Dystroglycan does not contribute significantly to kidney development or function, in health or after injury

Abstract

Dystroglycan (DG or DAG1) is considered a critical link between the basement membrane and the cytoskeleton in multiple tissues. DG consists of two subunits, an extracellular α-subunit that binds laminin and other basement membrane components, and a transmembrane β-subunit. DG-null mouse embryos die during early embryogenesis because DG is required for Reichert's membrane formation. DG also forms an integral part of the dystrophin-glycoprotein complex in muscle. Although no human DG mutations have been reported, multiple forms of muscular dystrophy have been linked to DG glycosylation defects, and targeted deletion of muscle DG causes muscular dystrophy in mice. Moreover, DG is widely distributed in endothelial and epithelial cells, including those in the kidney. There has therefore been significant interest in DG's role in the kidney, especially in podocytes. Previous reports suggested that DG's disturbance in podocytes might cause glomerular filtration barrier abnormalities. To fully understand DG's contribution to nephrogenesis and kidney function, we used a conditional DG allele and a variety of Cre mice to systematically delete DG from podocytes, ureteric bud, metanephric mesenchyme, and then from the whole kidney. Surprisingly, none of these conditional deletions resulted in significant morphological or functional abnormalities in the kidney. Furthermore, DG-deficient podocytes did not show increased susceptibility to injury, and DG-deficient kidneys did not show delayed recovery. Integrins are therefore likely the primary extracellular matrix receptors in renal epithelia.

Blood pressure influences end-stage renal disease of Cd151 knockout mice

“…The importance of an intact GBM-integrin-actin axis is illustrated by glomerular diseases in mice with podocyte-specific genetic ablation of Itga3 (2), Itgb1 (3,4), and integrin-linked kinase (5,6) as well as Pierson syndrome and focal segmental glomerulosclerosis in humans, which are caused by mutations in laminin-521 and α-actinin 4, respectively (7,8). In contrast, the contribution of dystroglycan to podocyte adhesion seems minor, as podocyte-specific Dag1-knockout mice do not display glomerular pathology or aggravate the renal phenotype of Itga3-null animals (9). Mice deficient for the tetraspanin Cd151 develop kidney abnormalities similar to, albeit less severe than, those of mice with podocyte-specific Itga3 knockout (2,10).…”

The podocyte's response to stress: the enigma of foot process effacement

“…Recently, it has been shown that deletion of Cd151, a member of the tetraspanin family, weakens the interaction of ␣3␤1 with laminin in the GBM and leads to a progressive glomerulopathy (5,75). Deletion of dystroglycans specifically from podocytes produces no obvious abnormalities (34). Very little is known about the changes in expression and distribution of integrins or dystroglycans in effaced foot processes compared with intact foot processes.…”

Integrating Activities of Laminins that Drive Basement Membrane Assembly and Function

“…Thus dystroglycan can constitutively link up with all three cytoskeletal systems. Despite this repertoire of interactions, dystroglycan is important as a basement membrane link for some (e.g., Reichert's membrane, skeletal muscle, brain cortex, Schwann cell nodes of Ranvier) but not all (e.g., kidney) tissues ( Jarad, Pippin, Shankland, Kreidberg, & Miner, 2011;Moore et al, 2002;Occhi et al, 2005;Saito et al, 2003;Williamson et al, 1997).…”