A translational study of Galectin-3 as an early biomarker and potential therapeutic target for ischemic-reperfusion induced acute kidney injury

J Crit Care 2021 Oct;65:192-199. doi: 10.1016/j.jcrc.2021.06.013. Epub 2021 Jul 2.
Haibing Sun, Jinyu Peng, Shuhan Cai, Qi Nie , Tianlong Li, John A. Kellum, Isaac Eliaz, Zhiyong Peng
1. Among 52 post-cardiac surgery patients, median serum and urine Gal-3 levels on ICU admission were higher in patients who developed AKI than those who did not.
2. Serum and urine Gal-3 levels were reliable biomarkers for detecting AKI at the hospital setting
3. In the rat renal I/R injury model, I/R caused an increase of Gal-3 quickly after reperfusion.
4. Gal-3 inhibition by Gal-3 blocker (P-MCP) significantly decreased Gal-3 release and expression, reduced interleukin (IL-6) release, decreased renal dysfunction, and reduced renal tubular injury.
5. Gal-3 is a potential early biomarker in the diagnosis of AKI. Inhibition of Gal-3 may provide therapeutic utility in the treatment of I/R-induced AKI.

Galectin-3 in septic acute kidney injury: a translational study

Crit Care 2021 Mar 18;25(1):109. doi: 10.1186/s13054-021-03538-0.
Haibing Sun, Huiping Jiang, Amity Eliaz, John A Kellum, Zhiyong Peng, Isaac Eliaz
1. Gal-3 levels were shown to be an independent prognostic factor and predictor of AKI followed by ICU mortality (based on 57 ICU patients with sepsis).
2. In the CLP rat experiment, serum Gal-3 peaked earlier than IL-6. Serum Gal-3 was significantly lower in both Gal-3 inhibitor groups compared to control.
3. In the Gal-3 inhibitor groups, 7-day mortality was significantly reduced Gal-3 inhibitor groups vs. control.
4. Rates of AKI per RIFLE criteria were significantly reduced in the Gal-3 inhibitor groups.
5. The study demonstrates the importance of Gal-3 in the pathogenesis of S-AKI, and its potential utility as a therapeutic target.

Cardiovascular Consequences of Acute Kidney Injury

N Engl J Med. 2020 Jun 4;382(23):2238-2247. doi: 10.1056/NEJMra1916393.Matthieu Legrand, Patrick Rossignol
1. Acute kidney injury (AKI) is recognized as a potential risk factor for future cardiovascular events, especially heart failure.
2. Up to 60% of patients with severe AKI who are admitted to an intensive care unit (ICU) die; the long-term risk of death associated with AKI is also increased.
3. Preclinical models and biomarkers have identified several likely pathways, apparently involving mitochondrial injury, inflammation, cellular death, and profibrotic.
4. The cardiac consequences of AKI may be mediated by galectin-3 (Gal-3), as shown in studies of mice with AKI in which Gal-3 induced cardiac inflammation, cardiac fibrosis, and cardiac failure. Furthermore, increased expression of Gal-3 has been associated with cardiac damage after AKI in critically ill patients.

Acute Kidney Injury Induces Remote Cardiac Damage and Dysfunction Through the Galectin-3 Pathway

