Mammalian kidney development: principles, progress, and projections

Abstract

The mammalian kidney is a vital organ with considerable cellular complexity and functional diversity. Kidney development is notable for requiring distinct but coincident tubulogenic processes involving reciprocal inductive signals between mesenchymal and epithelial progenitor compartments. Key molecular pathways mediating these interactions have been identified. Further, advances in the analysis of gene expression and gene activity, coupled with a detailed knowledge of cell origins, are enhancing our understanding of kidney morphogenesis and unraveling the normal processes of postnatal repair and identifying disease-causing mechanisms. This article focuses on recent insights into central regulatory processes governing organ assembly and renal disease, and predicts future directions for the field.

Figure 1.

Lineage relationships within the developing mammalian metanephros. The metanephros arises from the intermediate mesoderm, which gives rise to the nephric duct and the metanephric mesenchyme. The former gives rise to the cells of the collecting duct system, whereas the latter gives rise both to the epithelial components of the nephrons (excluding collecting duct) as well as stromal and vascular elements. Key marker genes for compartments are indicated in gray ovals.

Figure 2.

An overview of the major signaling pathways involved in ureteric epithelial branching. The diagram represents an epithelial cell at the tip of the ureteric epithelium (Utip) and an adjacent cap mesenchyme (CapM) cell. Growth factors (glial-derived neurotrophic factor [Gdnf], vascular endothelial growth factors [Vegfa], hepatocyte growth factor [Hgf], fibroblast growth factor 10 [Fgf10], epidermal growth factor [Egf], angiotensin I/II, formed via rennin cleavage of angiotensinogen [Agt]) from the adjacent cells bind to a variety of receptor-tyrosine kinases (Ret/Gfrα1, Kdr, Met, Fgfr2, Egfr, and Agtr1/2, respectively) on the surface of the Utip cell triggering signaling cascades that regulate cell proliferation, migration, and extracellular matrix (ECM) degradation. The combined actions of these signaling pathways is continued branching and elongation of the ureteric epithelium to form the collecting duct system. Target genes known to be induced via such signaling are indicated.

Figure 3.

A model of the nephrogenic niche. The key cellular compartments within the nephrogenic niche at the periphery of the developing kidney include the ureteric tip (Utip), cap mesenchyme (CapM), ureteric trunk (Utrunk), capsule, interstitium, and the forming nephrons (pretubular aggregates–renal vesicles [PA-RV]). Each compartment has a characteristic spatial arrangement in the embryonic kidney. Indicated within each compartment are the cellular activities occurring. Loss of CapM identity occurs when Smad4 is selectively removed from CapM (Bmp7Cre) (Oxburgh et al. 2004). Large arrows indicate the presence of signals between compartments to control development. Key marker genes for the compartments are indicated in gray text with small arrows indicating the compartment being influenced.

Figure 4.

Cessation of nephrogenesis. Two models can be envisaged to explain cessation of nephrogenesis in the immediate postnatal period. (A) Symmetric division of a homogeneous progenitor population with an active trigger at birth to induce differentiation, and hence loss, of the progenitor population around birth. (B) A stem/progenitor subpopulation (red) within the cap mesenchyme that divides asymmetrically to self-renew and form more committed daughter cell populations (orange). This stem/progenitor population is distributed between the newly arising tips. This results in a gradual exhaustion of the stem/progenitor until they are lost. (C,D) Coimmunofluroescence for dividing cells within the forming nephrons (Ccnd1; magenta), basement membrane (collagen IV [ColIV]; green) and nuclei (DAPI, blue) of kidney sections at E15.5 (C) and postnatal day 2 (P2) (D) illustrating the loss of cap mesenchyme and change in spatial relationships during cessation of nephrogenesis. Note: Isolated bright red dots in D (*) represent red blood cells in the forming vasculature. Ureteric bud (UB), renal vesicle (RV), comma-shaped body (CSB), S-shaped body (SSB). Dotted line illustrates the edge of the kidney.

Figure 5.

Inverse relationship between Wt1 and E-cadherin (Cdh1) during nephron segmentation. (A) Outline of the relationship between the level and location of Wt1 protein and the likely role of this protein during kidney development. (B) Coimmunofluorescence of E15.5 kidney illustrating the location of Wt1 (red) and E-cadherin (green) proteins during nephron formation and patterning. Cap mesenchyme (CM); renal vesicle (RV); pretubular aggregate (PA); comma-shaped body (CSB); S-shaped body (SSB). The ureteric epithelium expresses E-cadherin, whereas the surrounding Wt1⁺ CM does not. Nephron formation, which involves a mesenchyme-to-epithelial transition, it not uniform in that E-cadherin is not seen in the Wt1⁺ proximal segments of the RV, CSB, or SSB. These regions form the parietal and visceral (podocyte) epithelia of the glomerulus. Mesenchyme-to-epithelial transition (MET); epithelial to mesenchymal transition (EMT); metanephric mesenchyme (MM); mesonephric mesenchyme (mesoM); cap mesenchyme (CM); mesenchyme (M).