Nicotine Protects Kidney from Renal Ischemia/Reperfusion Injury through the Cholinergic Anti-Inflammatory Pathway

Abstract

Kidney ischemia/reperfusion injury (I/R) is characterized by renal dysfunction and tubular damages resulting from an early activation of innate immunity. Recently, nicotine administration has been shown to be a powerful inhibitor of a variety of innate immune responses, including LPS-induced toxaemia. This cholinergic anti-inflammatory pathway acts via the α7 nicotinic acetylcholine receptor (α7nAChR). Herein, we tested the potential protective effect of nicotine administration in a mouse model of renal I/R injury induced by bilateral clamping of kidney arteries. Renal function, tubular damages and inflammatory response were compared between control animals and mice receiving nicotine at the time of ischemia. Nicotine pretreatment protected mice from renal dysfunction in a dose-dependent manner and through the α7nAChR, as attested by the absence of protection in α7nAChR-deficient mice. Additionally, nicotine significantly reduced tubular damages, prevented neutrophil infiltration and decreased productions of the CXC-chemokine KC, TNF-α and the proinflammatory high-mobility group box 1 protein. Reduced tubular damage in nicotine pre-treated mice was associated with a decrease in tubular cell apoptosis and proliferative response as attested by the reduction of caspase-3 and Ki67 positive cells, respectively. All together, these data highlight that nicotine exerts a protective anti-inflammatory effect during kidney I/R through the cholinergic α7nAChR pathway. In addition, this could provide an opportunity to overcome the effect of surgical cholinergic denervation during kidney transplantation.

14S,21R-dihydroxy-docosahexaenoic Acid Treatment Enhances Mesenchymal Stem Cell Amelioration of Renal Ischemia/Reperfusion Injury

“…We found that I/R injury increased serum creatinine compared with sham at day 1 (1.2 -0.06 vs. 0.35 -0.04 mg/dL, P < 0.01) and day 3 (1.08 -0.14 vs. 0.35 -0.04 mg/dL, P < 0.05) post-I/R (Fig. 1B), which is in agreement with previous reports [8,51]. Mice transplanted with mMSCs exhibited lower serum creatinine levels than the I/R control at day 1 (0.98 -0.06 mg/dL, P = 0.08) and day 3 (0.6 -0.05 mg/dL, P < 0.05) post-I/R, which is also consistent with a previous report [8].…”

RAGE Does Not Contribute to Renal Injury and Damage upon Ischemia/Reperfusion-Induced Injury

“…The degree of tubular damage was assessed on periodic acid-Schiff diastase (PASD)-stained paraffinembedded tissue sections. The PASD score represents tubular damage, which is visually characterized by necrosis, dilation, cast deposition and loss of brush border [20] . The degree of necrosis was scored by a pathologist in a blinded fashion on a 5-point scale: 0 = no damage, 1 = 10% necrosis of the corticomedullary junction, 2 = 10-25%, 3 = 25-50%, 4 = 50-75%, 5 = more than 75%.…”

“…The degree of necrosis was scored by a pathologist in a blinded fashion on a 5-point scale: 0 = no damage, 1 = 10% necrosis of the corticomedullary junction, 2 = 10-25%, 3 = 25-50%, 4 = 50-75%, 5 = more than 75%. For immunostaining, 4-m tissue sections were incubated with specific antibodies for granulocytes (FITC-labeled anti-mouse Ly6G mAb; BD Biosciences-Pharmingen), apoptosis (rabbit anti-human active caspase-3; Cell Signaling Technology), GFP (rabbitanti GFP IgG; Molecular Probes), HMGB1 (rabbit-anti mouse HMGB1; Abcam), S100B (rabbit anti-S100B; Sigma-Aldrich) or CML ( N -epsilon carboxymethyl lysine) which has been identified as a major structure in advanced glycation end-products (AGE), mouse IgG, Biologo) followed by appropriate secondary antibodies as described before [15,16,[20][21][22][23]. To determine percentage of positive staining on kidney tissue slides, approximately 10 pictures of tissue section were taken under light microscopy (magnification !…”

Renal ischemia and reperfusion injury: influence of chorpromazine on renal function and lipid peroxidation

“…3,4 Lipid peroxidation is an autocatalytic mechanism leading to oxidative destruction of cellular membranes, and their destruction can lead to the production of toxic reactive aldehydic metabolites and cell death. [5][6][7][8] A range of drugs and methods have been tested with the intention to block the pathways of cell injury at different levels and to thereby enhance viability of the kidney challenged by ischemia/ reperfusion stress with variable results, such as: heat shock (interferes with the L-arginine-nitric oxide pathway), 9 antioxidants, 10,11 dipyridamole (increases endogenous adenosine), 12,13 nicotine (inhibit cholinergic antiinflammatory pathway), 14 calcium channel blockers or antagonists, [15][16][17][18] chlorpromazine, 19,20 etc. Chorpromazine (CPZ) is a membrane stabilizer and seems to be able to preserve mitochondria integrity and to reduce phospholipids degradation of microsomal membranes of liver cell provoked by ischemia/reperfusion.…”