The Pathology Lesion Patterns of Podocytopathies: How and why?

Abstract

Podocytopathies are a group of proteinuric glomerular disorders driven by primary podocyte injury that are associated with a set of lesion patterns observed on kidney biopsy, i.e., minimal changes, focal segmental glomerulosclerosis, diffuse mesangial sclerosis and collapsing glomerulopathy. These unspecific lesion patterns have long been considered as independent disease entities. By contrast, recent evidence from genetics and experimental studies demonstrated that they represent signs of repeated injury and repair attempts. These ongoing processes depend on the type, length, and severity of podocyte injury, as well as on the ability of parietal epithelial cells to drive repair. In this review, we discuss the main pathology patterns of podocytopathies with a focus on the cellular and molecular response of podocytes and parietal epithelial cells.

Keywords: collapsing glomerulopathy; diffuse mesangial sclerosis; focal segmental glomerulosclerosis; minimal change; minimal change disease; parietal epithelial cells; podocytopathies; renal progenitor.

FIGURE 1

Podocytopathies result from the equilibrium between the nature of injury and the glomerular capacity of repair. When podocyte injury does not determine net cell loss, no changes are present on light microscopy and only foot process effacement is detectable, as in minimal changes (MC). In a setting of fast podocyte loss in kids younger than 5 years old, massive attempt of repair takes place. Immature podocytes are generated and are visible as a halo of hypertrophic podocytes overlying capillary loops as in diffuse mesangial sclerosis (DMS). When severity or chronicity of podocyte injury overcomes the capacity of PECs to replace detached or loss podocytes, glomerular basement membrane denudation triggers an injury cascade. This results in the segmental solidification of the tuft with accumulation of extracellular matrix characteristic of focal segmental glomerulosclerosis (FSGS). Finally, if fast podocyte loss occurs in individuals where the regenerative capacity is inadequate, generation of new podocytes is hampered and proliferating progenitors accumulate in Bowman space in the form of pseudocrescents resulting in collapsing glomerulopathy (CG) (Hematoxylin and eosin stains, magnifications 40x. Bars= 50 μm). (Abbreviations: MC= minimal changes, DMS= diffuse mesangial sclerosis, FSGS= focal segmental glomerulosclerosis, CG= collapsing glomerulopathy, PEC= parietal epithelial cell, FPE= foot process effacement).

FIGURE 2

Podocytes are crucial for integrity of the filtration barrier. (A) Three-dimensional reconstruction of whole mouse glomeruli stained for nephrin upon optical tissue clearing by using confocal microscopy. The signal represents nephrin protein within the slit diaphragm. Z-series stacks were obtained from 80-μm kidney slices with images collected at 1 μ m intervals. On the left a representative glomerulus from a healthy mouse shows an intact filtration barrier. On the right a representative glomerulus from a mouse with secondary FSGS (obesity- related diabetic mouse, db/db mouse) shows large denudated areas with podocyte loss (asterisk) and foot process effacement (arrowhead). (B) Schematic drawing of representative podocytes, with their interdigitating foot processes, wrapped around a glomerular capillary loop. (C) Representative images of human podocyte foot processes by using STED-super resolution microscopy upon tissue clearing. Z-series stacks were obtained from 5-μm kidney slices. The green signal represents nephrin protein. On the left a representative image of a normal human kidney obtained from a patient who underwent nephrectomy for localized renal tumor. On the right a representative image of a kidney biopsy obtained from a patient with secondary FSGS, showing denudated areas with podocyte loss (asterisk) and foot process effacement (arrowhead) (Bars= 20 μm).

FIGURE 3

Progenitor cells generate novel podocytes during postnatal kidney growth. (A) The kidney is composed of functional units, nephrons, each of which is made of a glomerulus and a tubule. The glomerulus is composed of a tuft of capillaries covered by visceral epithelial cells, the podocytes, and surrounded by the Bowman capsule lined on the inner surface by flat epithelial cells, parietal epithelial cells (PEC). A subpopulation of PEC localized at the urinary pole is endowed with progenitor characteristics and progressively differentiate into podocytes toward the vascular pole of the glomerulus. This occurs as the kidney grows, during childhood and adolescence in mouse models and in humans. In (B,C) representative glomeruli from transgenic Pax2.rtTA;TetO.Cre;R26.Confetti mice, an established mouse model of renal progenitor cell lineage tracing. In this model, green, yellow, cyan or red fluorescent protein is randomly expressed by Pax2- expressing cells. Pax2 is expressed by PEC progenitor cells during kidney development but is lost upon their differentiation into mature podocytes in the post-natal kidney (magnification 63x). In (B) a representative glomerulus of Pax2.rtTA;TetO.Cre;R26.Confetti mouse, induced at postnatal day P5 (when the generation of new glomeruli from the metanephric mesenchyme has already ended) for 10 days and tracked until 5 weeks of age. Fluorescent Pax2+ cells are present in the parietal epithelium of the Bowman capsule as well as inside the glomerulus. These intraglomerular Pax2-derived cells expressed synaptopodin (cyan), demonstrating their podocyte nature. In (C) a representative glomerulus of a Pax2.rtTA;TetO.Cre;R26.Confetti adult mouse induced at 5 weeks of age for 10 days, showing Pax2+ cells only in Bowman capsule. Podocytes are not labeled. (D,E) In humans, the observation that the number of podocytes increases during glomerular growth and maturation in the early years after birth, suggest the involvement of a podocyte progenitor pool during postnatal kidney growth. In D a glomerulus of a 4 years old normal human kidney and in E a glomerulus of a 25 years old normal human kidney from two patients who underwent nephrectomy for localized renal tumor (Hematoxylin and eosin stain, magnification 40 x. Bars= 20 μm in B and C, bars= 50 μm in D and E).