Galectin-9 (Gal-9) is a multifunctional lectin that moderates inflammation and organ damage. In this study, we tested whether Gal-9 has a protective role in the pathogenesis of endotoxemic acute kidney injury.
We examined the levels of Gal-9 in control mice after lipopolysaccharide (LPS) administration. We developed Gal-9 knockout (KO) mice that lack Gal-9 systemically and evaluated the role of Gal-9 in LPS-induced proinflammatory cytokines, vascular permeability, and renal injury.
Gal-9 levels were increased in the plasma, kidney, and spleen within 4 h after LPS administration to wild-type mice. Gal-9 deficiency did not affect the LPS-induced increase in plasma tumor necrosis factor-α levels at 1 h or vascular permeability at 6 h. Lower urine volume and reduced creatinine clearance were observed in Gal-9-KO mice compared with wild-type mice after LPS administration. Gal-9-KO mice had limited improvement in urine volume after fluid resuscitation compared with wild-type mice. LPS reduced the body temperature 12 h after its administration. Hypothermia had disappeared in wild-type mice by 24 h, whereas it was sustained until 24 h in Gal-9-KO mice. Importantly, maintaining body temperature in Gal-9-KO mice improved the response of urine flow to fluid resuscitation.
Deficiency in Gal-9 worsened LPS-induced hypothermia and kidney injury in mice. The accelerated hypothermia induced by Gal-9 deficiency contributed to the blunted response to fluid resuscitation.
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Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. J Am Med Assoc. 2005;294:813–8.
Coca SG, Yusuf B, Shlipak MG, Garg AX, Parikh CR. Long-term risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis. 2009;53:961–73.
Doi K. Role of kidney injury in sepsis. J Intensive Care. 2016;4:17.
Nakano D. Septic acute kidney injury: a review of basic research. Clin Exp Nephrol. 2020;24:1091–102.
Wiewel MA, Harmon MB, van Vught LA, Scicluna BP, Hoogendijk AJ, Horn J, et al. Risk factors, host response and outcome of hypothermic sepsis. Crit Care. 2016;20:1–9.
Hirashima M, Niki T, Masaki T. Galectin-9 changes its function to maintain homeostasis. Trends Glycosci Glycotechnol. 2018;30:SE09-18.
Moritoki M, Kadowaki T, Niki T, Nakano D, Soma G, Mori H, et al. Galectin-9 ameliorates clinical severity of MRL/lpr lupus-prone mice by inducing plasma cell apoptosis independently of Tim-3. PLoS ONE. 2013;8:e60807.
Nio-Kobayashi J. Histological mapping and subtype-specific functions of galectins in health and disease. Trends Glycosci Glycotechnol. 2018;30:SE89-96.
Tsuboi Y, Abe H, Nakagawa R, Oomizu S, Watanabe K, Nishi N, et al. Galectin-9 protects mice from the Shwartzman reaction by attracting prostaglandin E2-producing polymorphonuclear leukocytes. Clin Immunol. 2007;124:221–33.
Kadowaki T, Morishita A, Niki T, Hara J, Sato M, Tani J, et al. Galectin-9 prolongs the survival of septic mice by expanding tim-3-expressing natural killer T cells and PDCA-1+ CD11c+ macrophages. Crit Care. 2013;17:1–11.
Kojima K, Arikawa T, Saita N, Goto E, Tsumura S, Tanaka R, et al. Galectin-9 attenuates acute lung injury by expanding CD14-plasmacytoid dendritic cell-like macrophages. Am J Respir Crit Care Med. 2012;184:328–39.
Naito Y, Hino K, Bono H, Ui-Tei K. CRISPRdirect: software for designing CRISPR/Cas guide RNA with reduced off-target sites. Bioinformatics. 2015;31:1120.
Nakano D, Kitada K, Wan N, Zhang Y, Wiig H, Wararat K, et al. Lipopolysaccharide induces filtrate leakage from renal tubular lumina into the interstitial space via a proximal tubular Toll-like receptor 4–dependent pathway and limits sensitivity to fluid therapy in mice. Kidney Int. 2020;97:904–12.
Swoap SJ, Rathvon M, Gutilla M. AMP does not induce torpor. Am J Physiol. 2007;293:468–73.
Carlin JL, Jain S, Duroux R, Suresh RR, Xiao C, Auchampach JA, et al. Activation of adenosine A2A or A2B receptors causes hypothermia in mice. Neuropharmacology. 2018;139:268.
Kitamura H, Nakano D, Sawanobori Y, Asaga T, Yokoi H, Yanagita M, et al. Guanylyl Cyclase A in both renal proximal tubular and vascular endothelial cells protects the kidney against acute injury in rodent experimental endotoxemia models. Anesthesiology. 2018;129:296–310.
