Abstract 18092: Source of Galectin-3 in Human Heart Failure, Chronic Kidney Disease and Cardio-renal Failure

Background: Galectin-3 (Gal-3) may promote cardiac and renal fibrosis in heart failure (HF). Plasma Gal-3 levels predict outcome in HF but are tightly correlated with renal function. The source of Gal-3 in human HF, chronic kidney disease (CKD) or cardio-renal failure (HF+CKD) is unclear. Objective: To assess Gal-3 presence and location in human heart or kidney tissue from patients with HF, CKD or HF+CKD. Methods: Plasma Gal-3 levels and LV tissue explanted at time of cardiac transplant in systolic HF (n=15) and autopsy renal sections from patients with normal kidneys (n=4), CKD (n=17) or CKD+HF (n=14) were examined (H&E, Masson’s trichrome and CD-68 and Gal-3 immunohistochemistry). In the systolic HF patients, we quantified the number of Gal-3+/CD-68+ cells per HPF in LV tissue and assessed the correlation with plasma Gal-3 levels. In autopsy renal tissue, we derived a Composite Gal-3 Score (CG3S) incorporating the % of Gal-3+ tubules per HPF, % of Gal-3+ cells/tubule per HPF, and intensity of Gal-3 staining and assessed the correlation of the CG3S with ante-mortem estimated glomerular filtration rate(eGFR). Renal macrophage Gal-3 staining was also assessed. Results: In systolic HF LV tissue, Gal-3 was present in macrophages rather than myocytes but Gal-3+/CD-68+ cells per HPF was not correlated with plasma Gal-3 levels (p> 0.9) which correlated inversely with eGFR (r = -0.89 for log Gal-3 vs eGFR, p<0.0001). In the kidney, Gal-3 was not present in macrophages but was localized to renal tubular cells (Figure). The CG3S increased exponentially as eGFR decreased (r = - 0.88 for log CG3S versus eGFR; p<0.0001) and this relationship was not different (p=0.44) in patients with or without HF (Figure). The log CG3S correlated with the degree of fibrosis (tubulointerstitial scarring) in the kidney (r=0.88; p<0.0001). Conclusion: Collectively, these data suggest that plasma Gal-3 is predominantly of renal tubular epithelial origin in human HF, CKD, and CKD+HF.

Download Full-text

A PILOT STUDY: PLASMA GALECTIN-3 LEVEL IN HEART FAILURE PATIENTS

Journal of Medicine and Pharmacy ◽

10.34071/jmp.2017.5.13 ◽

2017 ◽

pp. 101-106

Author(s):

Thi Thanh Hien Bui ◽

Hieu Nhan Dinh ◽

Anh Tien Hoang

Keyword(s):

Heart Failure ◽

Chronic Kidney Disease ◽

Acute Coronary Syndrome ◽

Kidney Disease ◽

Heart Failure Patients ◽

Coronary Syndrome ◽

Nyha Classification ◽

Galectin 3 ◽

Severe Chronic Kidney Disease ◽

Esc Guidelines

Background: Despite of considerable advances in its diagnosis and management, heart failure remains an unsettled problem and life threatening. Heart failure with a growing prevalence represents a burden to healthcare system, responsible for deterioration of patient’s daily activities. Galectin-3 is a new cardiac biomarker in prognosis for heart failure. Serum galectin-3 has some relation to heart failure NYHA classification, acute coronary syndrome and clinical outcome. Level of serum galectin-3 give information for prognosis and help risk stratifications in patient with heart failure, so intensive therapeutics can be approached to patients with high risk. Objective: To examine plasma galectin-3 level in hospitalized heart failure patients, investigate the relationship between galectin-3 level with associated diseases, clinical conditions and disease progression in hospital. Methodology: Cross sectional study. Result: 20 patients with severe heart failure as NYHA classification were diagnosed by The ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure (2012) and performed blood test for serum galectin-3 level. Increasing of serum galectin-3 level have seen in all patients, mean value is 36.5 (13.7 – 74.0), especially high level in patient with acute coronary syndrome and patients with severe chronic kidney disease. There are five patients dead. Conclusion: Serum galectin-3 level increase in patients with heart failure and has some relation to NYHA classification, acute coronary syndrome. However, level of serum galectin-3 can be affected by severe chronic kidney disease, more research is needed on this aspect Key words: Serum galectin-3, heart failure, ESC Guidelines, NYHA

