Ischemic damage and repair in the rat proximal tubule: Differences among the S1, S2, and S3 segments

Abstract

Rats were subjected to 25 min of unilateral renal artery occlusion and were studied at 5, 15, and 30 min and at 1, 2, 4, 8, 16, 24, and 48 hr following ischemia. The patterns of epithelial injury and repair in proximal tubule (PT) segments S1, S2, and S3 were followed, and associated changes in renal function were determined. We found that S1 and S2 cells alike are only reversibly injured and recover completely to normalcy within 4 hr, whereas S3 cells selectively undergo progressive cell injury and death and are exfoliated into tubular lumina. The necrotic S3 cells are replaced by mitotic division of survivor cells 24 to 48 hr following the ischemic insult. In addition, there was selective damage within tubular cells. Wiithin 5 min of blood reflow following ischemia, the majority of brush border microvilli (MV) in all three PT segments underwent coalescence by membrane fusion and thus were interiorized into the cytoplasm of PT cells. A minority of MV fragmented and were shed into PT lumina, but nephron obstruction by shed membranes was only mild and transient, unlike in the 1-hr ischemia model. Loss of MV reached a maximum of 15 min. By 30 min, MV began to reappear; by 2 hr, large numbers of MV had been regenerated; and by 4 hr, S1 and S2 cells appeared normal. The regenerative process included the luminal repositioning of previously interiorized MV membrane. MV regeneration occurred in S3 segments also, but before the process was complete, the cells developed features of irreversible cellular injury. Glomerular filtration rate (GFR) was 22% of control at 30 min of reflow, rose progressively to 55% of normal by 7 to 8 hr, and was normal at 24 hr. Single nephron filtration rate (SNGFR) was not significantly different from normal throughout. Proximal tubular sodium reabsorption was depressed and urinary sodium excretion increased at 30 min and at 2 to 3 hr, i.e., at times when MV alterations were prominent, but both were normal by 7 to 8 hr when MV in S1 and S2 cells had been fully reconstituted. Our major conclusions are: 1) There is differential susceptibility by cell type to ischemic injury in rat PT. 2) A rapid brush border loss/regeneration cycle occurs after ischemic injury. 3) Intact brush border may be required for normal sodium reabsorption by PT. Reasons for the GFR/SNGFR discrepancy are unclear, but tubular malfunction may partly explain the phenomenon.

Bimodal Acute Effects of A1 Adenosine Receptor Activation on Na+/H+ Exchanger 3 in Opossum Kidney Cells

“…The PKC pathway is thought to play a more significant role in modulating NHE3 activity in certain pathophysiologic conditions (e.g., hypoxia, ischemia) in which local production of adenosine is high [for review, see (8)]. By inhibiting NHE3 in particular under these conditions, adenosine could help to improve the oxygen demand and so reinstate the balance of energy supply: demand especially in the S3 segment of the proximal tubule, which is the primary site of injury in renal ischemia (42,43).…”

Hematopoietic Stem Cells Contribute to the Regeneration of Renal Tubules after Renal Ischemia-Reperfusion Injury in Mice

“…I/R injury is characterized by alterations in cell metabolism, inflammation, free radical generation, and apoptosis that result in the detachment of renal tubular cells from the basement membrane and shedding into the urine (14 -16). The S3 segments of the proximal tubules located in the outer stripe of the outer medulla are particularly susceptible to ischemic injury and are primarily responsible for the pathophysiological and clinical presentations of ARF (17)(18)(19). Recovery from ARF requires the replacement or regeneration of lost tubular epithelial cells.…”

Structure-function correlations in erythropoietin formation and oxygen sensing in the kidney

“…These results suggest an arterio-venous oxygen shunt. A diffusion exchange of gases between susceptibility of the kidney to hypoxic insults [2,29], as exemplified above by the damage to the proximal tubule in anemic rats, constitutes a further indication that the high oxygen content in the renal vein gives a false respresentation of the oxygen supply to the parenchyma. Considering the dependency of renal function on oxidative metabolism [14], the capacity of the kidney to play the role of oxygen sensor for the regulation of production of EPO is not surprising.…”

“…The second possibility could be described as indirect oxygen sensing because the sensing of POz would not take place in the EPOproducing cells but in the proximal tubule. The damages provoked by ischemia, hypoperfusion, and anemia in the proximal tubule indicate that the functioning of that segment is indeed markedly sensitive to oxygen delivery [22,29]. This might be a consequence of the very low rate of glycolysis in the proximal tubule in comparison with other parts of the nephron [i l, 25].…”

“…The damage to the proximal tubule during anemia is restricted to the convoluted part, which is confined to the cortical labyrinth. This can hardly be explained by intrisic differences in sensitivity to hypoxia among different parts of the proximal tubule, since in both ischemia and hypovolemic hypotension the straight part has been found to be at least as sensitive as the convoluted part [2,29]. In these two pathological conditions, in contrast with anemia, the transport work of the kidney is interrupted or strongly decreased.…”