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Modulation of renal cell injury by heat shock proteins: lessons learned from the immature kidney

Nature Clinical Practice Nephrology volume 2, pages 149–156 (2006)Cite this article

Abstract

The mechanisms that underlie tolerance to injury in immature animals and tissues have been a subject of interest since 1670. Observations in neonatal units that premature infants are less prone to develop acute renal failure than adults in critical care units have prompted a series of investigations. Although initially attributed to metabolic adaptation such as increased glycolytic capacity and preservation of high energy phosphate, more recent studies have indicated a prominent role for the heat shock response. Observed modulations of injury by heat shock proteins in the immature kidney have significant implications for advancement of our understanding of renal cell injury in both adults and children.

Key Points

  • The incidence of injury to the neonatal kidney, relative to the mature kidney, is lower than projected

  • In animal models, the heat shock response has a role in tolerance of the immature kidney to injury

  • Experimental inhibition of the heat shock response in immature renal tubules increases susceptibility to injury

  • 'Priming' the heat shock response of the mature kidney, either pharmacologically or via a preconditioning insult, confers protection against a subsequent injurious challenge

  • Profiling patient expression of genes involved in the heat shock response might identify those at greatest risk of acute kidney injury

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Figure 1: At steady-state, heat shock proteins (HSPs) are bound to heat shock transcription factor (HSF).
Figure 2: Developmental pattern of nuclear proteins stained for heat shock transcription factor (HSF; upper panel), and total homogenate stained for heat shock protein 70 (HSP70; lower panel) in rat kidney.
Figure 3: Addition of a heat shock transcription factor (HSF) decoy sharing homology with the heat shock transcription element to suspensions of rat renal tubules results in spontaneous uptake of decoy, diversion of trimerized HSF away from the nucleus, inhibition of activation of the heat shock transcription element, and reduction in heat shock protein messenger RNA and protein levels within the cell.
Figure 4: Effect of treatment with heat shock transcription factor (HSF) decoy on heat shock protein (HSP) expression and severity of rat renal tubular injury.
Figure 5: Tolerance to injury is high in immature rat tubules, and reversed by treatment with heat shock transcription factor (HSF) decoy.
Figure 6: Schematic representation of the effect of a preconditioning insult on the severity of a subsequent injury.
Figure 7: Independent overexpression (transfect) of either heat shock protein 70 (HSP70) or HSP27 substantially ameliorates detachment of Na+/K+-ATPase from the cytoskeleton in porcine proximal tubular cells subjected to 2 h of injury (as ATP depletion) followed by 4 h of recovery in normal culture media.
Figure 8: The relationship between abundance of heat shock proteins, and changes in cell polarity and integrity as a consequence of injury.

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Acknowledgements

We would like to thank the large number of colleagues and collaborators who have contributed to the studies from our laboratory that are reviewed here. We appreciate funding from the NIH (PO1-HD-32573 and PO1-DK-17433), National Kidney Foundation, American Heart Association and the Eden Fellowship (Royal College of Physicians, London).

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Authors and Affiliations

  1. Associate Research Scientist,

    Michael Riordan

  2. Senior Fellow,

    Rajasree Sreedharan

  3. Professor and Chief, all in the Division of Pediatric Nephrology at Yale University School of Medicine, New Haven, CT, USA

    Norman J Siegel

  4. Professor of Pathology, and Molecular Cellular and Developmental Biology at Yale University School of Medicine, New Haven, CT, USA

    Michael Kashgarian

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  1. Michael Riordan
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  2. Rajasree Sreedharan
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  3. Michael Kashgarian
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  4. Norman J Siegel
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Corresponding author

Correspondence to Norman J Siegel.

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Riordan, M., Sreedharan, R., Kashgarian, M. et al. Modulation of renal cell injury by heat shock proteins: lessons learned from the immature kidney. Nat Rev Nephrol 2, 149–156 (2006). https://doi.org/10.1038/ncpneph0117

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