F YANG1,2, E OZOLS1, K LEONG1, F MA1, X JIANG2, D NIKOLIC-PATERSON1
1Monash Health, Clayton, Australia, 2Department of Pediatrics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou , China
Aim: To investigate the role of the c-Jun amino terminal kinase (JNK) signalling pathway in mouse models of Aristolochic acid (AA)-induced acute and chronic kidney injury.
Background: AA is a toxin that damages tubular epithelial cells of the kidney and is the cause of Chinese Herb Nephropathy and Balkan Nephropathy. Exposure of cultured tubular epithelial cells to AA induces a pro-fibrotic response via the JNK pathway.
Methods: In the acute model, groups (n=7-8) of mice received a single injection of 5mg/kg AA and were treated with vehicle, JNK inhibitor (CC-930) at 75mg/kg/BID or untreated from day 0 until being killed on day 3. In the chronic model, mice (n=10) received 2mg/kg AA every second day from day 0 to day 22, and were treated with vehicle or CC-930 for the entire period.
Results: In the acute model, CC-930 treatment substantially inhibited JNK signalling and gave significant protection from AA-induced renal function impairment (normal 8.3±1.5; untreated 33.4±4.1; vehicle 35.0±5.8; CC-930 23.3±2.1 umol/L serum creatinine: P<0.001) and tubular cell damage (KIM-1 and NGAL mRNA levels; P<0.001). This protection was associated with reduced macrophage infiltration and reduced expression of pro-inflammatory molecules (TNF, IL-36A). In the chronic model, CC-930 treatment significantly inhibited JNK signalling, but did not affect AA-induced renal function impairment, tubular cell damage or renal fibrosis, despite a significant reduction in the macrophage pro-inflammatory response.
Conclusion: Blockade of JNK signalling with CC-930 suppressed the acute effects of AA on tubular cell damage and renal function impairment, but was unable to protect the kidney against the effects of chronic AA exposure.
Ms Fan Yang is a medical graduate from China who is studying for a PhD in experimental kidney disease through the Department of Pediatrics at the The First Affiliated Hospital of Sun Yat-sen University in Guangzhou and in the Department of Nephrology at Monash Medical Centre. Fan is keen to develop a career as a clinician/scientist in the filed of Nephrology.