title: Renal iron overload in rats with diabetic nephropathy.
abstract: Diabetic nephropathy (DN) remains incurable and is the main cause of end-stage renal disease. We approached the pathophysiology of DN with systems biology, and a comprehensive profile of renal transcripts was obtained with RNA-Seq in ZS (F1 hybrids of Zucker and spontaneously hypertensive heart failure) rats, a model of diabetic nephropathy. We included sham-operated lean control rats (LS), sham-operated diabetic (DS), and diabetic rats with induced renal ischemia (DI). Diabetic nephropathy in DI was accelerated by the single episode of renal ischemia. This progressive renal decline was associated with renal iron accumulation, although serum and urinary iron levels were far lower in DI than in LS. Furthermore, obese/diabetic ZS rats have severe dyslipidemia, a condition that has been linked to hepatic iron overload. Hence, we tested and found that the fatty acids oleic acid and palmitate stimulated iron accumulation in renal tubular cells in vitro. Renal mRNAs encoding several key proteins that promote iron accumulation were increased in DI. Moreover, renal mRNAs encoding the antioxidant proteins superoxide dismutase, catalase, and most of the glutathione synthetic system were suppressed, which would magnify the prooxidant effects of renal iron loads. Substantial renal iron loads occur in obese/diabetic rats. We propose that in diabetes, specific renal gene activation is partly responsible for iron accumulation. This state might be further aggravated by lipid-stimulated iron uptake. We suggest that progressive renal iron overload may further advance renal injury in obese/diabetic ZS rats.
authors.affiliation: Departments of Medicine, Indiana University School of Medicine, Indianapolis, Indiana Roudebush Veterans' Affairs Medical Center, Indianapolis, Indiana.
authors.forename: Jesus H
authors.initials: JH
authors.lastname: Dominguez
authors.affiliation: Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Departments of Medicine, Indiana University School of Medicine, Indianapolis, Indiana kajkelly@iu.edu.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Kelly
keywords: complement; diabetic nephropathies; ischemia; kidney failure, chronic