Biochemical composition of the glomerular extracellular matrix in patients with diabetic kidney disease

Abstract

In the glomeruli, mesangial cells produce mesangial matrix while podocytes wrap glomerular capillaries with cellular extensions named foot processes and tether the glomerular basement membrane (GBM). The turnover of the mature GBM and the ability of adult podocytes to repair injured GBM are unclear. The actin cytoskeleton is a major cytoplasmic component of podocyte foot processes and links the cell to the GBM. Predominant components of the normal glomerular extracellular matrix (ECM) include glycosaminoglycans, proteoglycans, laminins, fibronectin-1, and several types of collagen. In patients with diabetes, multiorgan composition of extracellular tissues is anomalous, including the kidney, so that the constitution and arrangement of glomerular ECM is profoundly altered. In patients with diabetic kidney disease (DKD), the global quantity of glomerular ECM is increased. The level of sulfated proteoglycans is reduced while hyaluronic acid is augmented, compared to control subjects. The concentration of mesangial fibronectin-1 varies depending on the stage of DKD. Mesangial type III collagen is abundant in patients with DKD, unlike normal kidneys. The amount of type V and type VI collagens is higher in DKD and increases with the progression of the disease. The GBM contains lower amount of type IV collagen in DKD compared to normal tissue. Further, genetic variants in the α3 chain of type IV collagen may modulate susceptibility to DKD and end-stage kidney disease. Human cellular models of glomerular cells, analyses of human glomerular proteome, and improved microscopy procedures have been developed to investigate the molecular composition and organization of the human glomerular ECM.

Keywords: Diabetes; Kidney disease; Glycosaminoglycans; Factor H; Sialic acid; Laminin; Collagen; Fibronectin-1; Extracellular matrix

Core Tip: Diabetic kidney disease is associated with profound disturbance in glomerular extracellular matrix (ECM). Understanding the mechanisms that regulate glomerular ECM synthesis and repair may contribute to design therapeutic strategies that improve clinical outcomes. The cytoskeleton inside the foot processes of podocytes is connected to the glomerular basement membrane (GBM) via associated proteins. There is a reciprocal interaction between the cellular cytoskeleton and the extracellular tissue that contribute to regulate ECM composition. Loss of anchor points in the GBM may lead to podocyte detachment. Likewise, alterations in the podocyte cytoskeleton may unfasten the cell and impair the filtration barrier.