CLUSTERIN EXPRESSION AND APOPTOSIS IN TISSUE REMODELING ASSOCIATED WITH RENAL REGENERATION

To analyze the role of clusterin in renal diseases involving a regener ative process, we have used a novel rodent model to compare temporal a nd spatial expression of clusterin mRNA. Thus, renal artery stenosis w as used to induce unilateral non-infarctive renal atrophy. After sever al weeks, when cellular pathology of atrophic kidneys involved minimal apoptosis or inflammatory response and mitosis was at normal levels, regeneration of atrophic kidneys was stimulated by removal of the cont ralateral healthy kidneys. The regrowth response was very rapid and in volved renal hyperplasia rather than hypertrophy. Regenerating kidneys were studied 0, 4, 8, 24 hours and 2, 3, 5, 7, and 14 days after cont ralateral nephrectomy. Several parameters were compared: level and loc alization of clusterin mRNA; cell proliferation; cell dedifferentiatio n and redifferentiation; and apoptosis. During the acute regenerative phase (first 24 hr) clusterin expression was markedly increased, decre asing to untraceable levels by five days of regeneration. Clusterin mR NA was localized in dilated or collapsed atrophic tubules that had los t identifying surface structures of normal tubular epithelium (termed dedifferentiated). Clusterin was also localized in the periphery of so me blood vessel walls. Cell proliferation peaked at three to five days of regeneration, and was also localized in dedifferentiated tubules. Despite the regenerative stimulus, an unexpected result was a transien t but marked increase in apoptotic cell death in atrophic tubules in t he first 24 hours of regeneration. Our results provide evidence of a t emporal association between increased clusterin expression and apoptos is, but in situ localization showed clusterin mRNA over apparently via ble, as well as apoptotic, cells in the epithelium of tubules showing clusterin expression. Clusterin mRNA was rarely identified over epithe lial cells in foci of non-atrophic (non-dedifferentiated) nephrons tha t responded to the regenerative stimulus by cellular hypertrophy. The dramatic response after initiation of regeneration, especially the ini tiation of apoptosis in the tubular epithelium, may have applications for the study of genetic changes leading to renal oncogenesis.