Background: Diabetic nephropathy (DN) is a major cause of chronic kidney disease. Proteinuria is a hallmark of DN. An active receptor-mediated pathway involving megalin and cubilin receptors and the Cl-/H+ antiporter ClC-5 is responsible for filtered albumin uptake in the proximal tubular epithelium. The aim of our pilot study was to analyze the patterns of megalin and ClC-5 expression in the kidney biopsies of patients with DN, minimal change disease (MCD), and controls, and their correlations with kidney dysfunction. Methods: Kidney biopsies of 10 DN and 8 MCD patients, and 9 controls (CTRs) were analyzed. Immunohistochemical and immunofluorescence staining, and morphometric analysis were performed to quantify megalin, ClC-5 and synaptopodin signals. Results: The ClC-5 glomerular signal was significantly reduced in DN and MCD compared with controls. In MCD, ClC-5 was detected in podocytes and parietal cells, while in DN it was detected only in parietal cells and colocalized with CD44 in hypertrophic parietal cells (ANXA3+). Megalin was also significantly reduced in DN compared with controls, and the correlation between ClC-5 and megalin was lost at the glomerular level. At the tubular level, the ClC-5 signal was reduced in DN and MCD compared with controls. In both glomerulopathies, tubular ClC-5 and megalin expression correlated with proteinuria and kidney function. In DN, glycosylated hemoglobin inversely correlated with tubular megalin expression. Conclusion: We found impairment of the endocytic process in DN and MCD patients. In pateints with DN, hyperglycemia appeared to be associated with an altered endocytic process at the glomerular and tubular levels.
Protein endocytosis dysfunction in kidney biopsies of patients with diabetic nephropathy and minimal change disease: a pilot study on ClC-5 and the megalin receptor
Del Prete, Dorella;Ceol, Monica;Radu, Claudia Maria;Priante, Giovanna;Martino, Francesca Katiana;Stefanelli, Federica;Nalesso, Federico;
2026
Abstract
Background: Diabetic nephropathy (DN) is a major cause of chronic kidney disease. Proteinuria is a hallmark of DN. An active receptor-mediated pathway involving megalin and cubilin receptors and the Cl-/H+ antiporter ClC-5 is responsible for filtered albumin uptake in the proximal tubular epithelium. The aim of our pilot study was to analyze the patterns of megalin and ClC-5 expression in the kidney biopsies of patients with DN, minimal change disease (MCD), and controls, and their correlations with kidney dysfunction. Methods: Kidney biopsies of 10 DN and 8 MCD patients, and 9 controls (CTRs) were analyzed. Immunohistochemical and immunofluorescence staining, and morphometric analysis were performed to quantify megalin, ClC-5 and synaptopodin signals. Results: The ClC-5 glomerular signal was significantly reduced in DN and MCD compared with controls. In MCD, ClC-5 was detected in podocytes and parietal cells, while in DN it was detected only in parietal cells and colocalized with CD44 in hypertrophic parietal cells (ANXA3+). Megalin was also significantly reduced in DN compared with controls, and the correlation between ClC-5 and megalin was lost at the glomerular level. At the tubular level, the ClC-5 signal was reduced in DN and MCD compared with controls. In both glomerulopathies, tubular ClC-5 and megalin expression correlated with proteinuria and kidney function. In DN, glycosylated hemoglobin inversely correlated with tubular megalin expression. Conclusion: We found impairment of the endocytic process in DN and MCD patients. In pateints with DN, hyperglycemia appeared to be associated with an altered endocytic process at the glomerular and tubular levels.
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