Elsevier

Biochemical Pharmacology

Volume 66, Issue 8, 15 October 2003, Pages 1589-1594
Biochemical Pharmacology

Targeting apoptosis in acute tubular injury

https://doi.org/10.1016/S0006-2952(03)00515-XGet rights and content

Abstract

Recent research has shown that apoptosis and its regulatory mechanisms contribute to cell number regulation in acute renal failure. Acute tubular necrosis is the most frequent form of parenchymal acute renal failure. The main causes are ischemia–reperfusion, sepsis and nephrotoxic drugs. Exogenous factors such as nephrotoxic drugs and bacterial products, and endogenous factors such as lethal cytokines promote tubular cell apoptosis. Such diverse stimuli engage intracellular death pathways that in some cases are stimulus-specific. We now review the role of apoptosis in acute renal failure, the potential molecular targets of therapeutic intervention, the therapeutic weapons to modulate the activity of these targets and the few examples of therapeutic intervention on apoptosis.

Section snippets

Acute tubular injury

ARF is a syndrome characterized by an acute loss of renal function. ARF has an incidence of 208 per million population in Europe [1]. Acute tubular necrosis is the most common form of ARF of renal origin. The treatment of acute tubular necrosis is symptomatic and consists in substitution of renal function by dialysis if renal failure is severe. There is no established therapy to accelerate the recovery and attempts at preventing ARF are not universally effective. Despite the reversibility of

Apoptosis

Apoptosis is an active mode of cell death (cell suicide) under molecular control [11], [12], [13], [14]. Indeed, apoptosis is defined by the requirement of energy for cell death to proceed. However, the distinction between different forms of cell death is not always clear-cut. Hence, from a therapeutic point of view, we are interested in any form of cell death that can be manipulated by maneuvers designed to interfere with the molecular pathways that regulate apoptosis.

Apoptosis is tightly

Overview of the molecular regulation of apoptosis

Cell death is usually a response to the cell microenvironment. The absence of certain factors (survival factors) or the presence of lethal factors promotes apoptosis. Surrounding cells, soluble mediators and the extracellular matrix regulate cell death and survival. Surrounding cells can synthesize survival or lethal factors or compete for such factors. A lethal cell microenvironment activates intracellular factors that promote apoptosis.

Regulation of apoptosis in renal tubular epithelium

Both endogenous mediators and exogenous toxins regulate survival and death in tubular epithelium and can contribute to cell death in ARF. Understanding the pathways for cell death engaged by these mediators may have an application in the therapeutic approach both to ARF or the chronic loss of tubular epithelium that characterizes chronic renal disease.

Targeting apoptosis

Current evidence suggests that apoptosis and its regulatory molecules contribute to the pathogenesis of ARF. From a therapeutic point of view we might be interested in prolonging parenchymal cell survival in the early phase of acute tubular injury, without interfering with the recovery of normal renal function.

The key to any successful therapeutic manipulation of apoptosis lies in limiting the interference to the cell type we want to manipulate and to a defined time period. Otherwise, we risk

Future research

At present there is evidence that apoptosis participates in ARF. Stimuli that induce renal tubular cell apoptosis in culture also induce renal injury in vivo, apoptosis has been observed during ARF, the expression and/or activity of apoptosis modulatory molecules changes in the course of ARF and caspase inhibition improved renal function in at least some experimental models of ARF. However, there is an incomplete understanding of the molecular regulation of apoptosis in renal cells. In

Acknowledgements

The author’s research has been financed by grants from FISSS 98/0637 and 01/0199, Comisión Interministerial de Ciencia y Tecnologı́a (SAF 97/0071), Fundación Conchita Rábago, Comunidad de Madrid (08.4/0007/1999 1, 08.2/0030/2000), Sociedad Española de Nefrologı́a, Instituto Reina Sofia de Investigaciones Nefrológicas.

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