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  • Review Article
  • Published:

Renal abnormalities and their developmental origin

Nature Reviews Genetics volume 8, pages 791–802 (2007)Cite this article

Key Points

  • The kidney is a central organ of the mammalian organism that, apart from blood filtration, is essential for the control of blood pressure and pH.

  • Congenital abnormalities of the kidneys and the urinary tract (CAKUT) are among the most frequent abnormalities in the newborn child, and often lead to renal failure in adult life.

  • Understanding kidney development is crucial to comprehending the molecular basis of CAKUT syndrome in humans, and to developing future therapeutic interventions, such as cell-replacement therapies and the growth of renal organs in vitro.

  • Central to the induction of the metanephros (permanent kidney) is the glial-derived neurotrophic factor (GDNF)–RET signalling pathway. Complex molecular networks tightly control GDNF expression, and restrict it to the presumptive metanephric mesenchyme to ensure outgrowth of a single ureter.

  • A molecular cascade including WNT–β-catenin signalling induces nephron formation in the metanephric mesenchyme surrounding the ureter.

  • Patterning of the nephron along the proximal–distal axis is controlled by transcription factors such as the Wilms tumour transcription factor (WT1) and Iroquois-class homeodomain proteins (IRX3), as well as signalling pathways such as the Notch–Delta pathway.

  • Wilms tumours are developmental tumours that can be caused by mutations in WT1 or WTX. New evidence suggests that the formation of Wilms tumours is tightly linked to abnormal β-catenin signalling.

  • The complex development of the kidney is achieved through multifunctional proteins and the combinatorial use of transcription factors to activate or repress genes in a specific cell type.

Abstract

Congenital abnormalities of the kidney and urinary tract (CAKUT) occur in 1 out of 500 newborns, and constitute approximately 20–30% of all anomalies identified in the prenatal period. CAKUT has a major role in renal failure, and there is increasing evidence that certain abnormalities predispose to the development of hypertension and cardiovascular disease in adult life. Moreover, defects in nephron formation can predispose to Wilms tumour, the most frequent solid tumour in children. To understand the basis of human renal diseases, it is essential to consider how the kidney develops.

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Figure 1: Overview of the various steps of kidney formation, and the developmental defects found in human patients.
Figure 2: Essential steps in kidney development.
Figure 3: Molecular pathways that control kidney induction.
Figure 4: Essential steps during nephron induction and patterning.
Figure 5: A model for Wilms tumour formation.

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Acknowledgements

I would like to thank A. Brändli for his valuable comments and for sharing unpublished data. I am also grateful to the members of my laboratory for critically reading this manuscript. The research group of A.S. is supported by grants from the FRM (Fondation pour la Recherche médicale) (France), the European Union (EuReGene, FP6) and the French National Research Agency (ANR, maladies rare).

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Authors and Affiliations

  1. INSERM, U636, Nice, F-06108, France

    Andreas Schedl

  2. Université de Nice-Sophia Antipolis, Laboratoire de Génétique du Développement Normal et Pathologique, Nice, F-06108, France

    Andreas Schedl

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DATABASES

OMIM

Axenfeld–Rieger syndrome

BOR syndrome

nail–patella syndrome

papillorenal syndrome

Wilms tumours

VUR

FURTHER INFORMATION

Andreas Schedl's homepage

EuReGene

Gene Paint

GenitoUrinary Development Molecular Anatomy Project

Kidney Development Database

MRC Mammalian Genetics Unit

National Kidney Foundation

Glossary

Nephron

The basic functional unit of the kidney, consisting of the glomerulus, proximal tubule, Henle's loop and distal tubule. Nephrons are connected to the ureter-derived collecting ducts.

Ciliary defects

The primary cilium is a microtubular organelle that appears to have an important function as a cellular mechanosensor. Multiple proteins that are disrupted in polycystic kidney disease seem to localize to the the primary cilium, suggesting that polycystic kidney disease (PKD) is the result of defects in this organelle.

Cortex

The outer portion of the kidney that contains the glomeruli and the proximal and distal tubules.

Medulla

The innermost part of the kidney, made up of the Henle's loops of the nephrons and blood vessels.

Primary hypertension

As opposed to secondary hypertension, primary (essential) hypertension is defined as high blood pressure for which no particular cause is known.

Glomerulus

The filtrating unit of the nephron that consists of vascular podocytes, endothelial and mesangial cells. Filtration occurs at the interface of fenestrated endothelial cells and glomerular foot processes through a specialized basement membrane. Also called the renal corpuscule.

Proximal tubule

A nephron segment located between the glomerulus and the Henle's loop and characterized by a brush-border that consists of densely packed microvilli. The proximal tubule is responsible for passive and active resorption of solutes from the pre-urine.

Henle's loop

The intermediate portion of the nephron (between the proximal and distal tubule) that functions in the resorption of water and ions from pre-urine.

Distal tubule

The last nephron segment located after Henle's loop and connected to the collecting ducts. The distal tubule has an important role in the regulation of pH and the salt concentrations of calcium, potassium and sodium.

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Schedl, A. Renal abnormalities and their developmental origin. Nat Rev Genet 8, 791–802 (2007). https://doi.org/10.1038/nrg2205

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