Diabetic changes in Human Kidney Renin-Angiotensin System – Looking beyond Angiotensin-Converting Enzyme
Blockade of the Renin-Angiotensin System (RAS) is beneficial for patients suffering from chronic kidney disease (CKD) by reducing morbidity and mortality. Classically, prevention of deleterious effects exerted by Angiotensin Ⅱ (alias Ang 1-‑8), including vasoconstriction, anti-diuresis and inflammation, is central in pharmacological RAS manipulation. Nevertheless, disease progression towards end-stage renal disease cannot be prevented by RAS blockade in most patients.
Since decades, angiotensin-converting enzyme inhibitors (ACEi) were used to block the angiotensin-converting enyzme (ACE)‑dependent formation of Ang 1-8. Recently, RAS research has expanded by the discovery of novel Ang 1-‑8 antagonizing effectors (Ang 1-‑7) and alternative enzymatic pathways such as neutral endopeptidase (NEP) and ACE2 possibly exhibiting protective roles. In diabetic nephropathy, the local RAS might be altered by disease-related and kidney-specific factors, resulting in less beneficial effects of ACEi than in other diseases. The clinical significance of these potential functional consequences and the underlying molecular mechanisms of alterations in angiotensin metabolism, remains controversial in animal studies and is undefined in humans.
Here, we will employ a unique clinical setting that allows for concurrent analysis of both human kidney biopsies (local RAS) and the circulation (systemic RAS) applying novel mass spectrometry‑based techniques to discern individual enzymatic pathways of angiotensin formation. Specifically, we will assess whether local production of Ang 1-‑8 is increased in an ACE‑independent fashion, while the formation of its principal antagonist, Ang 1-‑7 along with its corresponding enzymes – including NEP – are diminished in patients with diabetic nephropathy. As second aim, we will study whether ACEi therapy alters Ang 1-‑8 formation differently in local versus systemic RAS.
The results of this study will help to elucidate potential alterations of the RAS, both at the circulatory, as well as the tissue level in health and disease. Collectively, the picture gained from these analyses will stimulate innovative avenues for improving therapy and ultimately, outcomes of patients suffering from prominent forms of CKD.
Methods and Skills:
Western blot; RT-PCR; immunohistochemistry; cell culture
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