Molecular anatomy of the kidney: what have we learned from gene expression and functional genomics?

Abstract

The discipline of paediatric nephrology encompasses the congenital nephritic syndromes, renal dysplasias, neonatal renal tumours, early onset cystic disease, tubulopathies and vesicoureteric reflux, all of which arise due to defects in normal kidney development. Indeed, congenital anomalies of the kidney and urinary tract (CAKUT) represent 20-30% of prenatal anomalies, occurring in 1 in 500 births. Developmental biologists have studied the anatomical and morphogenetic processes involved in kidney development for the last five decades. However, with the advent of transgenic mice, the sequencing of the genome, improvements in mutation detection and the advent of functional genomics, our understanding of the molecular basis of kidney development has grown significantly. Here we discuss how the advent of new genetic and genomics approaches has added to our understanding of kidney development and paediatric renal disease, as well as identifying areas in which we are still lacking knowledge.

Fig. 1

Overview of mammalian metanephric development. a The kidney is initiated via reciprocal induction events between the epithelial ureteric bud (UB), which arises from the mesonephric duct, and the metanephric mesenchyme (MM), which condenses to form a cap mesenchyme (CM). b Around the advancing ureteric tips (UT), the CM is induced to form a pre-tubular aggregate (PA) which then undergoes a mesenchyme-to-epithelial transition to form a renal vesicle (RV) surrounded by a basement membrane. The formation of each RV represents the initiation of a single nephron. c The RV proliferates and elongates to form first a comma-shaped body (CB) and then an S-shaped body (SB). Vascular endothelial cells are drawn into the cleft at the proximal end of this structure to form the glomerular capillaries. The other end of the forming nephron fuses with the UT at the late RV stage [73]. d A single nephron in the mammalian kidney. e Continued patterning of the elongating uriniferous tubule results in segmentation into the various functional regions of the nephron, including the proximal tubule and the distal tubule with an intervening loop of Henle (LH). The recruitment of vasculature and mesangial cells into the proximal end of this tubule forms the renal corpuscle (RC). PCT Proximal convoluted tubule, PST proximal straight tubule, S1–3 segment 1–3, DCT distal convoluted tubule, DST distal straight tubule, CT connecting tubule, CCD cortical collecting duct, MCD medullary collecting duct

Fig. 2

Comparison of the segmental patterning of the developing excretory systems in the fly, zebrafish and Xenopus. a In the fly, there are two pairs of excretory tubules, the Malpighian tubules, which empty into the hindgut. These consist of blind-ended tubules containing nephrocytes. Hir Hindgut imaginal ring. b The zebrafish has a pair of nephrons that fuse to form a single central glomerulus. The pronephric tubules lead to pronephric ducts which empty into the cloaca. G Glomerulus, coS corpuscle of Stannius. c Xenopus contain a bilateral pair of nephrons where blood filtration occurs through a single glomus into the coelom, and filtrate enters the segmented nephron tubules via nephrostomes. Connecting tubules empty into the cloaca. G Glomus, c coelom, Ns nephrostome, PT1 proximal tubule 1, PT2 proximal tubule 2, PT3 proximal tubule 3, IT1 intermediate tubule 1, IT2 intermediate tubule 2, DT1 distal tubule 1, DT2 distal tubule 2, CT connecting tubule. Figure adapted from [74, 75] and [37] (used with permission)