Steven B Miller Babu J Padanilam

The kidney possesses a remarkable capacity for restoring its structure and functional ability following an ischemic or toxic insult. It is unique as a solid organ in its ability to suffer an injury of such magnitude that the organ can fail for weeks and yet recover full function. Studying the natural regenerative process after an acute renal insult has provided new insights into the pathogenesis of acute renal failure (ARF) and possible new therapies. These therapies may limit the extent of injury or even accelerate the regenerative process and improve outcomes for patients suffering with ARF. In this chapter we illustrate some of the molecular responses of the kidney to an acute insult and demonstrate the effects of therapy with growth factors in the setting of experimental models of ARF. We conclude by demonstrating strategies that will provide future insights into the molecular response of the kidney to injury.

The regions of the nephron most susceptible to ischemic injury are the distal segment (S3) of the proximal tubule and the medullary thick ascending limb of the loop of Henle. Following injury, there is loss of the epithelial lining as epithelial cells lose their integrin-mediated attachment to basement membranes and are sloughed into the lumen. An intense regenerative process follows. Normally quiescent renal tubule cells increase their nucleic acid synthesis and undergo mitosis. It is theorized that surviving cells situated close to or within the denuded area dedifferentiate and enter mitotic cycles. These cells then redifferentiate until nephron segment integrity is restored. The molecular basis that regulates this process is poorly-understood. After an injury, there is a spectrum of cell damage that is dependent on the type and severity of the insult. If the intensity of the insult is limited, cells become dysfunctional but survive. More severe injury results in detachment of cells from the tubule basement membranes, resulting in necrosis. Still other cells have no apparent damage and may proliferate to reepithelialize the damaged nephron segments. Thus, several

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