Pathogenic Role of MicroRNA Dysregulation in Podocytopathies

Abstract

MicroRNAs (miRNAs) participate in the regulation of various important biological processes by regulating the expression of various genes at the post-transcriptional level. Podocytopathies are a series of renal diseases in which direct or indirect damage of podocytes results in proteinuria or nephrotic syndrome. Despite decades of research, the exact pathogenesis of podocytopathies remains incompletely understood and effective therapies are still lacking. An increasing body of evidence has revealed a critical role of miRNAs dysregulation in the onset and progression of podocytopathies. Moreover, several lines of research aimed at improving common podocytopathies diagnostic tools and avoiding invasive kidney biopsies have also identified circulating and urine miRNAs as possible diagnostic and prognostic biomarkers for podocytopathies. The present review mainly aims to provide an updated overview of the recent achievements in research on the potential applicability of miRNAs involved in renal disorders related to podocyte dysfunction by laying particular emphasis on focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranous nephropathy (MN), diabetic kidney disease (DKD) and IgA nephropathy (IgAN). Further investigation into these dysregulated miRNAs will not only generate novel insights into the mechanisms of podocytopathies, but also might yield novel strategies for the diagnosis and therapy of this disease.

Keywords: IgA nephropathy; diabetic kidney disease; focal segmental glomerulosclerosis; membranous nephropathy; microRNA; minimal change disease; podocytopathy; therapeutic target.

FIGURE 1

The underlying causes and risk factors of podocytopathies across the lifespan. A number of causes and risk factors have been revealed, mainly including genetic factors, immunological and/or soluble factors, VEGF inhibition, adaptive podocyte stress, infectious agents and various toxins, that predispose individuals to development of podocytopathies. Different risk factors and/or causes of podocytopathies can present at certain phases of life or be preferentially associated with gender and race. For instance, genetic causes of podocytopathies are more frequent in children and young adults. Podocytopathies associated with VEGF inhibition are more common in pregnant women. Among the major risk factors leading to the development of podocytopathies, nephron loss, severe obesity and diabetes are more frequently observed in adult middle-age patients, whereas low nephron mass is more frequent in adolescence or early adulthood. Besides, the susceptibility gene APOL1 is more prevalent in patients of Black adult. Finally, podocytopathies induced by various toxins and infectious agents can occur at all ages. The color gradient in each cause and risk factor represents the incidence of podocytopathies at different ages. APOL1, apolipoprotein L1; HCV, hepatitis C virus; EBV, Epstein–Barr virus; SARS-CoV-2, the virus that causes COVID-19.

FIGURE 2

Schematic diagram showing the main dysregulated miRNAs and their corresponding downstream targets in various podocytopathies. Changes in miRNAs in podocytes occurring in focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranous nephropathy (MN), diabetic kidney diseases (DKD), and IgA nephropathy (IgAN). Dysregulation of indicated miRNAs contributes to podocyte injuries including podocyte foot process effacement and podocyte loss due to cell death or detachment from the glomerular basement membrane.