Effects of Heterozygous TfR1 (Transferrin Receptor 1) Deletion in Pathogenesis of Renal Fibrosis in Mice

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 75; no. 2; pp. 413 - 421
• Main Authors: Yasumura, Seiki, Naito, Yoshiro, Okuno, Keisuke, Sawada, Hisashi, Asakura, Masanori, Masuyama, Tohru, Ishihara, Masaharu
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01-02-2020
• Subjects: blood glucose; iron; ferritins; oxidative stress; transforming growth factors
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.119.13670

Renal fibrosis is the final pathological process common for several types of end-stage renal diseases, including obstructive nephropathy and diabetic kidney disease. Substantial renal iron loads and oxidative stress have been reported to contribute to the development of renal diseases. TfR1 (transferrin receptor 1) plays a crucial role in cellular iron transport. However, there are no studies investigating TfR1 in the pathophysiology of renal fibrosis. Here, we investigate the role of TfR1 in the development of renal fibrosis. Primarily, to ascertain an association of TfR1 in the pathophysiology of renal fibrosis, we induced unilateral ureteral obstruction in wild-type (WT) and heterozygous TfR1 deleted (TfR1+/−) mice. TfR1+/− mice exhibited attenuated renal fibrosis, along with reduced renal expression of ferritin and 4-hydroxynonenal as compared with WT mice after unilateral ureteral obstruction. In addition, renal expression of TGFβ-RI (transforming growth factor-β receptor I) and Smad2, downstream signaling of TGFβ-RI was attenuated in TfR1+/− mice compared with WT mice after unilateral ureteral obstruction. Next, we investigated the role of TfR1 in the development of diabetic kidney disease. No difference was observed in blood glucose levels and urinary albumin:creatinine ratios between WT and TfR1+/− diabetic mice after streptozotocin administration. In contrast, TfR1+/− mice showed suppressed renal fibrosis, along with reduced renal expression of ferritin, 4-hydroxynonenal, TGFβ-RI, and Smad2 compared with WT mice after streptozotocin administration. These results suggest that TfR1 plays an important role in the development of renal fibrosis.