Renal iron accelerates the progression of diabetic nephropathy in the HFE gene knockout mouse model of iron overload

Kapil Chaudhary, Aruna Chilakala, Sudha Ananth, Ashok Mandala, Rajalakshmi Veeranan-Karmegam, Folami L. Powell, Vadivel Ganapathy, Jaya P. Gnana-Prakasam

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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.

Original languageEnglish (US)
Pages (from-to)F512-F517
JournalAmerican Journal of Physiology - Renal Physiology
Volume317
Issue number2
DOIs
StatePublished - Aug 2019

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Keywords

  • Diabetic nephropathy
  • Hemochromatosis
  • High Fe iron
  • Iron
  • Renin-angiotensin system

ASJC Scopus subject areas

  • Physiology
  • Urology

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