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.

Accumulating evidence strongly implicates iron in the pathogenesis of aging and disease. Iron levels have been found to increase with age in both the human and mouse retinas. We and others have shown that retinal diseases such as age-related macular degeneration and diabetic retinopathy are associated with disrupted iron homeostasis, resulting in retinal iron accumulation. In addition, hereditary disorders due to mutation in one of the iron regulatory genes lead to age dependent retinal iron overload and degeneration. However, our knowledge on whether iron toxicity contributes to the retinopathy is limited. Recently, we reported that iron accumulation is associated with the upregulation of retinal and renal renin–angiotensin system (RAS). Evidences indicate that multiple genes/components of the RAS are targets of Wnt/β-catenin signaling. Interestingly, aberrant activation of Wnt/β-catenin signaling is observed in several degenerative diseases. In the present study, we explored whether iron accumulation regulates canonical Wnt signaling in the retina. We found that in vitro and in vivo iron treatment resulted in the upregulation of Wnt/β-catenin signaling and its downstream target genes including renin–angiotensin system in the retina. We confirmed further that iron activates canonical Wnt signaling in the retina using TOPFlash T-cell factor/lymphoid enhancer factor promoter assay and Axin2-LacZ reporter mouse. The presence of an iron chelator or an antioxidant reversed the iron-mediated upregulation of Wnt/β-catenin signaling in retinal pigment epithelial (RPE) cells. In addition, treatment of RPE cells with peroxisome proliferator-activated receptor (PPAR) α-agonist fenofibrate prevented iron-induced activation of oxidative stress and Wnt/β-catenin signaling by chelating the iron. The role of fenofibrate, an FDA-approved drug for hyperlipidemia, as an iron chelator has potentially significant therapeutic impact on iron associated degenerative diseases.

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The vessels of Wearn include the arterioluminal and arteriosinusoidal vessels and they are not Thebesian veins We read the article by Kim et al., and are obliged to clarify certain terms used therein [1]. The term "arterioluminal vessel" was introduced by Wearn in 1933 and contained two definitions [2]. For clarity, Wearn subclassified the aformentioned vascular communications between coronary arteries and heart chambers into the arterioluminal and arteriosinusoidal vessels [2]. For disambiguation, the term "vessels of Wearn" has been used to encompass the arterioluminal and arteriosinusoidal vessels. The 1933 article by Wearn notes that it was 1706 when the coronary artery-cameral connections were first reported by Raymond Vieussens [2,3]. The 1708 publication by Thebesius was about a study that discovered the coronary vein-cameral connections, which have been eponymously referred to as Thebesian veins [4]. It is fundamentally erroneous to classify an arterioluminal and/ or arteriosinusoidal vessel as a Thebesian vein. However, careful review of the original report published in 1933 by Wearn, i.e., the report that introduced the terms arterioluminal and arteriosinusoidal, should provide the reader and future authors with a uniform nomenclature. Also, many of the connections reported by Kim et al. may be of the arteriosinusoidal and not the arterioluminal subtype of the vessels of Wearn. The arteriocapillary connections were inaccurately reported as a type of Thebesian vein by Kim et al., and the possibility of an arteriocapillary type of coronary artery-cameral connection may warrant further study [1]. Parenthetically, coronary arteries normally flow toward coronary capillaries. Capillaries could theoretically transmit flow into the cardiac lumen in a manner similar to the myocardial sinusoids [2]. Regardless, none of the three terms reported by Kim et al. as Thebesian veins are properly attributable to Thebesius [1].The authors of this letter have been trying to correct the erroneous and misleading nomenclature that refers to the coronary artery-cameral connections "vessels of Wearn" as valveless Thebesian veins. Arteries and their tributaries are considered valveless. Thus, using the term "valveless Thebesian vein" to refer to a type of coronary artery-cameral connection facilitates obfuscation and not clarity. The word "valveless" is irrelevant, the word "Thebesius" incorrectly suggests that the artery-cameral connections were discovered by Thebesius, and the word "vein" misrepresents the nature of the vascular connection. We plead for authorship and advocacy by others to help create and establish medical terminology that is an accurate reflection of reality [5]. With the international use of consistent medical terminology, the natural history, prevalence, and prognosis should