Exposure of renal cells to a hostile environment initiates a complex molecular response including the activation of phosphorylation cascades and the expression of many genes. Many of these molecular responses are not confined to areas of regeneration and in fact are localized to nephron segments not undergoing obvious injury or repair. For example, a typical immediate early gene response (IEG), as indicated by c-fos and c-jun activation, occurs most prominently in areas not undergoing an increase in DNA synthesis. Because the sites of increased DNA synthesis are spatially separated from those of IEG expression and many of the responses, including the expression of chemokine genes, resemble the response observed in cells exposed to adverse environmental conditions such as ionizing radiation, oxidants, and hypertonicity, the expression of these genes under these circumstances has been termed the Stress Response. This response is thought to be a major determinant of whether cells survive the insult or not, and might be necessary for the repair of injured cells. Thus, the stress response may ultimately determine much of the proinflammatory, reparative, cytoreductive, and perhaps functional aspects of renal failure, as well as which cells survive the stress or not. Several elements in the stress pathway have been manipulated to effect whether cells survive a particular stress or not.
turn upregulates c-jun transcription via an AP-1 binding site. This pathway of activation is proliferative in nature. By contrast, oxidative stress and DNA damage, two stresses known to cause nephrotoxicity, increase c-fos and c-jun expression without provoking a proliferative response. The stress-associated expression of these genes is actually antiproliferative . Analysis of the activation of c-Jun under these circumstances has led to the discovery of unique stress-induced protein kinases termed SAPKs (stress activated protein kinases) . These kinases are comprised of the kinases JNK-1 and 2 (c-Jun N-terminal Kinase) and p38. Evidence to date suggests that the SAPKs are regulated by signal transduction paths separate from those that activate other MAPKs through distinct upstream regulators. JNK-1 and 2 have been shown to be the principal kinases responsible for c-Jun activation during oxi-dative stress and DNA damage while p38 seems to be the principal kinase activated by LPS and TNFa, all of which inhibit proliferation . This activation of c-Jun is antiproliferative in nature and can lead to either cell survival or to cell death.
Studies on the effect of ERK and JNK activation on cellular outcome have revealed that the consequence of this activation is cell type specific. While the activation of ERKs is often proliferative in nature, it may not always be so. For example, the induction of ERK by nerve growth factor in PC12 cells leads to terminal differentiation and exit from the cell cycle . In other cell types, the ability of the cell to survive an insult is often dependent on the balance between ERK and JNK
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