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

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

No difference in renal injury and fibrosis between wild-type and NOD1/NOD2 double knockout mice with chronic kidney disease induced by ureteral obstruction

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Additional file 2: of No difference in renal injury and fibrosis between wild-type and NOD1/NOD2 double knockout mice with chronic kidney disease induced by ureteral obstruction

FigureS2. Total collagen in kidneys of WT (white bars) and NOD1/2 DKO (black bars) mice after 0, 3, 7, and 14 days following obstruction. Total collagen was assessed by Picro Sirius Red staining which was digitally analysed (A, B). Data are expressed as mean ± SEM. N = 9/group. (TIFF 1068 kb

Additional file 1: of No difference in renal injury and fibrosis between wild-type and NOD1/NOD2 double knockout mice with chronic kidney disease induced by ureteral obstruction

Figure S1. The genotype of NOD1/2 DKO mice. Genomic DNA from mice was amplified by PCR with specific primers to detect the disrupted sequences on a 1% agarose gel with a 100 bp marker. First 5 bands are the KO mice and the last bands are the WT mice in A and B. N = 5/3 per group. (TIFF 12868 kb

Additional file 3: of No difference in renal injury and fibrosis between wild-type and NOD1/NOD2 double knockout mice with chronic kidney disease induced by ureteral obstruction

Figure S3. Renal inflammation in WT (white bars) and NOD1/2 DKO (black bars) mice after 0, 3, 7, and 14 days following obstruction. IL-1b (A) and TNF-α (B) were measured in total kidney homogenates with specific ELISAs. Data are expressed as mean ± SEM. Results were analysed with the non-parametric two-tailed Mann-Whitney U-test. *P < 0.05. N = 9/group. (TIFF 2728 kb

β-Cyclodextrin counteracts obesity in Western diet-fed mice but elicits a nephrotoxic effect

Obesity has become a worldwide health crisis and is associated with a plethora of comorbidities. The multi-organ effects of obesity have been linked to ectopic lipid accumulation. Thus, there is an urgent need to tackle the obesity crisis by developing effective lipid-lowering therapies. 2-hydroxypropyl-β-Cyclodextrin (2HP-β-CD) has been previously shown to reduce lysosomal cholesterol accumulation in a murine model of Niemann Pick Type C (NPC) disease. Using a murine model of Western diet-induced obesity (DIO), we report the effects of 2HP-β-CD in counteracting weight gain, expansion of adipose tissue mass and ectopic lipid accumulation. Interestingly, DIO caused intracellular storage of neutral lipids in hepatic tissues and of phospholipids in kidneys, both of which were prevented by 2HP-β-CD. Importantly, this report brings attention to the nephrotoxic effects of 2HP-β-CD: renal tubular damage, inflammation and fibrosis. These effects may be overlooked, as they are best appreciated upon assessment of renal histology

Nicotine pretreatment prevents neutrophil infiltration.

<p>LY-6G immunostaining was performed to assess neutrophil infiltration in the corticomedullary junction 24 hours after I/R (panel A, magnification ×40). Sham operated animals displayed no neutrophil (data not shown). Nicotine administration completely prevented neutrophil infiltration (panel B, magnification ×40). Quantification is represented in panel C. Black bars represent saline-treated animals and white bars nicotine-treated groups after either sham operation (n = 6 in each group) or I/R (n = 8 in each group). Data are expressed as mean ± SEM, (*) p≤0.05.</p

Nicotine reduces tubular epithelial cell apoptosis and subsequent proliferation.

<p>Immunostaining of cleaved caspase-3 (A, B) and Ki67 (D, E) were performed one day and 3 days after I/R, respectively. Panel A represents TEC apoptosis in saline-treated animals (magnification ×40) and panel B represents TEC apoptosis in nicotine pre-treated animals (magnification ×40). Graph C compares the quantification of apoptotic TECs in saline-treated (black bars) or nicotine-treated animals (white bars), either after sham operation (n = 6 in each group) or renal I/R (n = 7 in saline-treated group and n = 10 in nicotine pretreated group). Panels D and E compare Ki-67+ cells between saline-treated animals and nicotine-treated animals (magnification ×40). Graph F compares the quantification of proliferation 3 days after reperfusion (n = 5 in each group). Data are expressed as mean ± SEM, (*) p≤0.05.</p