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The Effect of Acute Ischemic Renal Failure and Ischemic Preconditioning on Renal Recruitment of Endothelial Progenitor Cells and Signaling Pathways Involved

Chapter 5 Discussion

Acute ischemic kidney injury is the most frequent cause of acute renal failure in daily clinical practice . Despite the significant progress that has been made in the fields of intensive care medicine and renal replacement therapy over the past 30 years, the mortality of acute renal failure in hospitalized patients still varies from 30 to 70% . Although hypoperfusion of the kidney, resulting from various pathologic conditions, primarily affects the function and structure of tubular epithelial cells, it has become increasingly recognized that microvascular endothelial cell dysfunction (ED) in peritubular capillaries inhibits the process of postischemic renal reperfusion and thereby prolongs kidney malfunction .

First studies came from Flores et al. : rats that underwent transient renal artery clamping showed intense swelling of all cellular elements in the kidney, leading to persistent renal hypoperfusion after the end of ischemia. Such no-reflow, which was in part also attributable to endothelial cell swelling, could effectively be treated by the injection of hypertonic mannitol solution, but remained unaffected by an equivalent expansion of the extracellular fluid volume with either isotonic saline or isotonic mannitol .

Further studies, published in 2001, showed that ischemia associated endothelial cell dysfunction in addition can result in permanent damage to peritubular capillaries. This damage worsens long-term outcome of kidney function . These data suggested that postischemic renal ED could potentially serve as new therapeutic target in the management of acute ischemic kidney injury. Therefore, newer investigations performed by Yamamoto and Brodsky focused on the treatment of postischemic ED by the administration of mature endothelial cells (HUVECs—human umbilical vein endothelial cells). In vivo microscopic analyses confirmed the aforementioned significant postischemic endothelial cell swelling within the peritubular capillary network, and in addition showed that complete normalization of microvascular tissue perfusion occurs as late as 24 hours after ischemia. In this setting, systemic administration of HUVECs markedly inhibited endothelial cell swelling and promoted a faster functional and structural recovery of the organ. Histologically, injected cells had partly been incorporated into the endothelial layer of small blood vessels surrounding the tubular integrity . These studies showed for the first time that targeting postischemic ED by the administration of cells of the endothelial lineage is a true option in the treatment of acute ischemic kidney injury.`

The present study showed that genistein, a tyrosine kinase inhibitor, also worsened the I/R injury not related to EPO (Group IV). The direct negative effects of genistein on I/R may be explained by the role of tyrosine kinase on self-responses of the cells to ischemia. Likewise, the protective effects of ischemic preconditioning, described as the protection of a short transient period of ischemia and reperfusion against a more prolonged ischemic episode, is also tyrosine kinase-dependent.

Successful ischemic preconditioning models have been shown in the heart, liver, brain and kidney. However, recent data indicate that the tyrosine kinase intracellular signalling pathway is involved in the beneficial roles ...
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