Podocyte Differentiation and Hereditary Proteinuria/Nephrotic Syndromes

Abstract

Abstract. The study of familial nephrotic syndromes (NS) and the analysis of murine models of glomerular diseases resulted in major progresses in the knowledge of podocyte physiology and pathology. Numerous proteins participating in the composition of the slit diaphragm region have been identified. The importance of several of them (nephrin, podocin, CD2AP, and Neph1) in the maintenance of the glomerular filtration barrier has been demonstrated by the occurrence of massive proteinuria when they are defective. The role of the cytoskeleton has been revealed by the development of proteinuria/NS in patients with ACTN4 mutation and the occurrence of early and severe NS in ␣-actinin-4 -deficient mice. Given the genetic heterogeneity of familial NS and the many other genes to be identified, further insights in the molecular basis of the role of the podocyte in the maintenance of the glomerular filtration barrier may be expected in the near future.

Increased Tubular Proliferation as an Adaptive Response to Glomerular Albuminuria

“…The rate of tubular proliferation was found to increase after day 5, peak on days 6-7, and return to baseline after day 8 ( Figure 4, B and C). This timing correlates closely with the onset (days [4][5] and resolution (day 8) of albuminuria seen with this dose of DT ( Figure 2D). Approximately 50% of the proliferating cells 1 week after partial podocyte ablation were in the proximal tubule based on co-staining with megalin, with the remaining proliferating cells found in the interstitial compartment, other tubular segments, and rarely in glomeruli (nonpodocytes) ( Figure 4C).…”

“…[1][2][3][4][5] This barrier can be compromised by injury to any of these cells, resulting in glomerular proteinuria that has in turn been associated with progressive renal dysfunction. Of these cells, podocyte damage is the most problematic because podocytes provide a critical component of the filtration barrier and seem to lack the ability to proliferate in response to cell loss.…”

Heparan Sulfate of Perlecan Is Involved in Glomerular Filtration

“…Further study will be necessary to understand the roles of perlecan core protein in the formation of the kidneys. Recent studies have revealed the important roles of slit diaphragms separating podocyte foot processes as filtration barriers (36,37,38). For instance, genes including NPHS-1 and NPHS-2, identified as responsible for nephrotic syndrome with the Mendelian hereditary trait, are expressed exclusively in slit diaphragms (39,40).…”

“…For instance, genes including NPHS-1 and NPHS-2, identified as responsible for nephrotic syndrome with the Mendelian hereditary trait, are expressed exclusively in slit diaphragms (39,40). Other genes, such as CD2AP, FAT, Neph-1, and MAG1-1, have been considered as proteinurina-associated genes (36). However, our findings clearly demonstrate a role for GBM HS in glomerular filtration and further suggest that HSPG2 may also be a candidate gene that provides a genetic background related to the susceptibility or progression of proteinuric diseases.…”

Ultrastructural Features and Expression of Cytoskeleton Proteins of Podocyte from Patients with Minimal Change Disease and Focal Segmental Glomerulosclerosis

“…[8][9][10] An alteration of the expression of these podocyte proteins in acquired NS was also reported. [11][12][13][14] Podocyte contains an elaborate and dynamic actin-based cytoskeleton that acts as a central organizer in maintaining the normal architecture of podocyte and interacting with other proteins and slit diaphragm.…”