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Kidney Int ; 94(5): 937-950, 2018 11.
Article in English | MEDLINE | ID: mdl-30190172

ABSTRACT

Diabetic nephropathy correlates more closely to defective mitochondria and increased oxidative stress in the kidney than to hyperglycemia. A key driving factor of diabetic nephropathy is angiotensin II acting via the G-protein-coupled cell membrane type 1 receptor. The present study aimed to investigate the role of the angiotensin II type 2 receptor (AT2R) at the early stages of diabetic nephropathy. Using receptor binding studies and immunohistochemistry we found that the mitochondria in renal tubules contain high-affinity AT2Rs. Increased renal mitochondrial AT2R density by transgenic overexpression was associated with reduced superoxide production of isolated mitochondria from non-diabetic rats. Streptozotocin-induced diabetes (28 days) caused a drop in the ATP/oxygen ratio and an increase in the superoxide production of isolated renal mitochondria from wild-type diabetic rats. This correlated with changes in the renal expression profile and increased tubular epithelial cell proliferation. AT2R overexpression in tubular epithelial cells inhibited all diabetes-induced renal changes including a drop in mitochondrial bioenergetics efficiency, a rise in mitochondrial superoxide production, metabolic reprogramming, and increased proliferation. Thus, AT2Rs translocate to mitochondria and can contribute to reno-protective effects at early stages of diabetes. Hence, targeted AT2R overexpression in renal cells may open new avenues to develop novel types of drugs preventing diabetic nephropathy.


Subject(s)
Diabetes Mellitus, Experimental/complications , Diabetic Nephropathies/prevention & control , Kidney Tubules/physiology , Mitochondria/physiology , Receptor, Angiotensin, Type 2/physiology , Adenosine Triphosphate/biosynthesis , Animals , Cell Proliferation , Gene Expression Profiling , Male , Mitochondria/chemistry , Rats , Reactive Oxygen Species/metabolism , Receptor, Angiotensin, Type 2/analysis , Streptozocin
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