Glomerular Expression of Dystroglycans Is Reduced in Minimal Change Nephrosis But Not in Focal Segmental Glomerulosclerosis

Abstract

Abstract. Extensive flattening of podocyte foot processes and increased permeability of the glomerular capillary filter are the major pathologic features of minimal change nephrosis (MCN) and focal segmental glomerulosclerosis (FSGS). Adhesion proteins anchor and stabilize podocytes on the glomerular basement membrane (GBM), and presumably are involved in the pathogenesis of foot process flattening. Thus far, α3 β1-integrin was localized to basal cell membrane domains. In this report, α- and β-dystroglycan (DG) were detected at precisely the same location by immunoelectron microscopy, and the presence of α- and β-DG chains was confirmed by immunoblotting on isolated human glomeruli. Because the major DG binding partners in the GBM (laminin, agrin, perlecan), and the intracellular dystrophin analogue utrophin are also present in glomeruli, it appears that podocytes adhere to the GBM via DG complexes, similar to muscle fibers in which actin is linked via dystrophin and DG to the extracellular matrix. As with muscle cells, it is therefore plausible that podocytes use precisely actin-guided DG complexes at their “soles” to actively govern the topography of GBM matrix proteins. Expression of the α/β-DG complex was reported to be reduced in muscular dystrophies, and therefore a search for similar pathologic alterations in archival kidney biopsies from patients with MCN (n = 16) and FSGS (n = 8) was conducted by quantitative immunoelectron microscopy. The density of α-DG on the podocyte's soles was significantly reduced to 25% in MCN, whereas it was not different in normal kidneys and FSGS. The expression of β-DG was reduced to >50% in MCN, and was slightly increased in FSGS. Levels of DG expression returned to normal in MCN after steroid treatment (n = 4). Expression of β1-integrin remained at normal levels in all conditions. These findings point to different potentially pathogenic mechanisms of foot process flattening in MCN and FSGS.

Collapsing focal segmental glomerulosclerosis in a patient with oral cavity cancer

“…[12] Podocyte detachment is critically related to a3b1 integrin or dystrolglycan in the glomerular basement membrane. [13,14] A decreasing number of podocytes is a consequence of a lack of appropriate proliferation after podocyte injury. [15] General measures for the treatment of collapsing FSGS include blood pressure control, minimization of proteinuria by angiotensin inhibition, and lipid-lowering therapy.…”

“…Podocyte apoptosis results from elevated transforming growth factor-β, angiotensin II, reactive oxygen species, and reduced levels of cyclin-dependent kinase inhibitors p21 and p27 [12] . Podocyte detachment is critically related to α3β1 integrin or dystrolglycan in the glomerular basement membrane [13,14] . A decreasing number of podocytes is a consequence of a lack of appropriate proliferation after podocyte injury [15] …”

LIM and SH3 protein 1 (LASP‐1): A novel link between the slit membrane and actin cytoskeleton dynamics in podocytes

“…In brief, tissue samples were fixed in 4% formaldehyde and 0.1% distilled glutaraldehyde (Merck, Darmstadt, Germany) in 100 mM phosphate buffer (pH 7.2) for 6 to 12 hours at 4°C. Samples were soaked in sucrose, frozen, and stored in liquid nitrogen until processing for indirect immunogold labeling, as described earlier …”

Biomarkers in Primary Focal Segmental Glomerulosclerosis in Optimal Diagnostic-Therapeutic Strategy

“…Studies about the role of DG in glomerulopathies are ambiguous. A decreased concentration of alpha and beta dystroglycan has been described in patients with MCD in comparison with the normal level in cases with FSGS [ 44 ]. The expression of β-chain DG in the podocytes did not differ in MCD and FSGS and, moreover, the presence of β-chain DG in podocytes did not influence the steroid sensitivity [ 45 ].…”

“…The expression of β-chain DG in the podocytes did not differ in MCD and FSGS and, moreover, the presence of β-chain DG in podocytes did not influence the steroid sensitivity [ 45 ]. On the other hand, Giannico et al observed increased DG expression in renal biopsies in patients with FSGS [ 44 , 109 ].…”