Activation of the kidney renin-angiotensin system (RAS) contributes to the development of diabetic nephropathy. This notion is based on indirect evidence and the known therapeutic benefit of RAS blockers. We hypothesize that increased angiotensinogen (AOG) and renin in urine from subjects with type 1 diabetes will provide an early signature of kidney RAS activation. The longitudinal follow-up of subjects with type 1 diabetes enrolled in the Diabetes Control and Complications Trial (DCCT) offers a unique opportunity to test this hypothesis. We propose to evaluate AOG and renin concurrently in urine samples from participants in the DCCT study who were not treated with RAS blockers or any other anti-hypertensive medications during a 9 year longitudinal follow-up. We will examine the question of whether the development of albuminuria, both in the microalbuminuric and macroalbuminuric range, could be predicted by the levels of urinary AOG and renin. Moreover, we plan to measure total AOG as well as active (intact) AOG. For measurement of intact AOG a novel ELISA assay will be used. Intact (or active) AOG reflects the potential for the formation of Ang I by renin cleavage better than total AOG as measured by current assays and the amount of AOG consumed in the process can be inferred from the ratio of intact to total AOG. Urinary renin appears to be regulated differently from renin in plasma and is increased in diabetes. Thus, unlike plasma renin activity, which is decreased in diabetes, urinary renin may be increased and reflect an over-active kidney RAS. A paracrine signaling pathway in the kidney has been recently identified whereby high levels of glucose trigger the release of renin. We hypothesize that improved metabolic control, as provided by intensive insulin therapy in DCCT participants exerted a more effective down-regulatory effect on the kidney RAS as compared to the conventional insulin therapy arm and that this will be manifested by reduced levels of urinary AOG and renin.
The specific aims are:
Aim 1. To define the urine RAS profile (AOG and renin) of type 1 diabetes with normoalbuminuria, microalbuminuria and macroalbuminuria based on the analysis of stored urine biosamples from subjects with type 1 diabetes in the DCCT study.
Aim 2. To determine whether an increase in urinary angiotensinogen and/or renin antedate the development of micro-albuminuria and macroalbuminuria based on the analysis of stored biosamples from subjects with type 1 diabetes in the DCCT study followed longitudinally for 9 years.
Aim 3. To determine if improved glycemic control provided by intensive insulin therapy in subjects with normo- albuminuria, micro-albuminuria and macroalbuminuria reduces urinary AOG and/or renin based on the analysis of stored urine biosamples from subjects with type 1 diabetes in the DCCT study who were followed longitudinally for 9 years.
The human urine contains components of the kidney renin-angiotensin system (RAS) called angiotensinogen and renin which we think will provide an early signature that this system is overactive in subjects with type 1 diabetes who later on will go on to develop signs of nephropathy. Angiotensinogen and renin will be measured in urine biosamples from participants in the Diabetes Control and Complications Trial (DCCT) study under the hypothesis that improved metabolic control, as provided by intensive insulin therapy, exerts a more effective suppressive effect on the kidney RAS as compared to conventional insulin therapy.
