberrant glycolysis and elevated lactate levels 16 . This metabolic reprogramming is believed to generate metabolites that sustain myofibroblasts' survival, contributing to fibrosis progression","journal":"Frontiers in Pharmacology","year":2025,"id":557656,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9509,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":304520,"name":"Swayam Prakash Srivastava","orcid":"0000-0002-7162-3091","position":1,"is_corresponding":false},{"id":249281,"name":"Divya Bhatia","orcid":"0000-0002-8236-3440","position":0,"is_corresponding":true}],"reference_count":32,"raw_metadata":null,"created_at":"2026-07-19T02:55:21.727661Z","pmid":"40351438","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}