IL-6 and Diabetic Kidney Disease

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2025 Jan 3

PMID 39749325

Authors

Lei Zhang

Futian Xu

Liyan Hou

Affiliations

Soon will be listed here.

Abstract

Diabetic kidney disease (DKD) is a severe microvascular complication of diabetes associated with high mortality and disability rates. Inflammation has emerged as a key pathological mechanism in DKD, prompting interest in novel therapeutic approaches targeting inflammatory pathways. Interleukin-6 (IL-6), a well-established inflammatory cytokine known for mediating various inflammatory responses, has attracted great attention in the DKD field. Although multiple and studies highlight the potential of targeting IL-6 in DKD treatment, its exact roles in the disease remains unclear. This review presents the roles of IL-6 in the pathogenesis of DKD, including immunoinflammation, metabolism, hemodynamics, and ferroptosis. In addition, we summarize the current status of IL-6 inhibitors in DKD-related clinical trials and discuss the potential of targeting IL-6 for treating DKD in the clinic.

References

Wueest S, Konrad D . The controversial role of IL-6 in adipose tissue on obesity-induced dysregulation of glucose metabolism. Am J Physiol Endocrinol Metab. 2020; 319(3):E607-E613. DOI: 10.1152/ajpendo.00306.2020. View

Wu R, Liu X, Yin J, Wu H, Cai X, Wang N . IL-6 receptor blockade ameliorates diabetic nephropathy via inhibiting inflammasome in mice. Metabolism. 2018; 83:18-24. DOI: 10.1016/j.metabol.2018.01.002. View

Kado S, Nagase T, Nagata N . Circulating levels of interleukin-6, its soluble receptor and interleukin-6/interleukin-6 receptor complexes in patients with type 2 diabetes mellitus. Acta Diabetol. 1999; 36(1-2):67-72. DOI: 10.1007/s005920050147. View

Hooke D, Gee D, Atkins R . Leukocyte analysis using monoclonal antibodies in human glomerulonephritis. Kidney Int. 1987; 31(4):964-72. DOI: 10.1038/ki.1987.93. View

Nechemia-Arbely Y, Barkan D, Pizov G, Shriki A, Rose-John S, Galun E . IL-6/IL-6R axis plays a critical role in acute kidney injury. J Am Soc Nephrol. 2008; 19(6):1106-15. PMC: 2396933. DOI: 10.1681/ASN.2007070744. View

Amdur R, Feldman H, Gupta J, Yang W, Kanetsky P, Shlipak M . Inflammation and Progression of CKD: The CRIC Study. Clin J Am Soc Nephrol. 2016; 11(9):1546-1556. PMC: 5012490. DOI: 10.2215/CJN.13121215. View

McInnes I, Thompson L, Giles J, Bathon J, Salmon J, Beaulieu A . Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study. Ann Rheum Dis. 2013; 74(4):694-702. PMC: 4392313. DOI: 10.1136/annrheumdis-2013-204345. View

Liu J, Han C, Xie B, Wu Y, Liu S, Chen K . Rhbdd3 controls autoimmunity by suppressing the production of IL-6 by dendritic cells via K27-linked ubiquitination of the regulator NEMO. Nat Immunol. 2014; 15(7):612-22. DOI: 10.1038/ni.2898. View

Kefaloyianni E, Muthu M, Kaeppler J, Sun X, Sabbisetti V, Chalaris A . ADAM17 substrate release in proximal tubule drives kidney fibrosis. JCI Insight. 2016; 1(13). PMC: 5026414. DOI: 10.1172/jci.insight.87023. View

10.

Martinez-Fabregas J, Wilmes S, Wang L, Hafer M, Pohler E, Lokau J . Kinetics of cytokine receptor trafficking determine signaling and functional selectivity. Elife. 2019; 8. PMC: 6914340. DOI: 10.7554/eLife.49314. View

11.

Moriyama T, FUJIBAYASHI M, Fujiwara Y, Kaneko T, Xia C, Imai E . Angiotensin II stimulates interleukin-6 release from cultured mouse mesangial cells. J Am Soc Nephrol. 1995; 6(1):95-101. DOI: 10.1681/ASN.V6195. View

12.

Gunes A, Schmitt C, Bilodeau L, Huet C, Belblidia A, Baldwin C . IL-6 Trans-Signaling Is Increased in Diabetes, Impacted by Glucolipotoxicity, and Associated With Liver Stiffness and Fibrosis in Fatty Liver Disease. Diabetes. 2023; 72(12):1820-1834. PMC: 10658070. DOI: 10.2337/db23-0171. View

13.

Manhiani M, Quigley J, Socha M, Motamed K, Imig J . IL6 suppression provides renal protection independent of blood pressure in a murine model of salt-sensitive hypertension. Kidney Blood Press Res. 2007; 30(4):195-202. DOI: 10.1159/000104094. View

14.

Gutierrez A, Gao Z, Hamidi V, Zhu L, Bermudez Saint Andre K, Riggs K . Anti-diabetic effects of GLP1 analogs are mediated by thermogenic interleukin-6 signaling in adipocytes. Cell Rep Med. 2022; 3(11):100813. PMC: 9729831. DOI: 10.1016/j.xcrm.2022.100813. View

15.

Bettelli E, Carrier Y, Gao W, Korn T, Strom T, Oukka M . Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006; 441(7090):235-8. DOI: 10.1038/nature04753. View

16.

Rose-John S . IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int J Biol Sci. 2012; 8(9):1237-47. PMC: 3491447. DOI: 10.7150/ijbs.4989. View

17.

Navarro J, Milena F, Mora C, Leon C, Garcia J . Renal pro-inflammatory cytokine gene expression in diabetic nephropathy: effect of angiotensin-converting enzyme inhibition and pentoxifylline administration. Am J Nephrol. 2006; 26(6):562-70. DOI: 10.1159/000098004. View

18.

Sadagurski M, Norquay L, Farhang J, DAquino K, Copps K, White M . Human IL6 enhances leptin action in mice. Diabetologia. 2009; 53(3):525-35. PMC: 2815798. DOI: 10.1007/s00125-009-1580-8. View

19.

Nowell M, Williams A, Carty S, Scheller J, Hayes A, Jones G . Therapeutic targeting of IL-6 trans signaling counteracts STAT3 control of experimental inflammatory arthritis. J Immunol. 2008; 182(1):613-22. DOI: 10.4049/jimmunol.182.1.613. View

20.

Kraakman M, Kammoun H, Allen T, Deswaerte V, Henstridge D, Estevez E . Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance. Cell Metab. 2015; 21(3):403-16. DOI: 10.1016/j.cmet.2015.02.006. View