ISCHEMIC-REPERFUSION INJURY IN THE KIDNEY - OVEREXPRESSION OF COLONICH-K+-ATPASE AND SUPPRESSION OF NHE-3()

Ischemic renal injury is associated with changes in the expression of a number of genes. Although pH regulation is undoubtedly important dur ing the recovery from ischemia, the expression of acid-base transporte rs during acute ischemic renal failure has not been studied. In the pr esent study, levels of mRNA encoding the colonic H+-K+-ATPase and four isoforms of the Na+/H+ exchanger (NHE-1, NHE-2, NHE-3 and NHE-4) were measured by quantitative Northern analysis in rat renal cortex and me dulla following ischemia-reperfusion injury. Rats were subjected to 30 minutes of renal artery occlusion and then sacrificed either 12 or 24 hours after the occlusion was released. The most striking changes fol lowed 30 minutes of occlusion and 12 hours of reperfusion and involved the mRNA for NHE-3 (involved in HCO3- reabsorption in proximal tubule and thick limb) and colonic H+-K+-ATPase (involved in HCO3- reabsorpt ion in collecting duct). These changes were: (1) a similar to 75% decr ease in NHE-3 mRNA in both cortex and medulla; and (2) an similar to 8 -fold increase in colonic H+-K+-ATPase mRNA in the cortex. At 12 hours of reperfusion, there was a 66% reduction in the Na+/H+ exchanger (NH E-3) activity as assayed by acid-stimulated Na-22(+) influx into brush border membrane vesicles (P < 0.01). After 24 hours of reperfusion, N HE-3 mRNA remained suppressed while cortical colonic H+-K+-ATPase mRNA declined to only twice the control level. Medullary colonic H+-K+-ATP ase mRNA did not change significantly. Gastric H+-K+-ATPase mRNA in co rtex or medulla remained the same at 0, 12, and 24 hours after reperfu sion. Cortical NHE-1 increased mildly at 12 and 24 hours of reperfusio n whereas a moderate decrease in NHE-2 and NHE-4 mRNAs was observed in cortex and medulla after both 12 and 24 hours of reperfusion. We sugg est that overexpression of colonic H+-K+-ATPase in the early phase of renal reperfusion injury may be responsible for compensatory reabsorpt ion of increased HCO3- load resulting from suppression of NHE-3. This was supported by a fourfold increase in colonic H+-K+-ATPase mRNA in r ats treated with acetazolamide, which causes renal HCO3-wasting. Rapid decline in colonic H+-K+-ATPase expression at 24 hours after reperfus ion is likely due to reduced HCO3- delivery to distal tubules resultin g from decreased GFR. Overexpression of H+-K+-ATPase maybe vital to ac id-base homeostasis in the early phase of acute ischemic renal failure .