Jandeleit-Dahm research group
Diabetes and Kidney Disease
Key terms: Diabetes, Diabetic complications, diabetic nephropathy, cardiovascular disease, oxidative stress, reactive oxygen species, instable plaque, novel targets, clinical translation
To understand how the vascular complications of diabetes develop and progress and how we can target specific pathways to delay, stop or reverse diabetic micro-and macrovascular complications including heart and kidney disease.
The Diabetes and Kidney Disease Laboratory aims to identify novel targets to prevent, treat and reverse diabetic complications. The laboratory therefore addresses important clinical questions: how to prevent and treat the micro-and macrovascular complications of diabetes.
Diabetes associated kidney disease is the major cause of end-stage renal disease requiring dialysis or transplantation. Diabetes also increases the risk of cardiovascular disease leading to the clinical consequences of heart attacks, stroke and amputations and contributing to increased morbidity and mortality observed in diabetes. This increased cardiovascular risk is further amplified if kidney disease is also present. Current treatment options fail to protect patients from the micro-and macrovascular complications of diabetes and thus new treatments are urgently needed.
The laboratory has an increasing national and international profile. The team has been highly successful with recent work published in the leading cardiovascular journals including Circulation, Circulation Research, in leading diabetes specialist journals such as Diabetes and Diabetolgia as well as in the leading kidney journals such as the Journal of the American Society of Nephrology and Kidney International.
To achieve its research goals, the laboratory employs a bench to bedside and vice versa approach and covers the whole range from experimental work using cells to sophisticated animal models of vascular complications of diabetes to clinical validation of basic and preclinical research findings. The laboratory has established state of the art technology including mouse, rat and human cell lines, unique mouse models including cell specific and inducible knockout and knockin mice, as well as having access to novel pharmacological agents as a result of close collaborations with biotechnology and major pharmaceutical companies.
Discoveries in the laboratory have been translated to novel treatment strategies as evidenced by the clinical development of novel Nox inhibitors (JDRF/ARC funded clinical trial with Nox-inhibitors in type 1 diabetic nephropathy, CIs Cooper, Jandeleit-Dahm et al), novel agents to interfere with the AGE/RAGE axis and novel inhibitors of vasoactive pathways such as the endothelin system.
Projects and Opportunities
Honours, Masters and PhD research projects are available in the laboratory. Please contact us to discuss the details of the projects and to see how they fit in your specific interests. Please refer to the following general description of our current projects.
Project 1: The role of Nox5 in diabetic nephropathy
This project seeks to validate Nox5 as a novel target in the treatment of diabetic nephropathy and other vascular complications. We use unique animal models of diabetic kidney disease and kidney fibrosis, including knockout and transgenic mice, the rabbit as well as a novel Nox5 knockout rabbit and our access to human kidney biopsy and nephrectomy samples to identify the role of Nox5 in disease. Furthermore, in in vitro studies we will perform a mechanistic analysis of Nox5 activation and downstream signaling pathways. We are co-located with the genomics core (Prof Assam El-Osta) and will perform RNA sequencing of renal cortex in the various animal models and cells. We have access to novel inhibitors of the Nox pathways and are actively collaborating with industry to develop novel and more specific Nox inhibitors for clinical translation.
Project 2: Nox5 as a novel biomarker for unstable cardiovascular disease
This project seeks to identify and validate Nox5 as a novel biomarker for cardiovascular disease, in particular in diabetes. Using FACS analysis we have shown increased NOx5 expression in circulating human monocytes. We will analyse Nox5 expression in monocytes in patients undergoing cardiac angiography in collaboration with the Alfred Hospital (in collaboration with Dr James Shaw, cardiologist, Alfred Health), in patients with and without diabetes and with and without cardiovascular events. We predict that Nox5 expression in monocytes may be a novel biomarker for unstable cardiovascular disease.
Project 3: The direct renoprotective effect of SGLT2 inhibitors
In this study we will investigate the direct kidney protection afforded by a novel class of drugs used to treat diabetes, SGLT-2 inhibitors. These drugs inhibit sodium/glucose co-transport in the tubule and thus reduce hyperglycemia. In large clinical studies it has been shown that these drugs afford cardiovascular (EMPA-REG) and renoprotection most likely over and above their glucose lowering ability. We will assess the mechanisms of such direct renal effects in animal models of diabetic complications and will measure parameters of renal fibrosis, albuminuria, oxidative stress and renal catecholamine levels.
