Proximal Tubular Expression Patterns of Megalin and Cubilin in Proteinuric Nephropathies

INTRODUCTION: Receptor-mediated endocytosis is responsible for protein reabsorption in the proximal tubules. For albumin this process involves at least 2 interacting receptors, megalin and cubilin. Albumin is not usually present in the urine, indicating a highly efficient tubular reuptake under physiological conditions. However, early appearance of albuminuria may mean that the tubular system is overwhelmed by large quantities of albumin or that the function is impaired. METHODS: To better understand the physiological role of megalin and cubilin in human renal disease, renal biopsies from 15 patients with a range of albuminuria and 3 healthy living donors were analyzed for proximal tubular expression of megalin and cubilin using immunohistochemistry (IHC) and semiquantitative immune-electron microscopy. Their expression in proteinuric zebrafish was also studied. RESULTS: Megalin and cubilin were expressed in brush border and cytoplasmic vesicles. Patients with microalbuminuric IgA nephropathy and thin membrane disease had significantly higher megalin in proximal tubules, whereas those with macro- or nephrotic-range albuminuria had unchanged levels. Cubilin expression was significantly higher in all patients. In a proteinuric zebrafish nphs2 knockdown model, we found a dose-dependent increase in the expression of tubular megalin and cubilin in response to tubular protein uptake. DISCUSSION: Megalin and cubilin show different expression patterns in different human diseases, which indicates that the 2 tubular proteins differently cooperate in cleaning up plasma proteins in kidney tubules.