Abstract
Objective: Cathepsin S (CTSS) is an important lysosomal cysteine protease. This study aimed at investigating the clinical significance of CTSS and underlying mechanism in immunoglobulin A nephropathy (IgAN).Methods: This study recruited 25 children with IgAN and age-matched controls and their serum CTSS levels were measured by enzyme-linked immunosorbent assay (ELISA). Following induction of IgAN in rats, their kidney CTSS expression, IgA accumulation and serum CTSS were characterized by immunohistochemistry, immunofluorescence, and ELISA. The impact of IgA1 aggregates on the proliferation of human mesangial cells (HMCs) was determined by Cell Counting Kit-8 and Western blot analysis of Ki67.Results: Compared to the non-IgAN controls, significantly up-regulated CTSS expression was detected in the renal tissues, particularly in the glomerular mesangium and tubular epithelial cells of IgAN patients, accompanied by higher levels of serum CTSS (P < 0.05), which were correlated with the levels of 24-h-urine proteins and microalbumin and urine erythrocytes and grades of IgAN Lee's classification in children with IgAN (P < 0.01 for all). Following induction of IgAN, we detected inducible IgA accumulation and increased levels of CTSS expression in the glomerular mesangium and glomerular damages in rats, which were mitigated by LY3000328, a CTSS-specific inhibitor. Treatment with LY3000328 significantly mitigated the Ki67 expression in the kidney of IgAN rats (P < 0.01) and significantly minimized the IgA1 aggregate-stimulated proliferation of HMCs and their Ki67 expression in vitro (P < 0.01).Conclusions: CTSS promoted the proliferation of glomerular mesangial cells, contributing to the pathogenesis of IgAN and may be a new therapeutic target for intervention of aberrant mesangial cell proliferation during the process of IgAN.
Highlights
Immunoglobulin A nephropathy (IgAN), known as Berger’s disease, is one of the most common glomerulonephritis worldwide
Enzyme-Linked Immunosorbent Assay (ELISA) revealed that the levels of serum Cathepsin S (CTSS) in 25 IgAN patients, including 19 with Lee’s classification (I + II), 6 with Lee’s classification (III + IV), were significantly higher than that in healthy subjects in this population, and the serum CTSS levels in (III + IV) IgAN patients were significantly higher than that in (I + II) IgAN patients (P < 0.05, Figure 1B)
Increased levels of CTSS expression were detected in renal tissues and serum samples from IgAN patients
Summary
Immunoglobulin A nephropathy (IgAN), known as Berger’s disease, is one of the most common glomerulonephritis worldwide. 15–25% of IgAN patients progress to end stage renal disease (ESRD) within 10 years after diagnosis [1]. IgAN is characterized by predominant IgA and extracellular matrix deposition in the glomerular mesangium, accompanied by mesangial cell proliferation with matrix expansion, focal necrosis, CTSS in IgA Nephropathy segmental sclerosis, and crescent formation in the glomeruli [2]. IgAN patients display hematuresis with different levels of proteinuria, hypertension and kidney function impairments, and some IgAN patients develop glomerular sclerosis, even irreversible progression to ESRD. Mesangial cells can regulate glomerular hemodynamics and are critical for renal glomerular function. Little is known on the molecular pathways that regulate glomerular mesangial cell proliferation and matrix accumulation as well as inflammatory cell infiltration during the process of IgAN [3].
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