ZIP14 is involved in iron deposition and triggers ferroptosis in diabetic nephropathy

Abstract

Ferroptosis is caused by lipid peroxidation and iron accumulation and can cause cell death. Abnormally expressed iron transporters are involved in ferroptosis in a variety of diseases. ZRT/IRT-like protein 14 (ZIP14) is a transport protein that can mediate cellular uptake of iron, zinc and manganese. Herein, we have tested the hypothesis that the divalent metal transporter ZIP14 is involved in the initiation of ferroptosis in diabetic nephropathy (DN). DN was induced in eight-week old male rats by streptozotocin (STZ) before analysis of the degree of renal tubular injury. In addition, an in vitro model of DN in HK2 cells was used. We showed that ZIP14 was upregulated and Fe2+ levels increased both in vivo and in vitro. Expression of glutathione peroxidase 4 (GPX4) and the level of glutathione (GSH) were reduced, whereas that of malondialdehyde (MDA) increased. Ferrostatin-1(Fer-1) treatment reduced the expression of ZIP14 and the levels of Fe2+ and MDA, which is consistent with ferroptosis. Fer-1 improved kidney function in DN rats. This was characterized by urine levels of protein-to-creatinine ratio, α 1-microglobulin and N-acetyl-β-D-glucosaminidase. Our study demonstrates a novel role for ZIP14 in diabetic kidney injury mediated by ferroptosis, and suggests a potential new therapeutic approach for the treatment of diabetic nephropathy.

Expression of Ferroptosis-Related Genes is Correlated with Immune Microenvironment in Diabetic Kidney Disease

“…37,38 Numerous metabolic pathways involving iron, lipids, and amino acids regulated the process of ferroptosis in DKD. [39][40][41][42] The importance of ferroptosis in regulating IME had been implicated in cancers. 17,43,44 Tumor cells need more iron than normal cells to promote their rapid proliferation, which make them more vulnerable to iron overload and ROS accumulation.…”

Natural Flavonoids and Ferroptosis: Potential Therapeutic Opportunities for Human Diseases

“…Particularly, AA and AdA in phospholipids are the common substrates of lipid peroxidation in ferroptosis. − Unrestrained lipid peroxidation on cellular membranes can lead to the destruction of lipid bilayer and even membrane rupture, which in turn promotes ferroptotic cell death . Meanwhile, the levels of lipid peroxide byproducts such as MDA and 4-hydroxynonenal (4-HNE) are increased during ferroptosis, suggesting that these active aldehydes may also contribute to the occurrence of cell death. , …”

“…52 Meanwhile, the levels of lipid peroxide byproducts such as MDA and 4hydroxynonenal (4-HNE) are increased during ferroptosis, suggesting that these active aldehydes may also contribute to the occurrence of cell death. 53,54 Consequently, the synthesis of PUFA-PLs is an important prerequisite for driving ferroptosis. Two specific membraneremodeling enzymes, acyl-coenzyme A synthetase long chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3), are involved in this biological process.…”

Ferroptosis, a Rising Force against Renal Fibrosis

“…However, this becomes a prerequisite for the occurrence of ferroptosis under some pathological conditions. Multiple studies have discovered ferroptotic phenotypes during chronic kidney injury from IgA nephropathy (IgAN), membranous glomerulonephritis (MN), crystalline nephropathy, and diabetic nephropathy (DN) [107][108][109][110][111][112][113][114][115][116][117]. In contrast to its dual-edged role in the progression of liver fibrosis [118], ferroptosis is thought to play an unfavorable role in renal fibrosis, mediating renal cell death.…”