Renoprotective Effects of a Highly Selective A3 Adenosine Receptor Antagonist in a Mouse Model of Adriamycin-induced Nephropathy

The concentration of adenosine in the normal kidney increases markedly during renal hypoxia, ischemia, and inflammation. A recent study reported that an A3 adenosine receptor (A3AR) antagonist attenuated the progression of renal fibrosis. The adriamycin (ADX)-induced nephropathy model induces podocyte injury, which results in severe proteinuria and progressive glomerulosclerosis. In this study, we investigated the preventive effect of a highly selective A3AR antagonist (LJ1888) in ADX-induced nephropathy. Three groups of six-week-old Balb/c mice were treated with ADX (11 mg/kg) for four weeks and LJ1888 (10 mg/kg) for two weeks as following: 1) control; 2) ADX; and 3) ADX + LJ1888. ADX treatment decreased body weight without a change in water and food intake, but this was ameliorated by LJ1888 treatment. Interestingly, LJ1888 lowered plasma creatinine level, proteinuria, and albuminuria, which had increased during ADX treatment. Furthermore, LJ1888 inhibited urinary nephrin excretion as a podocyte injury marker, and urine 8-isoprostane and kidney lipid peroxide concentration, which are markers of oxidative stress, increased after injection of ADX. ADX also induced the activation of proinflammatory and profibrotic molecules such as TGF-β1, MCP-1, PAI-1, type IV collagen, NF-κB, NOX4, TLR4, TNFα, IL-1β, and IFN-γ, but they were remarkably suppressed after LJ1888 treatment. In conclusion, our results suggest that LJ1888 has a renoprotective effect in ADX-induced nephropathy, which might be associated with podocyte injury through oxidative stress. Therefore, LJ1888, a selective A3AR antagonist, could be considered as a potential therapeutic agent in renal glomerular diseases which include podocyte injury and proteinuria.

The effect of non -xanthine adenosine receptor antagonist on ventricular remodeling and RAAS in chronic heart failure / 中国基层医药

Objective To analyze the effect of non -xanthine adenosine receptor antagonist (SLV320)on the ventricular remodeling and renin -angiotensin -aldosterone system (RAAS)in animal experimental models of chronic heart failure (CHF).Methods The 40 healthy male New Zealand rabbits were received adriamycin by intra-venous injection to establishing the experimental animal models and were randomly divided into 4 groups,which were high -dosage group (injected with SLV320,10.0μg·kg -1 ·d -1 ),medium -dosage group (injected with SLV320, 5.0μg·kg -1 ·d -1 ),low -dosage group (injected with SLV320,2.5μg·kg -1 ·d -1 )and furosemide group (fed with furosemide,2.0mg·kg -1 ·d -1 ).Each group had 10 rabbits and continuous treated for one week.The indexes of plasma renin activity (PRA),angiotensinⅡ (AngⅡ),aldosterone (ALD)and beta ntriuretic peptide (BNP)were detected at pre -and post -treatment,and compared among 4 groups.The indexes of left ventricular end -systolic dimension (LVESD),left ventricular end -diastolic dimension (LVEDD),left ventricular posterior wall (LVPW), left ventricle ejection fraction (LVEF),left ventricular fractional shortening (LVFS)and E /A at pre -and post -treatment were detected by echocardiography and compared among 4 groups.The wet weigh of the left and right ventri-cle were weigh accurately.And the indexes of left ventricle weight index (LVWI)and the body weight index (BWI) were calculated and compared among 4 groups.Results The plasma levels of PRA,AngⅡ,ALD and BNP were no different among 4 groups before study (all P >0.05).The sequence of 4 groups on the plasma levels of RAAS indexes was high -dosage group 0.05).The sequence of 4 groups on the levels of LVEF and LVFS was high -dosage group >medium -dosage group >low -dosage group >furosemide group,and the sequences of LVESD,LVEDD,LVPW and E /A were high -dosage group

The Protective Effect of Preconditioning Ischemia on Subsequent Cerebral Ischemic Insults

A brief period of cerebral ischemia produces neuronal damage in the vulnerable regions of the brain, such as the CA1 area of the hippocampus. However, mild ischemic episodes may limit damage from subsequent ischemic insults, the phenomenon known as ischemic tolerance or preconditioning. We used hippocampal slices as an experimental model to investigate the possible utilization of ischemic tolerance, and to determine the effects of various drugs acting on glutamate and adenosine receptors following a conditioned ischemic insult. Preconditioning ischemic insult was induced in hippocampal slices of 450nm thickness for 60-70 seconds. Glutamate and adenosine receptors were pretreated 1 hour later with D,L-2-amino-5-phosphonovaleric acid(AP-5, 50nM), propentofylline(PPF, 200nM), 6-cyano-7-nitroquinoxaline-2,3-dione(CNQX, 10nM), 8-cyclopentyl-3,7-dihydro-1,3-dipropyl-1H-purine-2,6-dione(DPCPX, 1, 10nM) and 2-chloro-N6-cyclopentyl-adenosine (CCPA, 1, 10, 50nM). The slices were reoxygenated for 3 hours, after then a second ischemic insult was induced by substituting 95% O2, 5% CO2 and glucose for 95% N2, 5% CO2 and sucrose for 10 minutes. Population spikes(PS) were estimated from extracellular electrophysiological recordings of the hippocampal CA3-CA1 synaptic conduction 1 hour following the second ischemic insult. The PS(mV) was 2.69+/-0.06 in the normal hippocampal slice, while it was reduced to 1.21+/-0.05 in the hippocampal slice induced with 10 minutes of ischemia. The effects of the A1 selective agonist CPPA revealed a reduction of PS to 0.98+/-0.06 with low concentration(1nM), similar PS as the control group with a concentration of 10nM, and an increase in ischemic tolerance of 1.78+/-0.05 at a higher concentration(50nM). The selective A1 antagonist DPCPX(1nM) showed minimal reduction in PS of 1.10+/-0.04, while the NMDA antagonist AP-5(5nM) had a more profound weakening effect(1.05+/-0.04). The adenosine uptake inhibitor profentophylline(200nM) augmented the PS to 1.56+/-0.06; this effect was not influenced by 1nM DPCPX(1.60+/-0.07), but was abolished by a higher concentration of 10nM(1.36+/-0.05). These results confirmed ischemic tolerance in the hippocampal experimental model. We conclude that adenosine plays an important role in ischemic tolerance as activation of adenosine receptors or adenosine uptake inhibition enhances ischemic tolerance.