Decoding diabetic kidney disease: a comprehensive review of interconnected pathways, molecular mediators, and therapeutic insights
Abstract Background Diabetic kidney disease (DKD) is a chronic kidney condition that arises from prolonged hyperglycaemia that can progress to kidney failure, severe morbidity, and mortality if left untreated. It is the major cause of chronic kidney disease among people who have diabetes, accounting...
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2025-06-01
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| Online Access: | https://doi.org/10.1186/s13098-025-01726-4 |
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| author | Esienanwan Esien Efiong Kathrin Maedler Emmanuel Effa Uchechukwu Levi Osuagwu Esther Peters Joshua Onyeka Ikebiuro Chisom Soremekun Ugwunna Ihediwa Jiefei Niu Markéta Fuchs Homa Bazireh Akang Leonard Bassey Peter Uchenna Amadi Qiuling Dong Njogu Mark Kimani Rebecca Chinyelu Chukwuanukwu Emmy Tuenter Sapna Sharma Harald Grallert |
| author_facet | Esienanwan Esien Efiong Kathrin Maedler Emmanuel Effa Uchechukwu Levi Osuagwu Esther Peters Joshua Onyeka Ikebiuro Chisom Soremekun Ugwunna Ihediwa Jiefei Niu Markéta Fuchs Homa Bazireh Akang Leonard Bassey Peter Uchenna Amadi Qiuling Dong Njogu Mark Kimani Rebecca Chinyelu Chukwuanukwu Emmy Tuenter Sapna Sharma Harald Grallert |
| author_sort | Esienanwan Esien Efiong |
| collection | DOAJ |
| description | Abstract Background Diabetic kidney disease (DKD) is a chronic kidney condition that arises from prolonged hyperglycaemia that can progress to kidney failure, severe morbidity, and mortality if left untreated. It is the major cause of chronic kidney disease among people who have diabetes, accounting for a significant percentage of patients with end-stage kidney disease who require kidney replacement therapy. Main body In DKD, numerous dysbalanced metabolic, haemodynamic, inflammatory signalling pathways, and molecular mediators interconnect, creating a feedback loop that promotes general kidney damage. Hyperglycaemia is the primary trigger for DKD and leads gradually to oxidative stress, inflammation, extracellular matrix deposition and fibrosis, glomerular hypertension, and intrarenal hypoxia. Key interconnected metabolic pathways are the hyperglycaemia-mediated polyol, hexosamine, protein kinase C, and advanced glycation end-products pathway hyperactivity. Concurrently, hyperglycaemia-induced renin–angiotensin–aldosterone system stimulation, alters the kidney intraglomerular haemodynamic leading to inflammation through Toll-like receptors, Janus kinase/signal transducer and activator of transcription, and nuclear factor-kappa B, transforming growth factor-beta-mediated excessive extracellular matrix accumulation and fibrosis. The resulting death signals trigger apoptosis and autophagy through Hippo, Notch, and Wnt/β-catenin pathway activation and microRNA dysregulation. These signals synergistically remodel the kidneys culminating in intrarenal hypoxia, podocyte dysfunction, hyperfiltration, epithelial-mesenchymal transition, and loss of kidney function. The resulting renal failure further upregulates these death pathways and mediators, giving rise to a vicious cycle that further worsens DKD. Conclusion This review provides an overview of the primary molecular mediators and signalling pathways leading to DKD; their interconnectivity at the onset and during DKD progression, the central role of transforming growth factor-beta via different pathways, the Hippo pathway kidney-specific response to hyperglycaemia, and how all mediators and transduction signals result in a vicious circle that exacerbates renal failure. The review gives therapeutic sights to these pathways as druggable targets for DKD management. Understanding these molecular events underlying the pathogenesis of DKD can bridge basic research and clinical application, facilitating the development of innovative management strategies. |
| format | Article |
| id | doaj-art-7959b0368a98433cafff95324272e2e9 |
| institution | DOAJ |
| issn | 1758-5996 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
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| series | Diabetology & Metabolic Syndrome |
| spelling | doaj-art-7959b0368a98433cafff95324272e2e92025-08-20T03:10:34ZengBMCDiabetology & Metabolic Syndrome1758-59962025-06-0117111810.1186/s13098-025-01726-4Decoding diabetic kidney disease: a comprehensive review of interconnected pathways, molecular mediators, and therapeutic insightsEsienanwan Esien Efiong0Kathrin Maedler1Emmanuel Effa2Uchechukwu Levi Osuagwu3Esther Peters4Joshua Onyeka Ikebiuro5Chisom Soremekun6Ugwunna Ihediwa7Jiefei Niu8Markéta Fuchs9Homa Bazireh10Akang Leonard Bassey11Peter Uchenna Amadi12Qiuling Dong13Njogu Mark Kimani14Rebecca Chinyelu Chukwuanukwu15Emmy Tuenter16Sapna Sharma17Harald Grallert18Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum MünchenIslet Biology Laboratory, Centre for Biomolecular Interactions, University of BremenDivision of Nephrology, Department of Internal Medicine, Faculty of Clinical Sciences, University of CalabarSchool of Medicine, Bathurst Rural Clinical School, Western Sydney UniversityFaculty of Science, Masaryk UniversityHuman and Animal Physiology Group, Wageningen University and ResearchResearch Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum MünchenEmergency Medicine, Royal