Understanding the role of adiponectin in kidney disease development at a population level

Reduced circulating adiponectin levels are associated with poor outcome in patients with diabetic kidney disease (DKD) (1). Adiponectin has been shown to be protective against the development of DKD in Type 2 diabetic models (2, 3, 4). We have shown, for the first time, that adiponectin can protect against DKD and albuminuria (albumin excreted into the urine) through a novel mechanism; restoration of the glomerular vascular glycocalyx layer. The glycocalyx is a protective gel-like layer that lines all blood vessels and glomeruli are the microvessels in the kidney that filter blood. Population studies have shown that circulating adiponectin levels are inversely associated with albuminuria (2) and have a causal effect on reduced glomerular filtration rate, both equating to loss of kidney function (5).

We hypothesise a causal relationship between adiponectin, albuminuria and kidney disease development.

Aims and objectives

Aim: To demonstrate a role for adiponectin in glycocalyx integrity/vascular disease at a population level.

Objectives

1. To demonstrate an association between adiponectin and glycocalyx depth
2. To demonstrate a causal relationship between adiponectin and kidney disease.
3. To demonstrate a causal relationship between adiponectin and kidney function

Methodology

1. The relationship between circulating adiponectin and measures of glycocalyx depth will be examined (n=>1000), within Avon Longitudinal Study of Parents and Children (http://www.bristol.ac.uk/alspac/researchers/our-data/). This is the largest population study where glycocalyx depth has been measured clinically.
2. The causal relationship between circulating adiponectin on DKD and chronic kidney disease (CKD), will be explored using GWASs of different populations and Mendelian randomization (MR), an applied genetic epidemiologic approach, coined at University of Bristol.
3. The causal relationship between circulating levels of adiponectin and albuminuria will be explored, using MR, and whether circulating enzymes, that we have previously shown cause glycocalyx damage in animal models of kidney disease (matrix metalloproteinases) mediate this effect.

Impact: This study will use will build upon our mechanistic pre-clinical studies to prove relevance to human disease, using a powerful approach that we predict will result in rapid translation to our patients living with diabetes.

Supervisors: Dr Rebecca Foster (primary supervisor), Dr Aldara Martin Alonso, Dr Emma Vincent (THS), Prof Simon Satchell (THS), Dr Carolina Borges (PHS)

How to apply for this project

This project will be based in Bristol Medical School - Translational Health Sciences in the Faculty of Health Sciences at the University of Bristol. Use this information to search for the relevant programme in our online application system.