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Renal iron accelerates the progression of diabetic nephropathy in the HFE gene knockout mouse model of iron overload.
- Source :
-
American journal of physiology. Renal physiology [Am J Physiol Renal Physiol] 2019 Aug 01; Vol. 317 (2), pp. F512-F517. Date of Electronic Publication: 2019 Jun 12. - Publication Year :
- 2019
-
Abstract
- Diabetic nephropathy (DN) is the most common cause of end-stage renal disease associated with high mortality worldwide. Increases in iron levels have been reported in diabetic rat kidneys as well as in human urine of patients with diabetes. In addition, a low-iron diet or iron chelators delay the progression of DN in patients with diabetes and in animal models of diabetes. Possible maladaptive mechanisms of organ damage by tissue iron accumulation have not been well studied. We recently reported that iron induced the retinal renin-angiotensin system (RAS) and accelerated the progression of diabetic retinopathy. However, whether iron regulates the systemic RAS is unknown. To explore if iron alters the expression of intrarenal RAS and its role in the progression of DN, we used the high Fe iron (HFE) knockout mouse, a genetic model of systemic iron overload. We found that diabetes upregulated the expression of iron regulatory proteins and augmented tissue iron accumulation in the kidneys of both type 1 and type 2 diabetic mouse models. Iron accumulation in the kidneys of HFE knockout mice was associated with increase in serum and intrarenal renin expression. Induction of diabetes in HFE knockout mice using streptozotocin caused a much higher accumulation of renal iron and accelerated the progression of nephropathy compared with diabetic wild-type mice. Treatment of diabetic mice with the iron chelator deferiprone reversed the renin upregulation and reduced kidney injury. Thus, our results establish a new link between renal iron and RAS activity. Exploring the mechanisms of iron-induced RAS activation further may have a significant therapeutic impact on hypertension and DN.
- Subjects :
- Animals
Deferiprone pharmacology
Deferiprone therapeutic use
Diabetes Mellitus, Experimental metabolism
Diabetic Nephropathies drug therapy
Disease Progression
Iron Chelating Agents pharmacology
Iron Chelating Agents therapeutic use
Male
Mice
Mice, Knockout
Renin biosynthesis
Renin-Angiotensin System drug effects
Diabetic Nephropathies genetics
Diabetic Nephropathies metabolism
Hemochromatosis Protein genetics
Hemochromatosis Protein metabolism
Iron metabolism
Iron Overload genetics
Iron Overload metabolism
Kidney metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1466
- Volume :
- 317
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Renal physiology
- Publication Type :
- Academic Journal
- Accession number :
- 31188032
- Full Text :
- https://doi.org/10.1152/ajprenal.00184.2019