NEDD4L AS A NEW REGULATOR OF DIABETIC NEPHROPATHY AND CHRONIC KIDNEY DISEASE
Jantina Manning1, Shilpa Jesudason2, Sharard Kumar1 1Centre for Cancer Biology, University of South Australia and SA Pathology, SA, Australia2Central Northern Adelaide Renal and Transplantation Service (CNARTS), Royal Adelaide Hospital, Adelaide, South Australia, SA, Australia
Abstract
Aim:
To uncover a new regulator of diabetic nephropathy (DN) by exploring the contribution of the NEDD4L/Nedd4-2 gene to nephropathy.
Background:
NEDD4L (mouse Nedd4-2) is a ubiquitin ligase that regulates ion channels and transporters by promoting their internalisation and 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) characterised by fibrosis, apoptosis and tubular dilation. This is due to aberrant ion transport, caused by elevated expression of Nedd4-2 substrates including ENaC (epithelial sodium channel). Clinically, 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 also contributes to development of this disease.
Methods:
NEDD4L/Nedd4-2 and substrate levels were measured in i) human kidney biopsies with and without DN and ii) at various stages in a mouse model of DN. CRISPR genetic reduction of Nedd4-2 was generated in mouse DN to investigate whether further deficiency of Nedd4-2 can exacerbate DN.
Results:
NEDD4L levels were significantly reduced in patients with DN. In a mouse model of DN, reduction of Nedd4-2 correlated with disease progression. Substrates of Nedd4-2, including ENaC, were elevated in DN, suggesting that Nedd4-2 contributes to disease pathology. Furthermore, genetic reduction of Nedd4-2 in the DN model modified disease progression and altered blood glucose levels, supporting the contribution of this gene to disease.
Conclusions:
NEDD4L/Nedd4-2 is a novel key player in DN that may serve as a biomarker for disease detection/severity and a potential future therapeutic target.
Biography
Jantina Manning is a mid-career research fellow in the Centre for Cancer Biology, Adelaide, Australia. She leads a research project focused on how the regulation of proteins by ubiquitination (particularly by the ubiquitin ligase Nedd4-2) protects against chronic kidney disease and diabetic nephropathy.