Expression and significance of hepcidin-ferroportin signaling pathway in rats with adenine-induced chronic kidney disease_West China Medical Journal

Authors：

LUO Shan ^1,2,3 , LIU Yiqin ^1,2,3 , KANG Ting ^1,2,3 , WU Weihua ^1,2,3 , LI Yan ^1,2,3 ,  OU Santao ^1,2,3

1. Department of Nephrology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P. R. China;
2. Sichuan Clinical Research Center for Nephrology, Luzhou, Sichuan 646000, P. R. China;
3. Sichuan Key Laboratory of Metabolic Vascular Diseases, Luzhou, Sichuan 646000, P. R. China;

Corresponding author：

OU Santao, Email: ousantao@163.com

Keywords：

Chronic kidney disease; renal fibrosis; ferroptosis; hepcidin; hepcidin-ferroportin 1; interleukin-6; nuclear factor kappa-B

DOI：

10.7507/1002-0179.202310075

Video：

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Objective To observe the expression of hepcidin-ferroportin (FPN) pathway in adenine-induced chronic kidney disease (CKD) rat model and to explore the mechanism of its involvement in renal fibrosis in CKD. Methods A total of 20 6-week-old male SD rats without specific pathogen were selected. The rats were divided into control group and CKD group, with 10 rats in each group, using a simple random method. Rats were sacrificed at the end of the second and sixth weeks after modeling. The levels of serum creatinine (Scr), blood urea nitrogen (BUN) and 24 h urine protein quantification were measured. The pathological changes of rats were observed. The iron content of rat kidney tissue was detected by colorimetric method, and the level of serum hepcidin-25 was detected by enzyme linked immunosorbent assay method in both groups. Immunohistochemistry and reverse transcription-polymerase chain reaction were used to detect the renal protein and mRNA expression of α-smooth muscle actin (α-SMA), collagen type Ⅰ (Col-Ⅰ), FPN1, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), nuclear factor kappa-B (NF-κB) P65. Results Compared with the control group, the levels of Scr, BUN, and 24 h urine protein quantification were higher in the CKD group at the end of the second and sixth weeks of modeling (P<0.05). The results of renal tissue staining showed that the CKD group had obvious glomerular structural disorders, tubular dilation, and interstitial collagen fiber deposition. Compared with the control group, the serum hepcidin-25 level and the iron content of kidney tissues in the CKD group were significantly higher, and correlation analysis suggested that both were positively correlated with the renal function of rats (P<0.05). Compared with the control group, the protein and mRNA expression levels of α-SMA, Col-Ⅰ, HAMP, IL-6, TNF-α, NF-κB P65 were higher (P<0.05), while FPN1 expression was lower in CKD group at the end of the second and sixth weeks of modeling (P<0.05). Correlation analysis results showed that HAMP mRNA expression was positively correlated with α-SMA, Col-Ⅰ, IL-6, TNF-α, and NF-κB p65 (P<0.001), which was negatively correlated with FPN1 mRNA expression (P<0.001). FPN1 mRNA expression was significantly negatively correlated with α-SMA, Col-Ⅰ (P<0.001). Conclusions Ferroptosis may be present in the adenine-induced rat model of CKD, and it may be involved in the process of renal fibrosis through the interaction of HAMP-FPN signaling pathway with the inflammatory response. Serum hepcidin-25 is expected to be a serological marker for the early diagnosis of CKD.

Citation： LUO Shan, LIU Yiqin, KANG Ting, WU Weihua, LI Yan, OU Santao. Expression and significance of hepcidin-ferroportin signaling pathway in rats with adenine-induced chronic kidney disease. West China Medical Journal, 2024, 39(7): 1102-1109. doi: 10.7507/1002-0179.202310075 Copy

