Apoptosis in the mammalian kidney: incidence, effectors, and molecular control in normal development and disease states.
In the preceding sections we have emphasized the current status of our knowledge concerning the involvement of apoptosis in normal and abnormal renal developmental processes, in control of the adult kidney size and capacity, in the development of renal disease states and in renal oncogenesis. At several points, we noted that studies of apoptosis in the kidney and in renal cells lag behind those in other organ systems. Even with the rudimentary knowledge now available, however, it is apparent that apoptosis is an extremely important process in the kidney. Recent observations lend credence to the view that continued study of this unique cell death process might enable the generation of novel and more effective therapies to treat renal diseases and renal malignancies. We wish to highlight several areas that require particular attention. First, the relationship between blood supply and apoptosis in the kidney requires further investigation. Benign human renal diseases are common in our population; and we now know that most of these diseases are associated with abnormal rates of apoptosis. Although the initiating agents for the various renal diseases vary, there is good reason to believe that much of the apoptosis that occurs in these adult diseases is the end result of reduced renal blood flow initiated by the causative agent. Cytokines or other extrinsic agents that can reduce the apoptotic loss of renal cells under these conditions hold theoretical promise in treating these diseases. Second, there is an urgent need to define the endocrine, paracrine, or autocrine roles of cytokines in normal renal physiology and in the pathogenesis of various renal syndromes. As indicated above, elaboration of fibrous extracellular material by fibroblasts in the tubulointerstitial regions of the kidney appears to be part of the final common pathway leading to end-stage renal disease. It is important to understand how the function of these fibroblasts is controlled. Conversely, apoptosis of glomerular or renal tubular cells also appears to play a role in the development of many of these syndromes. There is already experimental and clinical evidence showing that IGF-1 and hepatocyte growth factor therapies can be useful in renal diseases [57, 58]. It remains to be determined how much of the usefulness of these cytokines is related to their ability to suppress apoptosis as opposed to their ability to promote true growth. Finally, the analysis of apoptotic regulation during renal oncogenesis is critical. Maligant renal cell cancers are difficult to detect in adults before their metastases cause symptoms; and by this late stage renal tumors are almost invariably fatal. The ability of these tumors to regress spontaneously indicates that most apoptotic pathways are retained in these cells, yet their disappointing response to chemotherapy indicates that we have much to learn about how to trigger these pathways. Hopefully a better understanding of the control of these pathways will lead to improved therapy for this devastating group of neoplasms.