JUN PLAYS BOTH PROTECTIVE AND PATHOLOGIC ROLES IN ACUTE AND CHRONIC KIDNEY DISEASE
Sanduni Fernando1,2, Elyce Ozols1,2, William Mulley1,2, Frank Ma1,2, David Nikolic-Paterson1,2 1Monash Health, Clayton, VIC, Australia2Monash University, Clayton, VIC, Australia
Abstract
Aim: To investigate the role of Jun in kidney injury.
Background: JUN is a component of the AP-1 transcription factor that regulates genes in cell death, inflammatory and fibrotic responses. JUN is highly upregulated in acute and chronic kidney disease, most prominently in tubular epithelial cells. Tubulointerstitial JUN expression correlates with tubular damage (KIM1), inflammation and interstitial fibrosis in human kidney disease. However, JUN function in kidney disease is unknown.
Methods: Mice with a floxed Jun gene (Junf/f) were created and crossed with ER-Cre mice to create mice with tamoxifen-inducible global Jun deletion (JunIKO). Adult JunIKO and Junf/f controls received tamoxifen, and after a 2-week rest were studied in a 6hr LPS model (n=6/group) or a 7-day UUO model (n=9/group). Knock-out and wild type tubular cells were cultured in vitro.
Results: Western blotting, immunostaining and RT-PCR demonstrated efficient JUN deletion following tamoxifen. Adult mice showed no ill-effects of global JUN deletion (not previously reported). However, increased tubular damage (reduced KIM1) was evident in both LPS and UUO models (both p<0.05 vs Junf/f controls). Global JUN deletion had only minor effects on the inflammatory response in LPS and UUO models. JUN knock-out tubular cells grew well in culture and showed increased LPS-induced Tnf, Il1b, Il6 and Nos2 mRNA expression (all p<0.05). Global JUN deletion reduced Col1α1 mRNA levels by 55% (p<0.001) in the UUO model with no change in α-SMA expression, suggesting a role for JUN in myofibroblast collagen production.
Conclusions: JUN protects tubular cells from damage in response to inflammation and mechanical stretch, and limits the tubular inflammatory response. By contrast, JUN promotes renal interstitial fibrosis. Therapeutic targeting of JUN in myofibroblasts is proposed.
Biography
Sanduni (Sandy) is a nephrologist at Monash Health and currently completing the final year of her PhD with a view to submission later this year.