1.	Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and perspectives. Lancet, 2013, 382(9888): 260-272.
2.	Humphreys BD. Mechanisms of renal fibrosis. Annu Rev Physiol, 2018, 80: 309-326.
3.	李磊, 夏煜琦, 程帆. 铁死亡在肾纤维化中的作用研究进展. 疑难病杂志, 2022, 21(8): 872-876.
4.	Wang J, Wang Y, Liu Y, et al. Ferroptosis, a new target for treatment of renal injury and fibrosis in a 5/6 nephrectomy-induced CKD rat model. Cell Death Discov, 2022, 8(1): 127.
5.	Zhou L, Xue X, Hou Q, et al. Targeting ferroptosis attenuates interstitial inflammation and kidney fibrosis. Kidney Dis (Basel), 2021, 8(1): 57-71.
6.	刘义琴, 朱婷婷, 毛海霞, 等. 腺嘌呤诱导慢性肾病大鼠模型肾纤维化过程中铁死亡相关因子的变化. 中国比较医学杂志, 2023, 33(7): 85-91.
7.	Joachim JH, Mehta KJ. Hepcidin in hepatocellular carcinoma. Br J Cancer, 2022, 127(2): 185-192.
8.	Nemeth E, Ganz T. Hepcidin-ferroportin interaction controls systemic iron homeostasis. Int J Mol Sci, 2021, 22(12): 6493.
9.	Wang J, Liu W, Li JC, et al. Hepcidin downregulation correlates with disease aggressiveness and immune infiltration in liver cancers. Front Oncol, 2021, 11: 714756.
10.	Cheng K, Huang Y, Wang C. 1, 25(OH)2D3 inhibited ferroptosis in zebrafish liver cells (ZFL) by regulating keap1-Nrf2-GPx4 and NF-κB-hepcidin axis. Int J Mol Sci, 2021, 22(21): 11334.
11.	Sun YB, Qu X, Caruana G, et al. The origin of renal fibroblasts/myofibroblasts and the signals that trigger fibrosis. Differentiation, 2016, 92(3): 102-107.
12.	Nastase MV, Zeng-Brouwers J, Wygrecka M, et al. Targeting renal fibrosis: mechanisms and drug delivery systems. Adv Drug Deliv Rev, 2018, 129: 295-307.
13.	Diwan V, Brown L, Gobe GC. Adenine-induced chronic kidney disease in rats. Nephrology (Carlton), 2018, 23(1): 5-11.
14.	Chen X, Kang R, Kroemer G, et al. Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol, 2021, 18(5): 280-296.
15.	Liu P, Wang W, Li Z, et al. Ferroptosis: a new regulatory mechanism in osteoporosis. Oxid Med Cell Longev, 2022, 2022: 2634431.
16.	Martin-Sanchez D, Ruiz-Andres O, Poveda J, et al. Ferroptosis, but not necroptosis, is important in nephrotoxic folic acid-induced AKI. J Am Soc Nephrol, 2017, 28(1): 218-229.
17.	Fang X, Wang H, Han D, et al. Ferroptosis as a target for protection against cardiomyopathy. Proc Natl Acad Sci U S A, 2019, 116(7): 2672-2680.
18.	Wang Y, Bi R, Quan F, et al. Ferroptosis involves in renal tubular cell death in diabetic nephropathy. Eur J Pharmacol, 2020, 888: 173574.
19.	Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol, 2021, 22(4): 266-282.
20.	Gammella E, Correnti M, Cairo G, et al. Iron availability in tissue microenvironment: the key role of ferroportin. Int J Mol Sci, 2021, 22(6): 2986.
21.	Peters HP, Laarakkers CM, Swinkels DW, et al. Serum hepcidin-25 levels in patients with chronic kidney disease are independent of glomerular filtration rate. Nephrol Dial Transplant, 2010, 25(3): 848-853.
22.	Lai B, Wu CH, Wu CY, et al. Ferroptosis and autoimmune diseases. Front Immunol, 2022, 13: 916664.
23.	Xiao Z, Kong B, Fang J, et al. Ferrostatin-1 alleviates lipopolysaccharide-induced cardiac dysfunction. Bioengineered, 2021, 12(2): 9367-9376.
24.	Gotardo ÉM, Ribeiro Gde A, Clemente TR, et al. Hepcidin expression in colon during trinitrobenzene sulfonic acid-induced colitis in rats. World J Gastroenterol, 2014, 20(15): 4345-4352.
25.	徐秋郁, 陈罡, 李雪梅. Erythroferrone 在铁代谢与肾性贫血中的研究进展. 中华肾脏病杂志, 2023, 39(12): 951-956.
26.	Lv W, Booz GW, Wang Y, et al. Inflammation and renal fibrosis: recent developments on key signaling molecules as potential therapeutic targets. Eur J Pharmacol, 2018, 820: 65-76.
27.	Tang PM, Nikolic-Paterson DJ, Lan HY. Macrophages: versatile players in renal inflammation and fibrosis. Nat Rev Nephrol, 2019, 15(3): 144-158.

1. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and perspectives. Lancet, 2013, 382(9888): 260-272.
2. Humphreys BD. Mechanisms of renal fibrosis. Annu Rev Physiol, 2018, 80: 309-326.
3. 李磊, 夏煜琦, 程帆. 铁死亡在肾纤维化中的作用研究进展. 疑难病杂志, 2022, 21(8): 872-876.
4. Wang J, Wang Y, Liu Y, et al. Ferroptosis, a new target for treatment of renal injury and fibrosis in a 5/6 nephrectomy-induced CKD rat model. Cell Death Discov, 2022, 8(1): 127.
5. Zhou L, Xue X, Hou Q, et al. Targeting ferroptosis attenuates interstitial inflammation and kidney fibrosis. Kidney Dis (Basel), 2021, 8(1): 57-71.
6. 刘义琴, 朱婷婷, 毛海霞, 等. 腺嘌呤诱导慢性肾病大鼠模型肾纤维化过程中铁死亡相关因子的变化. 中国比较医学杂志, 2023, 33(7): 85-91.
7. Joachim JH, Mehta KJ. Hepcidin in hepatocellular carcinoma. Br J Cancer, 2022, 127(2): 185-192.
8. Nemeth E, Ganz T. Hepcidin-ferroportin interaction controls systemic iron homeostasis. Int J Mol Sci, 2021, 22(12): 6493.
9. Wang J, Liu W, Li JC, et al. Hepcidin downregulation correlates with disease aggressiveness and immune infiltration in liver cancers. Front Oncol, 2021, 11: 714756.
10. Cheng K, Huang Y, Wang C. 1, 25(OH)2D3 inhibited ferroptosis in zebrafish liver cells (ZFL) by regulating keap1-Nrf2-GPx4 and NF-κB-hepcidin axis. Int J Mol Sci, 2021, 22(21): 11334.
11. Sun YB, Qu X, Caruana G, et al. The origin of renal fibroblasts/myofibroblasts and the signals that trigger fibrosis. Differentiation, 2016, 92(3): 102-107.
12. Nastase MV, Zeng-Brouwers J, Wygrecka M, et al. Targeting renal fibrosis: mechanisms and drug delivery systems. Adv Drug Deliv Rev, 2018, 129: 295-307.
13. Diwan V, Brown L, Gobe GC. Adenine-induced chronic kidney disease in rats. Nephrology (Carlton), 2018, 23(1): 5-11.
14. Chen X, Kang R, Kroemer G, et al. Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol, 2021, 18(5): 280-296.
15. Liu P, Wang W, Li Z, et al. Ferroptosis: a new regulatory mechanism in osteoporosis. Oxid Med Cell Longev, 2022, 2022: 2634431.
16. Martin-Sanchez D, Ruiz-Andres O, Poveda J, et al. Ferroptosis, but not necroptosis, is important in nephrotoxic folic acid-induced AKI. J Am Soc Nephrol, 2017, 28(1): 218-229.
17. Fang X, Wang H, Han D, et al. Ferroptosis as a target for protection against cardiomyopathy. Proc Natl Acad Sci U S A, 2019, 116(7): 2672-2680.
18. Wang Y, Bi R, Quan F, et al. Ferroptosis involves in renal tubular cell death in diabetic nephropathy. Eur J Pharmacol, 2020, 888: 173574.
19. Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol, 2021, 22(4): 266-282.
20. Gammella E, Correnti M, Cairo G, et al. Iron availability in tissue microenvironment: the key role of ferroportin. Int J Mol Sci, 2021, 22(6): 2986.
21. Peters HP, Laarakkers CM, Swinkels DW, et al. Serum hepcidin-25 levels in patients with chronic kidney disease are independent of glomerular filtration rate. Nephrol Dial Transplant, 2010, 25(3): 848-853.
22. Lai B, Wu CH, Wu CY, et al. Ferroptosis and autoimmune diseases. Front Immunol, 2022, 13: 916664.
23. Xiao Z, Kong B, Fang J, et al. Ferrostatin-1 alleviates lipopolysaccharide-induced cardiac dysfunction. Bioengineered, 2021, 12(2): 9367-9376.
24. Gotardo ÉM, Ribeiro Gde A, Clemente TR, et al. Hepcidin expression in colon during trinitrobenzene sulfonic acid-induced colitis in rats. World J Gastroenterol, 2014, 20(15): 4345-4352.
25. 徐秋郁, 陈罡, 李雪梅. Erythroferrone 在铁代谢与肾性贫血中的研究进展. 中华肾脏病杂志, 2023, 39(12): 951-956.
26. Lv W, Booz GW, Wang Y, et al. Inflammation and renal fibrosis: recent developments on key signaling molecules as potential therapeutic targets. Eur J Pharmacol, 2018, 820: 65-76.
27. Tang PM, Nikolic-Paterson DJ, Lan HY. Macrophages: versatile players in renal inflammation and fibrosis. Nat Rev Nephrol, 2019, 15(3): 144-158.

West China Medical Journal

Expression and significance of hepcidin-ferroportin signaling pathway in rats with adenine-induced chronic kidney disease

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