A Model of Ischaemia-Induced Renal Interstitial Fibrosis in Mice with Established Diabetes

Abstract

ABSTRACT Background: Diabetes is a well-established clinical risk factor for the development of acute kidney injury (AKI) following an episode of renal ischaemia. However, we lack a robust animal model to investigate the pathological mechanisms underpinning the increased susceptibility of the diabetic kidney to ischaemia-induced AKI and the transition to chronic kidney disease. The aim of this study was to develop a mouse model in which renal ischaemia induces renal interstitial fibrosis in diabetic mice, but not in control mice. Methods: C57BL6/J mice were made diabetic via 5 low dose streptozotocin injections. 8 weeks later, diabetic mice underwent 12 min of bilateral renal ischaemia and were killed on days 1, 7 or 28 after reperfusion. For comparison, groups of age-matched non-diabetic mice underwent the same renal ischaemia/reperfusion injury (IRI) protocol. Results: Non-diabetic mice developed AKI on day 1 which showed a virtually complete recovery of structure and function by day 7. By contrast, diabetic mice exhibited a state of chronic renal inflammation and developed a much more severe AKI on day 1 after IRI. Diabetic mice showed a marked delay in the repair response on day 7, and exhibited chronic tubular damage, inflammation and robust interstitial fibrosis on day 28. Conclusion: We have developed a mouse model suitable for the dissection of the mechanisms by which diabetes makes the kidney highly susceptible to an ischaemic insult and the transition to chronic kidney disease.