JNK INHIBITION PREVENTS ACUTE ARISTOLOCHIC ACID-INDUCED KIDNEY INJURY

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.


Biography:
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.

Recent Comments
    Categories