Prof. David Nikolic-paterson1,2, A/Prof Greg Tesch1,2, Ms Elyce Ozols1,2, Dr Shawn Badal3, Dr John Liles3, Dr Frank Ma1,2
1Department of Nephrology, Monash Health, Clayton, Australia, 2Department of Medicine, Monash University, Clayton, Australia, 3Gilead Sciences, Foster City, USA
Aim: To identify new strategies to prevent and treat acute kidney injury (AKI).
Background: Ischaemia/reperfusion injury (IRI) involves activation of apoptosis signal-regulating kinase-1 (ASK1) leading to cell death and inflammation, and increased activity of ketohexokinase (KHK) causing increased fructose metabolism and mitochondrial dysfunction. We sought to determine: (1) whether combined ASK1 and KHK blockade gives added protection against AKI; and (2) if ASK1 or KHK inhibition can intervene to enhance recovery after IRI in susceptible diabetic mice.
Methods: Study 1: wild type (WT) or Ask1-/- mice were treated with KHK inhibitor, PF-06835919, or vehicle 1hr before IRI surgery and killed at 24hr. Study 2: mice with established streptozotocin-induced diabetes underwent IRI surgery and were treated with PF-06835919, or ASK1 inhibitor (GS-444217), or vehicle, starting 4hr after reperfusion until being killed on day 7.
Results: Study 1, vehicle treated WT IRI exhibited renal failure (139±26 vs 15±1umol/L plasma creatinine in sham controls); this was improved in vehicle Ask1-/- mice and PF-06835919 treated WT mice (89±29 and 80±20umol/L; P<0.001 vs vehicle WT IRI), with greater protection in PF-06835919 treated Ask1-/- mice (25±6umol/L; P<0.001). Study 2, vehicle treated diabetic mice exhibited renal impairment and ongoing tubular damage on day 7 after IRI. Intervention with PF-06835919 or GS-444217 improved renal function and tubular cell repair, reduced inflammation and prevented the early fibrotic response on day 7 (all P<0.001 versus vehicle IRI). Notably, KHK inhibition did not affect ASK1-JNK/p38 signalling, indicating distinct pathogenic mechanisms.
Conclusion: Targetting KHK or ASK1 is effective in preventing ischaemia-induced AKI, with added benefit from combined inhibition. Furthermore, as early intervention strategies, both approaches improved recovery from AKI despite the detrimental effects of established diabetes.
Biography:
Dr David Nikolic-Paterson investigates potential therapies to target cell death, inflammation and fibrosis in acute and chronic kidney disease. This includes developing new animal models to examine the impact of comorbidities on susceptibility to acute kidney injury and the transition to chronic kidney disease.