F MA1,2, J LIU1,2, E OZOLS1,2, PCHEW1,2, J HO1,2, Y HAN1,2, K BLEASE3, B BENNETT3, G TESCH1,2, D NIKOLIC-PATERSON1,2
1Dept of Nephrology, Monash Medical Centre, Clayton, Australia, 2Monash University Centre for Inflammatory Diseases, Clayton, Australia, 3Celgene, San Diego, USA
Aim: To determine whether JNK signalling in podocytes contributes to podocyte damage and proteinuria in glomerular disease.
Background: Activation of the c-Jun amino terminal kinase (JNK) is evident in podocytes and infiltrating macrophages in human and experimental glomerulonephritis. In vitro studies indicate that JNK signalling facilitates podocyte damage in response to inflammatory cytokines and toxins (e.g. puromycin aminonucleoside, PAN): however, the role of JNK in podocyte damage in glomerular disease remains unclear.
Methods: Podocyte damage (area of synaptopodin staining), proteinuria and macrophage infiltration was assessed in two disease models. WKY rats received a JNK inhibitor (CC-930), or vehicle, on days 7-28 of anti-GBM disease. Mice with Jnk gene deletion in podocytes (Jnk1f/fJnk2-/-PodCre known as JnkPod) were examined in the anti-GBM disease model with wild type and Jnk2-/- control groups. Finally, SD rats received a JNK inhibitor (CC-401), or vehicle, on days 0-8 of PAN-induced podocyte damage.
Results: Systemic JNK inhibition prevented podocyte damage, proteinuria and glomerular lesions in rat anti-GBM disease (all P<0.001 vs vehicle). This was associated with reduced macrophage infiltration and activation. JnkPod mice develop normally and exhibit normal kidney structure and function. However, JnkPod mice were not protected from podocyte damage, albuminuria, glomerular damage, renal function impairment or macrophage infiltration on day 7 of anti-GBM disease. PAN induced JNK activation in podocytes on day 4 which preceded the peak of proteinuria on day 8. However, systemic JNK inhibition failed to protect rats against PAN-induced podocyte damage or proteinuria.
Conclusions: Contrary to in vitro studies, JNK signalling in podocytes does not induce podocyte damage in vivo. Systemic JNK blockade reduces podocyte damage in anti-GBM disease via indirect effects, most probably on macrophages.
Dr Nikolic-Paterson is from the Department of Nephrology at Monash Medical Centre and his research interests focus on the mechanisms of renal inflammation and fibrosis.