JACC Basic Transl Sci. 2019 Oct 28;4(6):717-732. doi: 10.1016/j.jacbts.2019.06.005. eCollection 2019 Oct.Mathilde Prud'homme, Maxime Coutrot, Thibault Michel, Louis Boutin, Magali Genest, Françoise Poirier, Jean-Marie Launa, Bocar Kane, Satoshi Kinugasa, Niki Prakoura, Sophie Vandermeersch, Alain Cohen-Solal, Claude Delcayre, Jane-Lise Samuel, Ravindra Mehta, Etienne Gayat, Alexandre Mebazaa, Christos E Chadjichristos, Matthieu Legrand
1. AKI induces remote cardiac dysfunction, damage, injury, and fibrosis via a galectin-3 (Gal-3) dependentModified citrus pectin (MCP) inhibition of Gal-3 showed the elimination of the effects.
2. The effect was also eliminated in Gal-3 gene knock-out (Gal-3 KO) animals that cannot produce Gal-3.
3. The Gal-3 pathway is involved in remote cardiac damage after AKI and is associated with poor outcomes. MCP treatment prevented cardiac damage.
4. In Gal-3 KO mice with Gal-3 producing bone marrow, Gal-3 that originates from the bone marrow-derived immune cells traveled to the heart and produced cardiac damage.
5. A clinical study of 1,110 patients discharged from intensive care units (ICUs) found 645 (58%) patients developed AKI during ICU stay, including 252 patients with subclinical AKI and 134, 65, and 194 patients with AKI - KDIGO stages 1, 2, and 3, respectively. Plasma Gal-3 could predict who will get AKI and the severity of the AKI. The plasma level of Gal-3 showed a stepwise increase with the severity of AKI (from subclinical to stage 3).

Galectin 3 Inhibition Attenuates Renal Injury Progression in Cisplatin-Induced Nephrotoxicity

Biosci Rep. 2018 Dec 18;38(6):BSR20181803. doi: 10.1042/BSR20181803. Print 2018 Dec 21.Hong-Yan L, Shen Yang, Jing-Chun Li, Jian-Xun Feng

1. Kidney toxicity is a significant side-effect withGal-3 plays an essential role in kidney fibrosis and renal failure, and it is one of the critical factors for renal injury
2. Inhibition of Gal-3, mediated by MCP, antagonized the pro-apoptotic (cell death) effects.
3. MCP- treated mice demonstrated increased renal function and reduced renal fibrosis after cisplatin- induced MCP-treated mice showed decreased renal fibrosis and apoptosis (renal cell death)

Elevated Preoperative Galectin-3 Is Associated With Acute Kidney Injury After Cardiac Surgery

BMC Nephrol. 2018 Oct 20;19(1):280. doi: 10.1186/s12882-018-1093-0.Moritz Wyler von Ballmoos, Donald S Likosky, Michael Rezaee, Kevin Lobdell, Shama Alam, Devin Parker, Sherry Owens, Heather Thiessen-Philbrook, Todd MacKenzie, Jeremiah R Brown

1. Preoperative serum Gal-3 was measured in 1498 patients who underwent coronary artery bypass graft surgery and/or valve.
2. Patients in the highest third of Gal-3 levels had 2.95-greater odds of developing KDIGO Stage 2 or 3 (p < 0.001) and 1.71-increased odds of developing KDIGO Stage 1 (p = 0.001), compared to the lowest third.
3. Elevated preoperative Gal-3 levels significantly improve predictive ability over existing clinical models for postoperative AKI and to identify patients at the highest risk of developing AKI and AKI severity after cardiac surgery

Galectin-3 Aggravates Experimental Polymicrobial Sepsis by Impairing Neutrophil Recruitment to the Infectious Focus

J Infect. 2018 Nov;77(5):391-397. doi: 10.1016/j.jinf.2018.06.010. Epub 2018 Jul 4.Raphael G Ferreira, Lilian C Rodrigues, Daniele C Nascimento, Alexandre Kanashiro, Paulo H Melo, Vanessa F Borges, Aline Gozzi, Douglas da Silva Prado, Marcos C Borges, Fernando S Ramalho, Sean R Stowell, Richard D Cummings, Marcelo Dias-Baruffi, Fernando Q Cunha, Jose C Alves-Filho
1. Serum Gal-3 concentration increased in patients with septic shock and mice undergoing sepsis induced by a procedure called cecal ligation and puncture (CLP).
2. Mice genetically deficient in Gal-3 (Gal-3 KO) were more resistant to sepsis caused by CLP than wild-type mice (WT).
3. Gal-3 KO mice show an increased number of neutrophils in the initial stage of infection and reduced bacterial loads in the peritoneal cavity and blood.
4. Blood neutrophils from septic mice show higher levels of surface-bound Gal-3 than neutrophils from control mice.
5. Results indicate that Gal-3, secreted during sepsis, inhibits neutrophil migration into the infectious site, promoting the bacterial spread.

