Glycosylation, a fundamental biochemical process involving the attachment of complex sugar molecules to proteins, has emerged as a critical regulator in kidney physiology and pathology. This intricate modification governs protein folding, stability, immune recognition, and cellular signaling pathways, all of which are essential for maintaining renal function. However, disruptions in glycosylation patterns are increasingly recognized as central drivers in a plethora of kidney diseases, ranging from autoimmune disorders to inherited and metabolic renal conditions. Recent advances in glycoproteomic technologies have enabled unprecedented insight into these sugar-protein interactions, transforming our understanding of kidney disease mechanisms and paving the way for innovative diagnostic and therapeutic approaches.
Kidney diseases collectively affect nearly 700 million individuals worldwide, representing a significant global health burden with high mortality rates and escalating healthcare costs. Chronic kidney disease (CKD), characterized by gradual loss of renal function, leads to over 1.2 million deaths annually, while acute kidney injury (AKI) often serves as a critical trigger for progression toward chronic impairment. Despite these alarming statistics, therapeutic options remain limited. A primary obstacle in advancing treatment arises from the molecular complexity underlying renal pathology, much of which involves post-translational modifications such as glycosylation. Among the hundreds of known protein modifications, glycosylation stands out for its ubiquity and functional significance; more than half of all human proteins undergo glycosylation, highlighting its potential impact on kidney health and disease.
In a groundbreaking review published in Precision Clinical Medicine on July 11, 2025, researchers from Sichuan University and their collaborators dissect how aberrant glycosylation shapes renal disease pathogenesis. This comprehensive synthesis integrates molecular biology, cutting-edge glycoproteomic analysis, and clinical data to reveal how defects in glycan structures influence immune regulation, metabolic balance, and oncogenic signaling within the kidney. The authors catalog diverse glycosylation changes across various renal disorders, demonstrating how these modifications disrupt protein function and cellular communication to fuel inflammation, fibrosis, and structural deterioration.
One of the most illustrative cases is Immunoglobulin A nephropathy (IgAN), the world’s most common primary glomerulonephritis. Here, defective O-glycosylation produces galactose-deficient IgA1 molecules prone to forming pathogenic immune complexes that deposit in the glomerular mesangium. This aberrant glycosylation triggers complement activation and local inflammatory responses, driving progressive renal injury. Such molecular insights not only clarify previously enigmatic disease mechanisms but also suggest serum galactose-deficient IgA1 as a promising biomarker, enabling earlier diagnosis and personalized disease monitoring.
Similarly, diabetic kidney disease (DKD), a leading cause of end-stage renal failure, is tightly linked to altered glycosylation induced by chronic hyperglycemia. Elevated intracellular glucose levels enhance O-GlcNAcylation of proteins in mesangial cells, podocytes, and tubular epithelia. This excess glycan modification disrupts cellular signaling, promotes epithelial-to-mesenchymal transition, and instigates extracellular matrix deposition, culminating in glomerulosclerosis and proteinuria. Understanding the molecular crosstalk mediated by abnormal glycosylation in DKD could inform development of targeted therapies aimed at modulating specific glycosylation enzymes, potentially halting or reversing disease progression.
Autosomal dominant polycystic kidney disease (ADPKD) represents another paradigm where glycosylation defects exert profound biological effects. Abnormal N- and O-glycosylation of polycystin-1 and polycystin-2, key proteins involved in calcium signaling, leads to dysfunctional channel activity and aberrant cellular proliferation. These changes accelerate cystogenesis and kidney enlargement, hallmark features of ADPKD. By elucidating the glycan alterations disrupting polycystin function, researchers open avenues for therapeutic intervention targeting glycosyltransferases or glycosidases implicated in cyst growth dynamics.
Beyond inherited and metabolic disorders, glycosylation dysregulation also facilitates renal cell carcinoma (RCC) progression. Enhanced biosynthesis of N-glycans on tumor cell surface proteins modifies cell adhesion, migration, and immune evasion capacities, thereby promoting invasion and metastasis. Cutting-edge mass spectrometry-based glycoproteomics has unveiled tumor-specific glycan signatures, which hold promise as biomarkers for RCC diagnosis and prognostication. Moreover, targeting glycosylation pathways in cancer cells offers an innovative strategy to disrupt malignant behavior.
This expanding body of research has been propelled by technological breakthroughs. Mass spectrometry, lectin microarrays, and liquid chromatography techniques now enable detailed, site-specific mapping of glycan structures on proteins within complex biological samples. Such analytical precision facilitates not only identification of disease-associated glycosylation patterns but also dissection of the enzymes and pathways responsible for these modifications. Despite remarkable progress, challenges remain, including high costs, lack of standardized analytical protocols, incomplete glycan databases, and limited integration with genomic and metabolomic datasets. These bottlenecks underscore the necessity for interdisciplinary collaboration and methodological harmonization to fully harness glycosylation’s diagnostic and therapeutic potential.
Professor Yong Zhang, lead author of the review, eloquently described glycosylation as “a hidden language of the kidney.” Decoding this language promises to illuminate fundamental mechanisms of disease initiation and progression that have remained elusive to classical genetic or proteomic analyses alone. However, the enormous structural diversity and complexity inherent in glycan chemistry necessitate innovative tools and collaborative frameworks that bridge clinical nephrology and glycobiology. Such integration is essential for translating glycosylation research into tangible clinical applications.
Already, clinical studies highlight serum glycan signatures as non-invasive biomarkers capable of reflecting disease activity and therapeutic response across kidney disorders. For instance, aberrant IgG glycosylation patterns correlate with disease severity in lupus nephritis, while distinct glycan profiles forecast prognosis in membranous nephropathy. Parallel therapeutic efforts focus on modulating glycosylation enzyme activity to correct pathological modifications. Pharmacological inhibition of specific glycosyltransferases or enhancement of glycosidase function are under active investigation, aiming to restore normal glycan patterns and mitigate tissue damage.
Looking ahead, the convergence of glycoproteomics with multi-omics platforms—integrating genomics, transcriptomics, and metabolomics—heralds a new era of systems biology in kidney research. Such comprehensive approaches will enable holistic mapping of molecular networks driving renal disease, uncovering novel targets and stratifying patient populations with unprecedented precision. Ultimately, these advances may revolutionize nephrology by shifting the paradigm from symptomatic treatment to molecularly tailored interventions that enhance patient outcomes and quality of life.
In summary, glycosylation stands out as a pivotal molecular mechanism underlying kidney function and dysfunction. Its aberrations orchestrate diverse pathological processes that converge on inflammation, fibrosis, and malignancy within the renal milieu. Enhanced understanding of glycan biology offers not only fresh perspectives on disease etiology but also practical avenues for biomarker development and targeted therapy. As the field matures, collaborative efforts and technological innovation will be imperative to overcome prevailing challenges and fully realize glycosylation’s promise in transforming kidney disease diagnosis and management.
Subject of Research:
Not applicable
Article Title:
Glycosylation in kidney diseases
News Publication Date:
11-Jul-2025
References:
DOI: 10.1093/pcmedi/pbaf017
Image Credits:
Precision Clinical Medicine
Keywords:
Glycosylation