Current project funding
- 2014-2018: NHMRC Senior Research fellowship (Novel treatments for diabetic complications)
- 2017-18: Alfred Seed Grant: Nox5 is a novel biomarker for unstable cardiovascular disease
- 2017-18: Glaxo Smith Kline: commercial grant
- JDRF/NHMRC Diabetic Complications Centre for Research Excellence: Chief investigator
- 2015-17: A Watson (NHMRC New investigator grant): Renal nerves in diabetic nephropathy
- Jay C Jha: NHMRC early career fellowship: The role of Nox5 in diabetic complications
Pubmed link [Jandeleit-Dahm+K] (160 publications in total as of March 2017))
- Gray SP, Di Marco E, Okabe J, Szyndralewiez C, Heitz F, Montezano AC, deHaan JB, Koulis C, El-Osta A, Andrews KL, Chin-Dusting JPF, Touyz RM, Wingler K, Cooper ME, Schmidt HHHW, Jandeleit-Dahm KA. Nox1 plays a key role in diabetes accelerated atherosclerosis, Circulation, 2013, epub 5/04/13
- Watson A, Gray S, Jiaze L, Soro-Paavonen A, Wang B, Cooper ME, Bierhaus A, Pickering R, Tikellis C, Tsorotes D, Thomas MC, Jandeleit-Dahm KAM. Alagebrium reduces glomerular fibrogenesis and inflammation beyond preventing RAGE activation in diabetic apoE KO mice. Diabetes, 2012, 61:2105-13.
- Watson A. M. D., Soro-Paavonen A, Sheehy K, Li J, Calkin A. C. , Koitka A. , Rajan, S.N. , Brasacchio D., Allen, T.J. , Cooper M. E. , Thomas M. C. , Jandeleit-Dahm K. J. Delayed intervention with AGE inhibitors attenuates the progression of diabetes-accelerated atherosclerosis in diabetic apolipoprotein E knockout mice. Diabetologia, 2011, 54:681-9.
- A Watson, L Jiaze, C Schumacher, M deGasparo, MC Thomas, TJ Allen, ME Cooper, KAM Jandeleit-Dahm. The endothelin receptor antagonist avosentan ameliorates nephropathy and atherosclerosis in diabetic apoE KO mice. Diabetologia, 2010, 53: 192-203.
- AC Calkin, S Giunti, K Sheehy, C Chew, V Boolell, YS Rajaram, ME Cooper, K Jandeleit-Dahm. The HMG-CoA reductase inhibitor rosuvastatin and the angiotensin receptor antagonist candesartan attenuate atherosclerosis in diabetic apolipoprotein E deficient mice via effects on advanced glycation, oxidative stress and inflammation. Diabetologia, 2008, 51:1731-40.
- A Soro-Paavonen, A Watson, J Li, K Paavonen, A Koitka, AC Calkin, D Barit, MT Coughlan, M Thomas, JM Forbes, P Nawroth, A Bierhaus, ME Cooper, K Jandeleit-Dahm. RAGE deficiency attenuates the development of atherosclerosis in diabetes. Diabetes, 2008, 57:2461-9.
- Jandeleit-Dahm KAM, Lassila M, Quak E, Davis B, Allen TJ, Burrell LM, Johnston CI, Cooper ME. Vasculo-and renoprotective effects of omapatrilat in the diabetic apoE knockout mouse, Journal of Hypertension, 2005, 23: 2071-82.
- Jandeleit-Dahm KA, Tikellis C, Reid CM, Johnston CI, Cooper ME. Why blockade of the RAS reduces the incidence of diabetes. Journal of Hypertension, 2004, 15 (8): 2125-2138.
- Lassila M, She KK, Allen TJ, Thallas V, Thomas MC, Candido R, Burns WC, Forbes JM, Calkin AC, Cooper ME, Jandeleit-Dahm KAM. Accelerated nephropathy in diabetic apoE lipoprotein knockout mice- role of advanced glycation end products. Journal of the American Society of Nephrology, 2004, 15: 2125-38.
- Candido R, Lassila M, Allen TJ, Cao Z, Cooper ME, Jandeleit-Dahm K. Irbesartan but not amlodipine attenuates diabetes-associated atherosclerosis. Circulation, 2004, 109:1536-42.
- Jandeleit-Dahm K, Hannan KM, Farrelly CA, Allen TJ, Rumble JR, Gilbert RE, Cooper ME, Little PJ. Diabetes induced vascular hypertrophy is accompanied by activation of Na+/H+ exchange and prevented by Na+/H+ exchange inhibition. Circulation Research 87, 2000: 1133-1140.
- Candido R, Jandeleit-Dahm KA, Cao Z, Nesteroff S, Burns W, Twigg SM, Dilley RJ, Cooper ME, Allen TJ. Prevention of accelerated atherosclerosis by ACE inhibition in diabetic apolipoprotein e deficient mice. Circulation 106, 2002: 246-253.