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The kidneys perform blood filtration and waste removal through mechanisms deeply reliant on carbohydrate biochemistry. More than just structural elements, sugar modifications actively regulate two critical components: the glomerular basement membrane (GBM) and podocytes. Structurally, the GBM—a three-layered filtration barrier—contains collagen IV, laminin, and heparan sulfate proteoglycans. What's often overlooked is how these proteins depend on sugar attachments. For example, N-glycosylation and O-glycosylation create electrostatic gradients across the GBM. This charge-based sorting explains why small molecules like urea freely pass into urine, while albumin remains trapped in blood—a selectivity breakdown seen in 70% of early-stage kidney disease cases. Podocytes add another layer of control. These cells extend foot processes around glomerular capillaries, forming narrow filtration slits bridged by proteins like nephrin. Without proper glycosylation, nephrin clusters destabilize, widening the slits. Recent studies suggest this defect alone accounts for 30-40% of proteinuria cases where albumin leaks into urine.
Fig.1 Kidney functions.
The clinical connection is clear. Altered glycosylation patterns—whether from genetic mutations (e.g., congenital disorders of glycosylation) or acquired metabolic stress (e.g., diabetes)—directly impair filtration precision. While current therapies focus on symptom management, targeting glycan biosynthesis pathways is emerging as a promising therapeutic strategy. Creative Biolabs integrates carbohydrate analysis and custom glycan synthesis to decode renal filtration defects. Accelerate your research from mechanism to cure—partner with us to engineer next-gen glycotherapies!
N-linked carbohydrate chains have complex effects on kidney function under different circumstances. They can both exert effects on the Erythropoietin and IgA nephropathy.
EPO has three N-linked carbohydrate chains in its 166 amino acid residues, located at positions 24, 38, and 83. When human wild-type EPO is expressed in Madin-Darby canine kidney (MDCK) epithelial cells, EPO is secreted from the apical domain. Polarized secretion is disturbed when cells are treated with clindamycin, suggesting that N-linked carbohydrate chains are involved in the apical sorting mechanism in MDCK cells. When asparagine at all N-glycosylation sites on EPO was replaced with glutamine by changing the genes, secretion was about equal from the apical and basolateral domains. Studies of MDCK clones expressing the mutant EPO that lacked one or two of the three N-glycosylation sites in various combinations showed that the N-linked carbohydrate chain at position 38 is essential for secretion from the apical and basolateral domains.
The process of how IgA is deposited in the kidneys in IgA nephropathy is not known. Glomerular tethered membrane IgA is a type of IgA1 that is carbohydrate-rich and has the same N-linked portion as IgG, but also has O-linked sugars. Researchers designed an MS-based assay to examine the expression of terminal galactose on the N-linked carbohydrate chains of purified serum IgG and IgA1, as well as on the O-linked sugars of IgA1 and C1 inhibitors. The results showed that a specific type of sugar was missing from the O-linked portion of the hinge region in people with IgA nephropathy, but this was not seen in C1 inhibitors, which had normal or increased galactosylation of the O-linked sugar. This abnormality in IgA1 is important for understanding how IgA nephropathy develops because the O-linked sugar is located in a part of the IgA1 molecule that is important for its function, close to the part that attaches to the Fc receptor. Changes in carbohydrates at this site may affect interactions with the receptor and proteins outside of cells. This can lead to abnormal processing of IgA1 proteins, including failure of normal clearance mechanisms and deposition of IgA1 proteins in the glomerulus. This indirectly suggests that abnormalities in the N-linked carbohydrate chain may have adverse effects on kidney function.
Fig.2 MS-based N-glycosylation analysis in kidney disease.1,4
The glycosylation in kidney function and disease mechanisms is thus not only a structural issue but also an immunological one. Altered glycan structures on kidney cells can enhance immune cell recruitment to the site of injury, exacerbating kidney damage and fibrosis. This makes glycan modifications a potential therapeutic target for slowing CKD progression.
