Angiotensinogen (AGT) is the only known substrate for renin, which is the rate-limiting enzyme of the renin-angiotensin system (RAS). Because the levels of AGT are close to the Michaelis-Menten constant for renin, not only renin levels, but also AGT levels can dictate the activity of the RAS, and up-regulation of AGT levels may lead to increased angiotensin peptide formation and consequent renal injury. Enhanced intrarenal AGT mRNA and/or protein levels have been observed in diabetic animals. Thus, intrarenal AGT plays an important role in the development and progression of diabetic nephropathy. While there is evidence that the intrarenal RAS is stimulated in various diseases and pathophysiologic states, there are no means currently available to directly quantitate the magnitude of the activation of the intrarenal RAS. We previously reported that urinary excretion rates of AGT provide a specific index of intrarenal RAS status in angiotensin II-infused rats. To facilitate quantitative measurements, we recently developed a direct method to measure urinary AGT using human AGT enzyme-linked immunosorbent assays (ELISA). Using technology developed in our laboratory, based on several preliminary data described below, this clinical translational study will define and characterize the urinary AGT levels in juveniles and young adults with type 1 diabetes mellitus (T1DM). The overall hypothesis is that urinary AGT levels can be a novel biomarker of the intrarenal RAS status. In accord with this hypothesis, the following Specific Aims are targeted: 1) To establish a cutoff value of urinary AGT levels in juvenile control subjects and patients with T1DM, which will be used in Specific Aim 4. 2) To demonstrate that urinary AGT levels are higher in T1DM juveniles compared to that in age and gender-matched control subjects in a prospective study. 3) To demonstrate that urinary AGT levels are higher in T1DM juveniles with nephropathy compared to that in T1DM juveniles without nephropathy using GoKindD collection. 4) To demonstrate in T1DM juveniles that the high baseline of urinary AGT levels at the entry are causally linked to the progression of renal dysfunction and further increased urinary AGT levels, while renal function and urinary AGT levels are stable in patients with the low baseline of urinary AGT levels at the entry. The quantitative aspects of our ELISA approach allow us to compare data among subjects over time with ease. If the aims of the proposed study are achieved, the activated intrarenal RAS can be monitored by measuring urinary AGT levels in these patients. Therefore, this research project holds the potential to achieve the greatest impact for individualized patient management in DM.
Our overall hypothesis is that urinary angiotensinogen (AGT) levels are useful as a novel biomarker of the status of the intrarenal renin-angiotensin system (RAS) and potentially serve as a predictor of the risks for developing renal injury. If the aims of the proposed study are successful, the intrarenal RAS can be monitored by measuring urinary AGT levels in patients. Therefore, this research project has the potential to achieve significant impact for individualized patient management in patients with type 1 diabetes using urinary AGT as a biomarker to optimize treatments with RAS blockades, and the success of this proposed study can lead to improved health and economic burden of chronic kidney disease and cardiovascular disease in the US.
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