Effects of JNK inhibitor on puromycin aminonucleoside-induced nephropathy in rats
Creators: name: Alfarano, Chiara
name: Guérard, Marc
name: Abadie, Claire
name: Deloche, Catherine
name: Jean-Marc Combette
name: Lluel, Philippe
Publisher: name: F1000Research
Year: 2016

description: INTRODUCTION AND AIMS: Puromycin aminonucleoside (PAN) is a podocyte toxin inducing a loss and fusion of podocytes foot processes. Repeated PAN injections in rats (1) lead to a direct DNA damage via the production of reactive oxygen species (ROS) and tissue damages, including glomerulosclerosis and interstitial fibrosis (2) in the chronic phase. The glomerular morphologic and fibrotic changes seen in PAN rats are similar to those observed in human minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS; 3). JNK is a stress-activated protein kinase which can be induced by various stimuli including ROS and pro-inflammatory cytokines (4). JNK activation seems to play an important role in the development and progression of kidney diseases. The aim of this study was to evaluate the effect of JNK inhibitor (XG-102) in a chronic rat model of puromycine aminonucleoside (PAN)-induced nephropathy.<br><br>METHODS: Nephropathy was induced in male Wistar rats by administration of PAN at day 0 (130 mg/kg; i.p.) and at day 14 (60 mg/kg; i.p.). XG-102 (1, 2 or 4 mg/kg) or its vehicle (saline) were administrated into the tail vein (i.v.) once a week starting from first PAN injection for a total of 7 injections until the end of the protocol (56 days; preventive protocol). A separate group of animal (curative protocol) was treated with XG-102 (4 mg/kg; i.v.) once a week starting from day 21 for a total of 4 injections. Kidney histological lesions were evaluated by haematoxylin eosin, periodic acid Shiff-methenamine and Sirius red staining and histopathological analysis.<br><br>RESULTS: Histological analysis revealed kidney lesions in PAN- compared to vehicle-treated rats. These include glomerular hypertrophy, FSGS, fibrosis and a mild degree of tubular degeneration and inflammation. XG-102 at the doses of 2 and 4 mg/kg administered preventively significantly reduced PAN-induced glomerulosclerosis in term of severity of lesions (glomerular injury score of 0.88±0.05 and 0.80±0.05 for XG-102 at 2 and 4 mg/kg respectively vs 1.36±0.03 for vehicle). A significant decrease of glomerular damage incidence (percentage of injured glomeruli of 76.13±2.61 and 73.07±3.65 for XG-102 at 2 and 4 mg/kg respectively vs 88.40±1.73 for vehicle) was also observed. XG-102 at the dose of 4 mg/kg administered curatively led to a strong effect on glomerulosclerosis in term of both severity of lesions (glomerular injury score of 0.37±0.02 vs 1.36±0.03 for vehicle) and glomerular damage incidence (percentage of injured glomeruli of 30.13±1.27 vs 88.40±1.73 for vehicle). These effects are more important than those observed in the preventive protocol design.<br><br>CONCLUSIONS: The positive effects of XG-102 in both preventive and curative treatment schedules on PAN-induced kidney lesions suggest that JNK inhibition should be useful for the treatment of focal segmental glomerulosclerosis in humans.<br><br>1) Nakajima T et al., J Saitama Med Univ, 37:1-10, 2010<br>2) Hewitson TD et al., Methods Mol Biol, 466:41-57, 1984<br>3) Pippin JW et al., Am J Physiol Renal Physiol, 296:213-29, 2008<br>4) Kanellis J et al, Nephrol Dial Transplant, 25:2898-908, 2010