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Effects of Endothelin‐A Receptor and Angiotensin Converting Enzyme Inhibition on the Development of Progressive Proteinuria in Diabetic Dahl SS Rats with Pre‐existing Renal Disease
Author(s) -
Spires Denisha,
Taylor Lateia,
McPherson Kasi,
Williams Jan
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.959.8
Subject(s) - proteinuria , lisinopril , medicine , diabetic nephropathy , endothelin receptor , endocrinology , streptozotocin , diabetes mellitus , ace inhibitor , blockade , angiotensin converting enzyme , kidney , blood pressure , receptor
The endothelin (ET) system has recently emerged as an interesting therapeutic target for the treatment of diabetic nephropathy (DN). Recently, we observed that ETA receptor blockade prevented the progression of renal disease in diabetic Dahl salt‐sensitive (STZ‐SS) rats with pre‐existing renal disease. Since angiotensin converting enzyme inhibitors (ACEi) are the first‐line of therapy for patients with DN, the present study examined whether treatment with an ACEi (lisinopril) in combination with an ETA receptor blocker (ABT‐627) would have a more beneficial effect on the progression of renal disease in STZ‐SS than ETA receptor blockade alone. Nine week‐old SS rats were treated with streptozotocin (STZ, 50 mg/kg, i.p.) to induce diabetes. After 3 weeks of diabetes, proteinuria increased to 353±34 mg/day. The rats were then separated into three groups: (1) vehicle (drinking water) and (2) ABT‐627 (5mg/kg/day) and (3) ABT‐627+lisinopril (10mg/kg/day). After 6 weeks of treatment, MAP (via telemetry) and proteinuria decreased by 15% and 40%, respectively, in STZ‐SS rats treated with ABT‐627 alone. However, we observed a greater effect with combination therapy which produced a 20% and 70% reduction in MAP and proteinuria, respectively, in STZ‐SS rats. These results indicate that chronic ETA receptor blockade alone or in combination with an ACEi delays the development of progressive proteinuria during diabetes‐induced renal injury by primarily reducing arterial pressure.This research was supported by NIGMS NIH P20GM104357 and AHA 12SDG9440034.