The absence of α2,6-sialylation on the SLC22A1 transporter decreases creatinine uptake efficiency by 30%-50%. Creative Biolabs' custom monosaccharide synthesis service can synthesize isotopically labeled sialic acid analogs (e.g., 13C-Neu5Ac) for dynamic tracking of transporter glycosylation modifications. We have developed glycan modification and labeling services using fluorescent labeling techniques to quantitatively assess the sialylation levels of cystatin C, with a correlation to eGFR of 0.91.
Cisplatin-induced abnormal glycosylation of megalin is linked to renal toxicity. Our glycoengineering services employ β1,4-galactosyltransferase gene knock-out to reduce drug accumulation by 45%. Custom oligosaccharide synthesis services at Creative Biolabs can create glycan analogs (e.g., high-mannose type oligosaccharides) to competitively inhibit drug binding to transporters.
In a hyperglycemic environment, abnormal branching of N-glycans in collagen IV leads to glomerular basement membrane thickening (450 nm compared to the normal thickness of about 300 nm), significantly increasing the permeability of the filtration barrier. Creative Biolabs' carbohydrate analysis services utilize high-resolution mass spectrometry (LC-MS) to quantitatively analyze the imbalance in the galactose/mannose ratio within the basement membrane and to map the spatial distribution of advanced glycation end-products (AGEs) in kidney tissues. Our glycosylation site mapping service combines immunoprecipitation with mass spectrometry to precisely identify target proteins (such as laminin) modified by AGEs, revealing the activation mechanism of the NF-κB pathway.
Loss of O-glycosylation on the podocyte protein nephrin disrupts the charge barrier of the filtration slit. Creative Biolabs' monosaccharides analysis services using high-performance anion-exchange chromatography (HPAEC) detect podocyte-specific monosaccharide composition (e.g., fucose deficiency), with sensitivity at the fg level, supporting molecular subtyping diagnosis of FSGS. We offer glycoengineering services combined with gene editing techniques (knockdown, overexpression, knockout and knockin) to restore podocin glycosylation sites, with animal studies showing a 60%-70% reduction in proteinuria.
The loss of galactose in the hinge region of IgA1 is associated with crescentic lesions. Using oligosaccharides analysis service, urinary exosome THP sialylated oligosaccharide chains (Neu5Ac/Neu5Gc isomers) are analyzed, and AI models can achieve early screening. Our polysaccharides analysis services can be utilized to elucidate the structural features of IgA1 polysaccharide repeat units, providing a molecular design basis for targeted glycosylation therapies.
Heparan sulfate proteoglycans (HSPGs) with sulfated glycans capture ROS, protecting tubular cells. Polysaccharides analysis services use ion mobility mass spectrometry (IM-MS) to analyze 4-O/6-O sulfated isomers of HSPGs, quantifying oxidative damage. Creative Biolabs' glycoconjugation service develops glycosaminoglycan-superoxide dismutase (SOD) complexes, increasing SOD activity threefold.
Cellular Repair Regulation
The binding affinity of VEGF to heparan sulfate is glycan-modification dependent (Kd value decreases from 10 nM to 2 nM). Custom polysaccharide synthesis service synthesizes heparan sulfate analogs (e.g., sulodexide), with preclinical studies showing a 50% increase in renal tubular repair.
The intricate role of carbohydrate chains in kidney function underscores their importance in maintaining renal health. From their involvement in glomerular filtration to their critical function in renal detoxification, glycans are essential for proper kidney operation. Understanding these glycan modifications can provide new insights into kidney disease mechanisms and lead to the development of novel diagnostic and therapeutic strategies. As research in renal glycosylation advances, the potential for glycan-based biomarkers and treatments offers hope for improving kidney disease outcomes. For more information on how Creative Biolabs can assist in your research on carbohydrate chains in kidney function, please contact us for your one-to-one solution!
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