Galectin-3 Pharmacological Inhibition Attenuates Early Renal Damage in Spontaneously Hypertensive Rats

J Hypertens. 2018 Feb;36(2):368-376. doi: 10.1097/HJH.0000000000001545.Ernesto Martínez-Martínez, Jaime Ibarrola, Amaya Fernández-Celis, Laurent Calvier, Celine Leroy, Victoria Cachofeiro, Patrick Rossignol, Natalia López-Andrés
1. Kidney damage markers, plasma creatinine, and albuminuria significantly increased in spontaneously hypertensive rats (SHRs) and reduced by MCP.
2. In the kidneys of SHR rats, Gal-3, as well as downstream fibrotic markers (collagen type I, TGF-β, and connective tissue growth factor) and tissue fibrosis were all elevated.
3. MCP treatment reduced Gal-3 levels, as well as kidney fibrosis.
4. The epithelial-mesenchymal transition (EMT) molecules (fibronectin, α-smooth muscle actin, and β-catenin) were elevated in SHR, and normalized by Gal-3 inhibition.
5. Gal-3 inhibition prevented early renal damage in SHR as indicated by reduced albuminuria, improved renal function. It decreased renal fibrosis, EMT, and inflammation, independently of blood pressure levels.

Galectin-3 Blockade Reduces Renal Fibrosis in Two Normotensive Experimental Models of Renal Damage

PLoS One. 2016 Nov 9;11(11):e0166272. doi: 10.1371/journal.pone.0166272. eCollection 2016.Ernesto Martinez-Martinez, Jaime Ibarrola, Laurent Calvier, Amaya Fernandez-Celis, Celine Leroy, Victoria Cachofeiro, Patrick Rossignol, Natalia Lopez-AndresAnnotations
1. Gal-3 is increased in kidney injury and its inhibition by MCP reduces renal damage in AKI, hyperaldosteronism, and hypertension
2. Gal-3 inhibition was studied in an early renal damage model associated with obesity and aortic stenosis (AS).
3. The increase in renal Gal-3 expression correlated with renal fibrosis, inflammation, andThe kidney damage prevented by Gal-3 inhibition.
4. Gal-3 is a leading player in renal molecular, histological, and functional changes at the early stages of kidney damage.
5. The early-stage has a very important clinical application in both AKI and CKD.

The Impact of galectin-3 Inhibition on Aldosterone-Induced Cardiac and Renal

JACC Heart Fail. 2015 Jan;3(1):59-67. doi: 10.1016/j.jchf.2014.08.002. Epub 2014 Nov 11.Laurent Calvier, Ernesto Martinez-Martinez, Maria Miana, Victoria Cachofeiro, Elodie Rousseau, J Rafael Sádaba, Faiez Zannad, Patrick Rossignol, Natalia López-Andrés
1. In experimental hyperaldosteronism, the increase in Gal-3 expression was associated with cardiac and renal fibrosis and dysfunction.
2. The damage was prevented by MCP inhibition, as well as by genetic disruption of Gal-3.
3. Results suggest a crucial role for Gal-3 in heart/kidney remodeling and dysfunction induced by aldosterone and the prevention of the remodeling and dysfunction by Gal-3 blockade.
4. Gal-3 could be used as a new bio target for specific pharmacological interventions

Obesity and IL-6 Interact in Modulating the Response to Endotoxemia in Mice

Cytokine. 2013 Jan;61(1):71-7. doi: 10.1016/j.cyto.2012.08.027. Epub 2012 Sep 23.Maria Pini, Karla J Castellanos, Davina H Rhodes, Giamila FantuzAnnotations
1. Obesity is associated with elevated levels of the cellular messenger IL-6.
2. High IL-6 is prognostic of mortality in sepsis, while controversial data link obesity to sepsis, while controversial data link obesity to sepsis.
3. Plasma TNFα, IFNγ, Gal-3, and leptin were significantly elevated in response to LPS and were each differentially affected by obesity and/or IL-6 deficiency.
4. The blood disorder, leukopenia with relative neutrophilia, and thrombocytopenia developed in each group after injection of endotoxin.
5. Both IL-6 and obesity modulate the response to endotoxemia, suggesting a complex interaction that needs to be considered when evaluating the effect of obesity on septic patients' outcomes.