Cornwall HospitalResearch Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum MünchenResearch Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum MünchenResearch Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum MünchenDevelopmental Biology and Cancer Research & Teaching Department, UCL Great Ormond Street Institute of Child HealthDepartment of Pediatrics, Faculty of Medicine and Dentistry, University of AlbertaResearch Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum MünchenDepartment of Physical Sciences, University of EmbuDepartment of Internal Medicine 3, Uniklinikum Erlangen and Deutsches Zentrum Für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Department of Pharmaceutical Sciences, University of AntwerpenResearch Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum MünchenResearch Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum MünchenAbstract Background Diabetic kidney disease (DKD) is a chronic kidney condition that arises from prolonged hyperglycaemia that can progress to kidney failure, severe morbidity, and mortality if left untreated. It is the major cause of chronic kidney disease among people who have diabetes, accounting for a significant percentage of patients with end-stage kidney disease who require kidney replacement therapy. Main body In DKD, numerous dysbalanced metabolic, haemodynamic, inflammatory signalling pathways, and molecular mediators interconnect, creating a feedback loop that promotes general kidney damage. Hyperglycaemia is the primary trigger for DKD and leads gradually to oxidative stress, inflammation, extracellular matrix deposition and fibrosis, glomerular hypertension, and intrarenal hypoxia. Key interconnected metabolic pathways are the hyperglycaemia-mediated polyol, hexosamine, protein kinase C, and advanced glycation end-products pathway hyperactivity. Concurrently, hyperglycaemia-induced renin–angiotensin–aldosterone system stimulation, alters the kidney intraglomerular haemodynamic leading to inflammation through Toll-like receptors, Janus kinase/signal transducer and activator of transcription, and nuclear factor-kappa B, transforming growth factor-beta-mediated excessive extracellular matrix accumulation and fibrosis. The resulting death signals trigger apoptosis and autophagy through Hippo, Notch, and Wnt/β-catenin pathway activation and microRNA dysregulation. These signals synergistically remodel the kidneys culminating in intrarenal hypoxia, podocyte dysfunction, hyperfiltration, epithelial-mesenchymal transition, and loss of kidney function. The resulting renal failure further upregulates these death pathways and mediators, giving rise to a vicious cycle that further worsens DKD. Conclusion This review provides an overview of the primary molecular mediators and signalling pathways leading to DKD; their interconnectivity at the onset and during DKD progression, the central role of transforming growth factor-beta via different pathways, the Hippo pathway kidney-specific response to hyperglycaemia, and how all mediators and transduction signals result in a vicious circle that exacerbates renal failure. The review gives therapeutic sights to these pathways as druggable targets for DKD management. Understanding these molecular events underlying the pathogenesis of DKD can bridge basic research and clinical application, facilitating the development of innovative management strategies.https://doi.org/10.1186/s13098-025-01726-4Diabetic nephropathySignal pathwaysChronic kidney diseaseEnd-stage kidney diseaseRenin–angiotensin–aldosterone systemToll-like receptors |
| spellingShingle | Esienanwan Esien Efiong Kathrin Maedler Emmanuel Effa Uchechukwu Levi Osuagwu Esther Peters Joshua Onyeka Ikebiuro Chisom Soremekun Ugwunna Ihediwa Jiefei Niu Markéta Fuchs Homa Bazireh Akang Leonard Bassey Peter Uchenna Amadi Qiuling Dong Njogu Mark Kimani Rebecca Chinyelu Chukwuanukwu Emmy Tuenter Sapna Sharma Harald Grallert Decoding diabetic kidney disease: a comprehensive review of interconnected pathways, molecular mediators, and therapeutic insights Diabetology & Metabolic Syndrome Diabetic nephropathy Signal pathways Chronic kidney disease End-stage kidney disease Renin–angiotensin–aldosterone system Toll-like receptors |
| title | Decoding diabetic kidney disease: a comprehensive review of interconnected pathways, molecular mediators, and therapeutic insights |
| title_full | Decoding diabetic kidney disease: a comprehensive review of interconnected pathways, molecular mediators, and therapeutic insights |
| title_fullStr | Decoding diabetic kidney disease: a comprehensive review of interconnected pathways, molecular mediators, and therapeutic insights |
| title_full_unstemmed | Decoding diabetic kidney disease: a comprehensive review of interconnected pathways, molecular mediators, and therapeutic insights |
| title_short | Decoding diabetic kidney disease: a comprehensive review of interconnected pathways, molecular mediators, and therapeutic insights |
| title_sort | decoding diabetic kidney disease a comprehensive review of interconnected pathways molecular mediators and therapeutic insights |
| topic | Diabetic nephropathy Signal pathways Chronic kidney disease End-stage kidney disease Renin–angiotensin–aldosterone system Toll-like receptors |
| url | https://doi.org/10.1186/s13098-025-01726-4 |
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