OBSTRUCTION OF PROXIMAL TUBULES INITIATES CYTORESISTANCE AGAINST HYPOXIC DAMAGE

Following acute tubular necrosis (ATN), cytoresistance to further rena l injury results. However, the initiating events and the subcellular d eterminants of this phenomenon have not been defined. Since tubular ob struction is a consequence of ATN, this study evaluated whether it alt ers tubular susceptibility to hypoxic damage. Extrarenal obstruction ( ureteral ligation in rats) was used for this purpose to dissociate obs tructive effects from those of ATN. Twenty-four hours following ureter al ligation or sham surgery, cortical proximal tubular segments (PTS) were isolated and subjected to hypoxic (15 or 30 min)/reoxygenation in jury. Since oxidant stress, cell Ca2+ overload, and PLA(2) attack are purported mediators of hypoxic/reoxygenation injury, degrees of FeSO4, Ca2+ ionophore, and phospholipase A(2)-induced PTS damage also were a ssessed. The cell injury (% LDH release) which resulted from each of t he above was consistently less in PTS obtained from obstructed kidneys . This cytoresistance: (a) did not require prior uremia to develop (se en with unilateral obstruction); (b) it did not appear to correlate wi th a tubular proliferative response (assessed by proliferating cell nu clear antigen expression); (c) it was uninfluenced by early tubular re pair (unchanged by 24 hrs of obstruction release); and (d) it occurred without increased heat shock protein (HSP-70) or antioxidant enzyme ( superoxide dismutase, catalase) expression. Total adenylate pools were higher in obstructed versus control PTS during injury; however, this appeared to be a correlate of the protection, rather than a mediator o f it. In contrast, obstructed tubules manifested a primary increase in plasma membrane resistance to PLA(2) attack (similar to 3-fold less l ysophosphatidylcholine and free fatty acid generation in obstructed vs . control PTS during incubation with exogenous PLA(2)). In sum, these results indicate that: (1) tubular obstruction protects PTS from injur y, suggesting that its development during ATN may initiate cytoresista nce; and (2) this cytoresistance appears to be mediated, at least in p art, by a direct increase in plasma membrane resistance to PLA(2) and potentially other forms (such as, oxidant stress, cytosolic Ca2+ loadi ng) of attack.