Renal protection by delayed ischaemic preconditioning is associated with inhibition of the inflammatory response and NF‐κB activation

Abstract

Brief and sublethal ischaemia renders an organ tolerant to subsequent prolonged ischaemia, which is called ischaemic preconditioning (IPC). In regard to the beneficial effects and endogenous mechanisms of renal delayed IPC, few data are available. In this study, we aim at determining reno-protective effects of delayed IPC against ischaemia-reperfusion (I/R) injury, and illustrating whether these effects are associated with suppressing inflammation and nuclear factor-kappaB (NF-kappaB) activation. I/R injury was induced by clamping both renal pedicles for 40 min, followed by 24 h of reperfusion. The rats were subjected to ischaemia for 20 min (preconditioning) or sham surgery (non- preconditioning) at day 4 before I/R. Functional and morphological parameters were evaluated at 24 h after reperfusion. At the same time, macrophage (ED-1(+)) infiltration, and the expression of intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor-alpha (TNF-alpha) were assessed by immunohistochemistry. Moreover, I kappa B-alpha degradation and NF-kappaB/DNA binding activity were analyzed. Compared with rats exposed to I/R injury, preconditioned rats had a significant decrease in levels of serum creatinine (Scr, 384.3 +/- 21.8 micromol/L vs. 52.5 +/- 21.7 micromol/L; p<0.001), blood urea nitrogen (BUN, 40.4 +/- 2.7 mmol/L vs. 15.9 +/- 4.2 mmol/L; p<0.001) and serum aspartate aminotransferase (AST, 486.7 +/- 58.6 IU/L vs. 267.3 +/- 43.9 IU/L; p<0.001). Parallel to the above changes, preconditioned rats preserved structural integrity and decreased tubulointerstitial damage scores (3.4 +/- 0.3 vs. 0.2 +/- 0.05; p<0.001) and ED-1(+) cell infiltration (25.3 +/- 3.5 vs. 6.2 +/- 1.2 cells/HPF, p<0.01). Furthermore, our results showed that the expression of ICAM-1 and TNF-alpha, the degree of I kappa B-alpha degradation, and NF-kappaB/DNA binding activity were reduced by IPC. Taken together, our results demonstrated that delayed IPC offered both functional and histological protection, which may be related to suppression of inflammation in preconditioned kidneys.

Ischemic limb preconditioning downregulates systemic inflammatory activation

“…24 The endothelium regulates this latter reaction, since it produces adhesion molecules which enhance PMN attachment and consequent PMN-derived oxidative damage. Although in vitro studies have pointed to reduced ICAM-1 signaling after IPC following an ischemic trigger, 25 and kidney IPC reduced the expressions of ICAM-1 and TNF-alpha and NF-kappaB/ DNA-binding activity, 26 we could not prove similar effects in our model. As ICAM-1 expression can be initiated by proinflammatory cytokines and TNF-alpha, 27 similarly to what was seen with CD11b, reduced TNF release by IPC can make an important contribution to this protection.…”

Oxidative Stress in 5/6 Nephrectomized Rat Model: Effect of Alpha-Lipoic Acid

“…The RK model is widely considered to be a classic model of CKD. Abundant evidence has accumulated indicating that CKD causes oxidative stress [15][16][17] and oxidative stress accelerates the progression of renal injury directly by inducing cytotoxicity and indirectly by promoting inflammation. 1,[16][17][18] Oxidative stress is a known feature of CKD, and its presence is evidenced by the reported elevation of lipid peroxidation products, MDA, and depressed antioxidant capacity.…”

“…Details of this technique in our laboratory have been published previously. 15 Positive cells were evaluated in tubulointerstitial areas of the cortex (positive cells/Â200 visual field).…”

Renal Protection by Ischemic Preconditioning Is Associated with p50/p50 Homodimers

“…Previous studies have demonstrated that renal protection by IPC was associated with the inhibition of NF-ĸB activation [22,23]. In this study, we investigated DNA-binding activities of NF-ĸB with EMSA from nuclear protein fractions of the kidneys.…”