Podocyte-Parietal Epithelial Cell Interdependence in Glomerular Development and Disease

Abstract

Podocytes and parietal epithelial cells (PECs) are among the few principal cell types within the kidney glomerulus, the former serving as a crucial constituent of the kidney filtration barrier and the latter representing a supporting epithelial layer that adorns the inner wall of Bowman's capsule. Podocytes and PECs share a circumscript developmental lineage that only begins to diverge during the S-shaped body stage of nephron formation-occurring immediately before the emergence of the fully mature nephron. These two cell types, therefore, share a highly conserved gene expression program, evidenced by recently discovered intermediate cell types occupying a distinct spatiotemporal gene expression zone between podocytes and PECs. In addition to their homeostatic functions, podocytes and PECs also have roles in kidney pathogenesis. Rapid podocyte loss in diseases, such as rapidly progressive GN and collapsing and cellular subtypes of FSGS, is closely allied with PEC proliferation and migration toward the capillary tuft, resulting in the formation of crescents and pseudocrescents. PECs are thought to contribute to disease progression and severity, and the interdependence between these two cell types during development and in various manifestations of kidney pathology is the primary focus of this review.

Figure 1

Specific transitions during stages of kidney development leading to podocyte and PEC differentiation. The molecular crosstalk between the UB and cap mesenchyme is coordinated by Pax2 and Osr1 expression, respectively. This initial stage of kidney formation gives way to two stages–formation of the pretubular aggregate which subsequently coalesces into the appearance of the renal vesicles. Both of these steps represent a window in kidney glomerular development characterized by wholesale METs. The comma-shaped body then forms at the lateral edges of what was previously the cap mesenchyme, with Notch signaling driving predominantly glomerular fate via this structure. The S-shaped body stage which appears next in orderly developmental timing finally sees the molecular and functional divergence of podocyte and PEC fates, with the former working to erect a mature GBM and the latter upregulating Wnt signaling to ensure proper final positioning on the inner wall of Bowman's capsule. The S-shaped body stage, therefore, progresses into the formation of individual, fully mature, nephron segments.

Figure 2

Divergence and spatial reorganization of PECs and podocytes across the comma-shaped/S-shaped stage boundaries of kidney development. During the early stages of comma-shaped periods of kidney development, podocytes and PECs begin to acquire their respective fates, through the podocyte-specific upregulation of (1) WT1, (2) nephrin, and (3) podocin–and the PEC-specific increase in claudin-1 and Pax2. During the transition from the late comma-shaped body stage to the S-shaped body stage, PECs reorient themselves around an early version of Bowman's capsule, thereby assuming a more fully developed glomerular posture.

Figure 3

Graphic of healthy versus injured glomerulus, implicating specific pathways in kidney disease development. On the left the healthy glomerulus displays physiological proportions of the four key glomerular cell-types: (1) PECs, (2) podocytes, (3) endothelial cells, and (4) mesangial cells. The graphic on the right displays the progression of PEC activation, specifically in terms of an increased proliferative state, where overlapping cascades of cells grow toward the glomerular tuft–forming crescents and pseudocrescents, depending on the patient's specific disease course. A number of pathways have been shown to participate in this process of PEC activation, including but not limited to: (1) Notch, (2) Mif/Cd74, (3) Cd44, (4) EGFR, (5) MCP-1/CCR2, (6) JAK/STAT, (7) SDF-1/CXCR4, (8) AngII/AT1, (9) Cd74, and (10) Cd9. These disease initiating/modifying factors are described at length, in earlier individual subheading on kidney pathophysiology. JAK/STAT, Janus kinase/signal transducer and activator of transcription; MCP-1, monocyte chemoattractant protein-1.