The protective effect of FK506 pretreatment against renal ischemia/reperfusion injury in rats

Abstract

The effect of pretreatment with FK506 on renal ischemia and reperfusion (I/R) injury was investigated using a rat model. Animals were assigned to one of two groups (20 rats each). Group 1 animals (controls) received 0.5 ml saline while group 2 animals received FK506 (0.3 mg/kg), administered intravenously 24 hr prior to the induction of renal ischemia. A 60-min period of ischemia of the right kidney was induced, and upon reperfusion a left nephrectomy was performed. Blood samples for estimation of BUN, creatinine, and tumor necrosis factor were collected on days 0 (preischemia), 1, 2, 3, 5, 7, and 10 (postischemia). Rats were sacrificed after day 10 and renal tissue was examined histologically. All animals survived the ischemic episode. FK506 pretreatment significantly reduced the serum levels of BUN (P less than 0.02), creatinine (P less than 0.02), and TNF (P less than 0.05) as compared with that seen in controls. Histologically, at day 10, the kidneys showed the expected sequelae of prior renal I/R with various degrees of tubular damage. However, no objective differences were evident between the two groups. Based upon these data, it can be concluded that (1) FK506 pretreatment ameliorates the functional renal injury associated with I/R, (2) renal ischemia induces the release of TNF, and (3) FK506 pretreatment results in a significant inhibition of TNF production. These data suggest that the release of TNF may be responsible for the increasing of BUN and creatinine levels seen after renal I/R and that pretreatment of renal donors with FK506 may improve renal function in the immediate post-transplant period.

Figure 1

Serum BUN levels (mg/dl) in the animals studied. The points represent the mean level and the brackets indicate the SEM ([*] P<0.02).

Figure 2

Serum creatinine levels (mg/dl) in the animals studied. The points represent the mean level and the brackets indicate the SEM ([*] P<0.02).

Figure 3

Serum TNF levels (U/ml) in the animals studied. The points represent the mean level and the brackets indicate the SEM ([*] P <0.05).

Figure 4

Correlation between mean serum levels of TNF and BUN in saline-pretreated animals (r=0.929, [*] P<0.05) and in FK506-pretreated animals (2=0.824, [*]P<0.05).

Figure 5

Correlation between mean serum levels of TNF and creatinine in saline-pretreated animals (r=0.90, [*] P<0.05) and in FK506-pretreated animals (r=0.82, [*] P<O.05) and in FK506-pretreated animals (r=0.82, [*]P<0.05).