Alberto Ortiz, Silvia González Cuadrado, Corina Lorz, Jesús Egido.

Division of Nephrology. Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.

Received 12/01/95; Accepted 01/26/96; On-line 03/01/96

5. PERSPECTIVES FOR MODULATION OF APOPTOSIS IN THE THERAPY OF RENAL DISEASES

Understanding the role and regulation of apoptosis in renal disease may improve our knowledge of the mode of action of current therapies, and it may also provide the basis for the design of new therapeutic strategies. These newer therapies may include drugs that interfere with apoptosis, antisense strategies, local delivery of protective genes, and antagonism of cytokines or lipid mediators. Although the precise timing and potential cellular and genetic targets of apoptosis modulatory therapies remain to be defined, evidence is accumulating that it may be beneficial to interfere with apoptosis in renal disease. In this sense, two of the most widely used drugs for the therapy of renal transplant recipients and patients with glomerulonephritis, corticosteroids and cyclosporine A, promote lymphocyte apoptosis (36,125).

Among the cellular targets, we might be interested in prolonging parenchymal cell survival in chronic renal atrophy. Identification of the survival signals for leukocytes may help to selectively manipulate their survival without a deleterious effect on renal cells, in order to resolve inflammation. Identification of cell-specific promoters may facilitate targeting of genes that promote apoptosis to fibroblasts to treat renal fibrosis (198).

Tools employed to influence apoptosis may include cytokines and cytokine antagonists, which have already been used in experimental renal disease. Therapy with EGF improves the evolution of experimental acute renal failure and decreases internucleosomal DNA degradation (199,200). The administration of IGF-I to Bcl-2+/- pregnant mice resulted in a 49% increase in the weight of kidneys of Bcl-2-/- offsprings (193). This may be a basis for intrauterine therapy of renal dysplasia. Antagonism of TNF-alpha improves the evolution of experimental models of acute renal failure and several glomerulonephritis (reviewed in 164). Antagonism of TGF-ß1 has also been shown to be protective (201). Although both cytokines may induce apoptosis, the contribution of apoptosis blockage to the therapeutic effect of their antagonists has not been addressed.

Extracellular matrix-cell interactions might also be targeted in the therapy of renal diseases. In cancer therapy blockage of integrin receptors leads to apoptosis of new vessels and subsequent tumor regression (202). In nephrology it is unclear the possible relationship between the beneficial effect of therapies involving extracellular matrix components such as fibronectin (138) with their ability to interfere with apoptosis.

Specific targeting of proteins carrying the death domain, Bcl-2 like proteins and apoptosis proteases may also be of value in the therapy of renal diseases.

Another approach is to improve disposal of the apoptotic cells, preventing their lysis. For example, CD36 gene transfer confers the capacity to cells to ingest apoptotic cells if the vitronectin receptor is also expressed and thrombospondin is available (203).