Dr Priyanka Subramani1,2,3, Dr Frank Ma1,2, Elyce Ozols1,2, Dr Jessica Ryan1,2, Dr Greg Tesch1,2, Dr David Nikolic-Paterson1,2
1Department of Medicine, Monash University, Clayton, Australia, 2Department of Nephrology, Monash Health, Clayton, Australia, 3Department of Nephrology, St Vincent’s Hospital Melbourne, Fitzroy, Australia
Biography:
Bio to come
Aim:
To investigate the role of Jun in myeloid cells in acute kidney injury (AKI).
Background:
Myeloid cells play an important pathogenic role in acute ischaemia-reperfusion injury (IRI). The transcription factor, Activator Protein-1 (AP-1), is considered to augment the inflammatory response in myeloid cells. Therefore, we deleted the Jun gene, a key member of the AP-1 family, in myeloid cells and investigated the effects in a mouse model of AKI.
Methods:
Mice lacking Jun in myeloid cells were created by crossing Junf/f and LysMCre mice. Bone marrow macrophages (BM-MΦ) were cultured and stimulated with LPS. JunMyKO and control Junfl/fl mice (n=8/group) underwent IRI surgery and were killed 24hr later.
Result:
JunMyKO mice are healthy with normal blood and tissue myeloid populations. In vitro LPS stimulation of JunMyKO BM-MΦ resulted in significantly increased TNF, IL6 and IL1b mRNA levels compared to LPS-stimulated Junfl/fl BM-MΦ (all p<0.01 ). As expected Junfl/fl mice had elevated plasma creatinine levels after IRI (35.0±13.9 vs 10.2±1.8umol/L in sham controls; P<0.01). JunMyKO mice exhibited worse renal function after IRI (68.6±25.9umol/L; P<0.01 vs Junfl/fl). However, there was no significant difference in tubular damage, neutrophil or macrophage accumulation between JunMyKO and Junfl/fl IRI groups. Furthermore, bulk RNA-seq of whole kidney tissue did not identify differences in myeloid cell activation between the JunMyKO and Junfl/fl IRI groups, suggesting that the protective effect of Jun deletion operates at the protein level, possibly via regulation of renal haemodynamics.
Conclusion:
Jun expression in myeloid cells limits both LPS-induced inflammation in vitro and ischaemia-reperfusion-induced AKI in vivo.
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