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Obstructive nephropathy: towards biomarker discovery and gene therapy

Nature Clinical Practice Nephrology volume 2, pages 157–168 (2006)Cite this article

Abstract

Obstructive nephropathy is a major cause of renal failure, particularly in infants and children. Cellular and molecular mechanisms responsible for the progression of the tubular atrophy and interstitial fibrosis—processes that lead to nephron loss—have been elucidated in the past 5 years. Following urinary tract obstruction and tubular dilatation, a cascade of events results in upregulation of the intrarenal renin–angiotensin system, tubular apoptosis and macrophage infiltration of the interstitium. This is followed by accumulation of interstitial fibroblasts through proliferation of resident fibroblasts and epithelial–mesenchymal transformation of renal tubular cells. Under the influence of cytokines, chemokines and other signaling molecules produced by tubular and interstitial cells, fibroblasts undergo transformation to myofibroblasts that induce expansion of the extracellular matrix. The cellular interactions that regulate development of interstitial inflammation, tubular apoptosis and interstitial fibrosis are complex. Changes in renal gene expression and protein production afford many potential biomarkers of disease progression and targets for therapeutic manipulation. These include signaling molecules and receptors involved in macrophage recruitment and proliferation, tubular death signals and survival factors, and modulators of epithelial–mesenchymal transformation. Targeted gene deletion and various forms of gene therapy have been used in experimental obstructive nephropathy, mostly rodent models of unilateral ureteral obstruction or cell culture techniques. Further refinement of these models is needed to develop a matrix of biomarkers with clinical predictive value, as well as molecular therapies that will prevent or reverse the renal structural and functional consequences of obstructive nephropathy.

Key Points

  • A leading cause of chronic renal failure in children, obstructive nephropathy is characterized by inflammation, tubular atrophy and interstitial fibrosis

  • Research using rodent models in the past 5 years has shed new light on the molecular mechanisms underlying these processes

  • Current biomarkers in congenital obstructive nephropathy are urine levels of tumor-necrosis factor-α, transforming growth factor-β, monocyte chemoattractant protein-1 and epidermal growth factor

  • Potential new biomarkers of disease progression and therapeutic targets include molecules involved in macrophage recruitment and proliferation, tubular death and survival, and epithelial–mesenchymal transformation

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Figure 1: Light micrographs illustrating renal cellular responses to complete unilateral ureteral obstruction (UUO) in the neonatal mouse.
Figure 2: Renal cellular interactions in the evolution of obstructive nephropathy.
Figure 3: Pathogenesis of renal interstitial inflammation in obstructive nephropathy.
Figure 4: Pathogenesis of renal tubular apoptosis in obstructive nephropathy.
Figure 5: Pathogenesis of renal fibrosis in obstructive nephropathy.

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Acknowledgements

The author's studies are supported by grants from the National Institutes of Health: DK52612, DK45179, and DK62328. Photomicrographs (Figure 1) were produced by Michael S Forbes.

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  1. Chair of the Department of Pediatrics at the University of Virginia, Charlottesville, VA, USA

    Robert L Chevalier

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Chevalier, R. Obstructive nephropathy: towards biomarker discovery and gene therapy. Nat Rev Nephrol 2, 157–168 (2006). https://doi.org/10.1038/ncpneph0098

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