Dr Jantina Manning1, Prof Shilpanjali Jesudason2,3, Mr Paul Moretti1, Prof Stuart Pitson1,3, Ms Meriam Shabbar1, Prof Sharad Kumar1,3
1University Of South Australia, Adelaide, Australia, 2Central Northern Adelaide Renal and Transplantation Service (CNARTS), Royal Adelaide Hospital, Adelaide, Australia, 3Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia
Biography:
Jantina is a research fellow in the Centre for Cancer Biology at UniSA. After completion of her PhD in 2010, she was awarded a Mary Overton Fellowship from the Royal Adelaide Hospital to work on a gene found to be important in kidney health.
Since this time, Jantina has explored how this gene protects against chronic kidney disease, and how dietary salt influences this. Recently, she has begun investigating a new role for this gene in diabetes and diabetic kidney disease.
Jantina’s work has been published in high impact factor journals, and she has won several awards for scientific excellence.
Aim:
To investigate NEDD4L as a new regulator of diabetes and diabetic nephropathy (DN).
Background:
NEDD4-2 (human NEDD4L) is a ubiquitin ligase that regulates ion channels and transporters by promoting their degradation, thereby affecting many signalling and physiological outcomes. We have demonstrated the importance of NEDD4-2 in the kidney, as loss of this gene in mice results in chronic kidney disease (CKD) due to aberrant ion transport, caused by elevated expression of NEDD4-2 substrates including ENaC (epithelial sodium channel). One of the biggest risk factors for CKD is diabetes, as up to 50% of diabetic patients develop DN. Variants of Nedd4-2 are associated with DN, therefore we hypothesized that this gene may regulate development of this disease.
Methods:
NEDD4-2 and substrate levels were measured in kidneys at various stages in a mouse model of type 2 diabetes (db/db). CRISPR genetic ablation of Nedd4-2 in the kidneys of db/db mice was utilised to investigate whether deficiency of Nedd4-2 influences diabetes and DN.
Results:
In the db/db mouse model of diabetes and DN, reduction of NEDD4-2, and elevation of its substrates correlated with disease progression. Remarkably, genetic reduction of renal Nedd4-2 in the DN model did not exacerbate nephropathy but corrected blood glucose levels and metabolic parameters, via restoration of aldosterone levels and insulin signalling.
Conclusions:
Renal NEDD4-2 is a novel regulator of blood glucose levels. Lower levels of this gene may be protective in diabetes and could serve as a biomarker for disease detection/severity and a potential future therapeutic target.
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