Pargyline reduces renal damage associated with ischaemia-reperfusion and cyclosporin.
BACKGROUND
The slow deterioration of the kidney graft is characterized histologically by interstitial fibrosis and tubular atrophy (IFTA). Immunological and non-immunological stress is the main cause of progression towards IFTA. Our study focused on the non-immunological injuries induced by ischaemia-reperfusion (IR) and cyclosporin (CsA) toxicity, which remain the two stress factors putting a damper on the outcome of the renal graft. Endogenous reactive oxygen species (ROS) are essentially produced by mitochondria, and we have previously shown that the blockage of the mitochondrial enzymes monoamine oxidases (MAOs) prevents H2O2 production in the early reperfusion stage following IR.


METHODS
We used a rat model of IFTA consisting in unilateral nephrectomy followed by IR and daily CsA administration. Four weeks after IR, we analysed renal function, histological alterations and a number of inflammatory and fibrotic genes.


RESULTS
We observed, 28 days after pargyline-mediated blockade of MAO (before or after IR), improved renal function as well as a net decrease in renal inflammation associated to lower IL-1β and TNF-α gene expression. However, significant reduction in apoptosis, necrosis and fibrosis was only observed when pargyline was administrated before IR. This protective effect was associated to decreased expression of TGF-β1, collagen types I, III and IV and also to the normalization of antioxidant (SOD1, catalase) and inflammatory (COX2, LOX5) gene expression.


CONCLUSIONS
It appears that the blockage of ROS produced by MAO and subsequent cell death might be an effective protective strategy against IFTA progression.
Chaaya
Rana
R
INSERM, U858-31432, Université Toulouse III Paul Sabatier, Toulouse Cedex 4, France.
Alfarano
Chiara
C
Guilbeau-Frugier
Céline
C
Coatrieux
Christelle
C
Kesteman
Anne-Sylvie
AS
Parini
Angelo
A
Fares
Nassim
N
Gue
Michelle
M
Schanstra
Joost P
JP
Bascands
Jean-Loup
JL
D000818:Animals; D016572:Cyclosporine / Q000009:adverse effects*; D004195:Disease Models, Animal; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007668:Kidney / Q000187:drug effects; D007674:Kidney Diseases / Q000209:etiology / Q000517:prevention & control / Q000628:therapy*; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010293:Pargyline / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy*
D007166:Immunosuppressive Agents; D008996:Monoamine Oxidase Inhibitors; D017382:Reactive Oxygen Species; D016572:Cyclosporine; D010293:Pargyline