Urinary Exosomes and Exosomal CCL2 mRNA as Biomarkers of Active Histologic Injury in IgA Nephropathy

Abstract

IgA nephropathy (IgAN) features variable renal pathology and a heterogeneous clinical course. Our aim was to search noninvasive biomarkers from urinary exosomes for IgAN patients; membrane nephropathy and minimal change disease were included as other glomerulopathy controls. Transmission electron microscopy and nanoparticle tracking analysis confirmed the size and morphology characteristic of urinary exosomes. Exosome markers (Alix and CD63) as well as renal cell markers [aquaporin 2 (AQP2) and nephrin] were detected, which indicate the renal origin of urinary exosomes. Exosome excretion was increased markedly in IgAN patients compared with controls and correlated with levels of proteinuria and tubular injury. More important, urinary exosome excretion correlated with greater histologic activity (mesangial hypercellularity, crescents, and endocapillary hypercellularity). Profiling of the inflammation-related mRNA revealed that exosomal chemokine (C-C motif) ligand 2 (CCL2) was up-regulated in IgAN patients. In a validation study, CCL2 was exclusively highly expressed in IgAN patients compared with healthy controls as well as minimal change disease and membrane nephropathy patients. Also, a correlation between exosomal CCL2 and estimated glomerular filtration rate levels was found in IgAN. Exosomal CCL2 was correlated with tubulointerstitial inflammation and C3 deposition. High CCL2 levels at the time of renal biopsy were associated with subsequent deterioration in renal function. Thus, urinary exosomes and exosomal CCL2 mRNA are promising biomarkers reflecting active renal histologic injury and renal function deterioration in IgAN.

New insight into the role of extracellular vesicles in kidney disease

“…Further study showed that CD2AP mRNA from exosome was correlated with both kidney function and severity of fibrosis . Importantly, urinary exosomes and exosomal CCL2 mRNA are promising biomarkers reflecting active renal histologic injury and predicting renal function deterioration in IgAN …”

“…72 Importantly, urinary exosomes and exosomal CCL2 mRNA are promising biomarkers reflecting active renal histologic injury and predicting renal function deterioration in IgAN. 73 Moreover, the stability and enrichment of miRNA in exosome make it a promising candidate biomarker for kidney disease. Exosome miRNA was stable despite repeated frozen-thaw cycles and long-term storage.…”

Roles for Exosome in Various Kidney Diseases and Disorders

“…For example, level of urinary exosomal miR-193a was greater in children with primary focal segmental glomerulosclerosis as compared to those with minimal change nephrotic syndrome (NS) . Urinary exosomal excretion and chemokine (C-C motif) ligand-2 (CCL2) mRNA level were increased in IgA nephropathy and correlated with the disease activity (Feng et al, 2018). Additionally, 30 urinary exosomal miRNAs were markedly increased in children with idiopathic NS .…”

Podocyte Lysosome Dysfunction in Chronic Glomerular Diseases

“…This property positions EV as a potential source for the discovery of novel biomarkers of different diseases. In this regard, the urinary exosome has been reported to be a novel biomarker for renal disease [207][208][209]. Moreover, the stability and enrichment of miRNA in the exosome make it a promising candidate as a biomarker for different glomerular diseases [210][211][212][213][214][215].…”