Leisman DE, Fernandes TD, Bijol V, Abraham MN, Lehman JR, Taylor MD, et al. Impaired angiotensin II type 1 receptor signaling contributes to sepsis-induced acute kidney injury. Kidney Int. 2021;99:148–60.
Wu J, Agbor LN, Fang S, Mukohda M, Nair AR, Nakagawa P, et al. Failure to vasodilate in response to salt loading blunts renal blood flow and causes salt-sensitive hypertension. Cardiovasc Res. 2021;117:308.
Xu H, Ma Z, Lu S, Li R, Lyu L, Ding L, et al. Renal resistive index as a novel indicator for renal complications in high-fat diet-fed mice. Kidney Blood Press Res. 2017;42:1128–40.
Hong Y-H, Chao W-W, Chen M-L, Lin B-F. Ethyl acetate extracts of alfalfa (Medicago sativa L.) sprouts inhibit lipopolysaccharide-induced inflammation in vitro and in vivo. J Biomed Sci. 2009;16:64.
Nakano D, Doi K, Kitamura H, Kuwabara T, Mori K, Mukoyama M, et al. Reduction of tubular flow rate as a mechanism of oliguria in the early phase of endotoxemia revealed by intravital imaging. J Am Soc Nephrol. 2015;26:3035–44.
Billeter AT, Hellmann J, Roberts H, Druen D, Gardner SA, Sarojini H, et al. MicroRNA-155 potentiates the inflammatory response in hypothermia by suppressing IL-10 production. FASEB J. 2014;28:5322.
Broman LM, Carlström M, Källskog Ö, Wolgast M. Effect of nitric oxide on renal autoregulation during hypothermia in the rat. Pflugers Arch. 2017;469:669.
van Deventer S, Buller H, ten Cate J, Aarden L, Hack C, Sturk A. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood. 1990;76:2520–6.
Xu C, Wu X, Hack BK, Bao L, Cunningham PN. TNF causes changes in glomerular endothelial permeability and morphology through a Rho and myosin light chain kinase-dependent mechanism. Physiol Rep. 2015;3:e12636.
Cunningham PN, Dyanov HM, Park P, Wang J, Newell KA, Quigg RJ. Acute renal failure in endotoxemia is caused by TNF acting directly on TNF receptor-1 in kidney. J Immunol. 2002;168:5817–23.
Aksu U, Bezemer R, Demirci C, Ince C. Acute effects of balanced versus unbalanced colloid resuscitation on renal macrocirculatory and microcirculatory perfusion during endotoxemic shock. Shock. 2012;37:205–9.
Sakaki H, Tsukimoto M, Harada H, Moriyama Y, Kojima S. Autocrine regulation of macrophage activation via exocytosis of ATP and activation of P2Y11 receptor. PLoS ONE. 2013;8:59778.
Dosch M, Zindel J, Jebbawi F, Melin N, Sanchez-Taltavull D, Stroka D, et al. Connexin-43-dependent ATP release mediates macrophage activation during sepsis. Elife. 2019;8:e42670.
Boffa J-J, Just A, Coffman TM, Arendshorst WJ. Thromboxane receptor mediates renal vasoconstriction and contributes to acute renal failure in endotoxemic mice. J Am Soc Nephrol. 2004;15:2358–65.
Kirkby NS, Sampaio W, Etelvino G, Alves DT, Anders KL, Temponi R, et al. Cyclooxygenase-2 selectively controls renal blood flow through a novel PPARβ/δ-dependent vasodilator pathway. Hypertension. 2018;71:297–305.
Hunter RW, Craigie E, Homer NZM, Mullins JJ, Bailey MA. Acute inhibition of NCC does not activate distal electrogenic Na+ reabsorption or kaliuresis. Am J Physiol - Ren Physiol. 2014;306:F457.
We thank Yoshihide Fujisawa, Ph.D., from the Life Science Research Center, Kagawa University (Kagawa, Japan) and Yoshiko Watanabe, B.S., from the Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University (Kagawa, Japan) for technical assistance and for help in maintaining the mouse colony. We thank J. Ludovic Croxford, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
This work was supported in part by a 2021 grant from the Kagawa University Research Promotion Program (to KO), and a JSPS KAKENHI grant (no. 24590466 to MH).
Conflict of interest
The authors have declared that no conflict of interest exists.
This study was approved by the Institutional Animal Care and Use Committee of Kagawa University (#20616) and followed standard guidelines for the humane care and use of animals in scientific research.
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Onishi, K., Fu, H.Y., Sofue, T. et al. Galectin-9 deficiency exacerbates lipopolysaccharide-induced hypothermia and kidney injury. Clin Exp Nephrol (2021). https://doi.org/10.1007/s10157-021-02152-2
- Lipopolysaccharide (LPS)
- Acute kidney injury (AKI)