Modified Citrus Pectin Reduces Galectin-3 Expression and Disease Severity in Experimental Acute Kidney Injury

PLoS One. 2011 Apr 8;6(4):e18683. doi: 10.1371/journal.pone.0018683.Maria Kolatsi-Joannou, Karen L Price, Paul J Winyard, David A Long
1. Gal-3 is known to be upregulated in AKI. Experimentally modulated Gal-3 in folic acid (FA)-induced AKI.
2. Mice were pre-treated with normal drinking water or water supplemented with the Gal-3 inhibitor MCP one week before FA injection to induce AKI.
3. During the initial injury phase, FA-treated mice lost weight and exhibited pathologic kidney enlargement.
4. The pathologic kidney changes were significantly decreased in the MCP group. On a tissue level, MCP reduced renal cell proliferation.
5. Later, during the recovery phase at 2 weeks, MCP-treated mice demonstrated reduced Gal-3 as well as decreased renal fibrosis, macrophages, pro-inflammatory cytokine expression, and cell death.

A Role for Galectin-3 in Renal Tissue Damage Triggered by Ischemia and Reperfusion Injury

Transpl Int. 2008 Oct;21(10):999-1007. doi: 10.1111/j.1432-2277.2008.00705.x. Epub 2008 Jul 24.Ana Paula Fernandes Bertocchi, Gabriela Campanhole, Pamella Huey Mei Wang, Giselle Martins Gonçalves, Márcio José Damião, Marcos Antônio Cenedeze, Felipe Caetano Beraldo, Vicente de PaulaAntunes Teixeira, Marlene Antônia Dos Reis, Marilda Mazzali, Alvaro Pacheco-Silva, Niels Olsen Saraiva Câmara
1. Gal-3 has a broad range of activities such as the promotion of neutrophil adhesion, induction of oxidative stress, mast cell migration and degranulation, and production of pro-inflammatory cytokines.
2. Gal-3 KO and wild type mice were subjected to 45 min of renal pedicle occlusion.
3. Gal-3 KO presented less acute tubular necrosis and a more prominent tubular regeneration compared with controls concurrently with lower expression of IL-6, IL-1beta, less macrophage infiltration, and lower ROS production at early time points.
4. Gal-3 plays a role involving the secretion of macrophage-related chemokine, pro-inflammatory cytokines, and ROS

Up-regulation of Galectin-3 in Acute Renal Failure of the Rat

Am J Pathol. 2000 Sep;157(3):815-23. doi: 10.1016/S0002-9440(10)64595-6.J Nishiyama, S Kobayashi, A Ishida, I Nakabayashi, O Tajima, S Miura, M Katayama, H Nogami

1. Gal-3 is associated with cellular injury in two types of acute renal failure (ARF): ischemic and toxic ARF.
2. In ischemia/reperfusion renal injury in rats (bilateral renal pedicles clamped for 40 minutes), Gal- 3 mRNA began to increase at 2 hours and extended by 6.2-fold at 48 hours (P: < 0.01 versus normal control rats), and then decreased by 28 days after injury.
3. In folic acid-induced ARF, Gal-3 mRNA was found to be upregulated at 2 hours after injury. Increased levels continued until at least 7 days post-injury.
4. At 2 hours following reperfusion, Gal-3 began to develop in nearby tissue. From 6 hours up to 48 hours, Gal-3 was also found in proximal straight tubules, distal tubules, thick ascending limbs, and collecting ducts.
5. In later stages of regeneration, Gal-3 expressions were found in macrophages. The Gal-3 expression is markedly upregulated in both ischemic and toxic types of ARF.Gal-3 plays a vital role in acute injury and the following regeneration stage.

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