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The resistance of the immature kidney to ischemic injury is well documented, but the mechanisms involved in this tolerance have been elusive. Previous studies have demonstrated that tubules obtained from immature rats exhibit a bigger stress response than mature tubules. Consequently, we evaluated the developmental expression of HSP-72 in the postnatal kidney and determined whether or not that pattern of expression was correlated with the previously known tolerance of the immature kidney to injury. A distinct pattern of HSP-72 expression with a peak abundance at postnatal day 10 (P10), with a subsequent decline toward values seen in mature rats, was found. Moreover, this stress protein is located predominantly in tubular segments, the site of ischemic injury. To determine if this constitutive, non-induced expression of HSP-72 in the immature rat could be protective of cellular integrity and renal function, both immature (P10) and mature (8 weeks) rats were subjected to 45 min of bilateral renal artery ischemia. The postischemic induction of HSP-72 in the P10 animals was robust and the peak expression 2 h after ischemia was even greater than that detected in mature animals. Thus, the constitutive enhanced expression of HSP-72 did not prohibit or mute the inducible response of this stress protein in the immature animals. Immature animals, when compared with mature rats, also experienced cytoprotection, demonstrated by decreased detachment of Na-/K-ATPase from the cytoskeleton and substantial protection of renal function determined by serum creatinine level. These findings suggest that the developmental expression of heat shock proteins may play a critical and fundamental role in the well-observed tolerance of immature tubules to ischemic or anoxic injury.

The tolerance of immature tissues to injury has been noted over the past several decades. Traditional teaching relates this tolerance to energy derived from anaerobic glycolysis. This mini-review describes investigations of the hypothesis that the immature kidney is less susceptible to oxygen deprivation than the mature kidney. Utilizing proximal tubule suspensions from immature and mature rats, studies assessing ATP levels as an index of cellular energy and lactate dehydrogenase (LDH) release as a determinant of plasma membrane damage demonstrate the developing kidney is resistant to prolonged anoxia. ATP is maintained at twofold higher levels during anoxia in the immature tubule compared with the mature tubule. The contribution of anaerobic glycolysis to the tolerance of the immature renal tubules is investigated by two inhibitors of the glycolytic pathway, L-glucose and iodoacetate. Following 70%-90% inhibition of glycolysis, ATP is decreased to similar levels in immature and mature tubules. However, immature tubules remain resistant to anoxic damage with no significant change in LDH release. Therefore, enhanced glycolytic activity does not play a dominant role in the tolerance of the developing kidney to anoxia, and this tolerance is not primarily dependent on preservation of cellular ATP.

In order to elucidate the pattern of redistribution of cellular energy and the restoration of basic cellular metabolism following an ischemic renal insult, suspensions enriched in proximal tubule segments were studied after 45 min of bilateral artery occlusion and 15 min and 2 h of reflow from rats given either normal saline (control), ATP-MgCl2 (which enhances postischemic recovery of ATP), or alpha, beta-methyl adenosine diphosphate (AMPCP), which inhibits nucleotide degradation during ischemia. In non-ischemic control animals, approximately half of the energy is distributed to functional pump activity and half directed for non-transport purposes. When cellular ATP is reduced to 56% of control values, functional pump activity is significantly reduced to 61% of control, while energy delegated for non-transport purposes is decreased by a significantly smaller increment to only 78% of control at 15 min of reflow. In animals given ATP-MgCl2, the cellular and metabolic profile at 15 min of reflow was no different from ischemic control animals with cellular ATP levels similar at 58%. However, by 2 h, cellular ATP levels had increased significantly to 74%, and this was associated with a redistribution of cellular energy to functional pump activity (119% of control) with little change in non-transport function (76%). In animals treated with AMPCP, the cellular ATP levels were 74% of controls, similar to ATP-MgCl2-treated rats after 2 h of reflow. Despite the differences in reflow interval, the distribution of cellular energy was similar (functional pump activity 120% and non-transport activity 79%). By 2 h, cellular ATP was at 95% and both functional pump activity and non-transport activity were 100%.(ABSTRACT TRUNCATED AT 250 WORDS)

To evaluate the effect of thyroxin (T4) on recovery from ischemic acute renal failure, rats were treated with T4 (10 or 20 micrograms/100 g body wt.) or normal saline (NS) either immediately prior to, immediately after or 24 h after 45 min of renal ischemia. Animals given T4 prior to ischemia had no significant increase in Inulin clearance (Cin) (377 +/- 40 microliters/min per 100 g body wt.) as compared with saline-treated ischemic controls (306 +/- 54). In contrast, animals treated immediately after ischemia with either dose of T4 demonstrated significantly better kidney function (Cin 515 +/- 59 microliters/min per 100 g body wt., Uosm 842 +/- 88 mosmol/kg, FENa 0.52% +/- 0.12% and Cin 543 +/- 71, Uosm 939 +/- 103, FENa 0.48 +/- 0.12, for 10 and 20 micrograms/100 g body wt., respectively). Moreover, the improvement in renal function was sustained and Cin was significantly better at day 3 (748 +/- 70) and day 7 (990 +/- 75) compared with saline controls (560 +/- 30 and 732 +/- 45, respectively). Animals which received T4 24 h after ischemia showed significantly higher Cin when compared with ischemic controls. To assess the impact of T4 on recovery of renal ATP, 31P-NMR was used. T4-treated rats demonstrated 90% +/- 5% recovery of renal ATP by 120 min of reflow, whereas NS animals had only 64% +/- 1%. In addition, cellular morphology was better preserved in T4 animals. These data indicate that animals treated postischemically with T4 showed accelerated and sustained recovery from acute renal failure. This beneficial effect appears to be related to cellular mechanisms which are essential for the restoration of sublethally injured cells.