Download Full-text

Permissive effect of GSK3β on profibrogenic plasticity of renal tubular cells in progressive chronic kidney disease

Cell Death and Disease ◽

10.1038/s41419-021-03709-5 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Bohan Chen ◽

Pei Wang ◽

Xianhui Liang ◽

Chunming Jiang ◽

Yan Ge ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Renal Fibrosis ◽

Binding Protein ◽

Renal Tubules ◽

Genetic Ablation ◽

Renal Tubular Cells ◽

Renal Tubular ◽

Renal Fibrogenesis ◽

Tgf Β1

AbstractRenal tubular epithelial cells (TECs) play a key role in renal fibrogenesis. After persistent injuries that are beyond self-healing capacity, TECs will dedifferentiate, undergo growth arrest, convert to profibrogenic phenotypes, and resort to maladaptive plasticity that ultimately results in renal fibrosis. Evidence suggests that glycogen synthase kinase (GSK) 3β is centrally implicated in kidney injury. However, its role in renal fibrogenesis is obscure. Analysis of publicly available kidney transcriptome database demonstrated that patients with progressive chronic kidney disease (CKD) exhibited GSK3β overexpression in renal tubulointerstitium, in which the predefined hallmark gene sets implicated in fibrogenesis were remarkably enriched. In vitro, TGF-β1 treatment augmented GSK3β expression in TECs, concomitant with dedifferentiation, cell cycle arrest at G2/M phase, excessive accumulation of extracellular matrix, and overproduction of profibrotic cytokines like PAI-1 and CTGF. All these profibrogenic phenotypes were largely abrogated by GSK3β inhibitors or by ectopic expression of a dominant-negative mutant of GSK3β but reinforced in cells expressing the constitutively active mutant of GSK3β. Mechanistically, GSK3β suppressed, whereas inhibiting GSK3β facilitated, the activity of cAMP response element-binding protein (CREB), which competes for CREB-binding protein, a transcriptional coactivator essential for TGF-β1/Smad signaling pathway to drive TECs profibrogenic plasticity. In vivo, in mice with folic acid-induced progressive CKD, targeting of GSK3β in renal tubules via genetic ablation or by microdose lithium mitigated the profibrogenic plasticity of TEC, concomitant with attenuated interstitial fibrosis and tubular atrophy. Collectively, GSK3β is likely a pragmatic therapeutic target for averting profibrogenic plasticity of TECs and improving renal fibrosis.

Download Full-text

Abstract MP012: Plasma Galectin-3 Levels and Subsequent Risk of Incident Chronic Kidney Disease

Circulation ◽

10.1161/circ.135.suppl_1.mp012 ◽

2017 ◽

Vol 135 (suppl_1) ◽

Author(s):

Casey M Rebholz ◽

Elizabeth Selvin ◽

Menglu Liang ◽

Christie M Ballantyne ◽

Ron C Hoogeveen ◽

...

Keyword(s):

Heart Failure ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Proportional Hazards ◽

Disease Risk ◽

Positive Association ◽

Cox Proportional Hazards ◽

Diabetes Status ◽

Incident Chronic Kidney Disease ◽

Galectin 3

Introduction: Galectin-3 is a 35 kDa β-galactoside-binding lectin which has been proposed as a novel biomarker of heart failure primarily due to its involvement in myocardial fibrosis. Elevated levels of galectin-3 may be associated with fibrosis of other organs, such as the kidney, and increase the risk of developing kidney disease. Methods: Using Cox proportional hazards regression, we prospectively analyzed Atherosclerosis Risk in Communities (ARIC) study participants with measurements of plasma galectin-3 levels at baseline (visit 4, 1996-98) and without prevalent kidney disease or heart failure (N=9,647). Incident chronic kidney disease was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 accompanied by 25% eGFR decline, chronic kidney disease-related hospitalization or death, or end-stage renal disease between baseline and December 31, 2013. Results: 2,105 participants (22%) developed incident chronic kidney disease over a median follow-up of 16 years. The mean (standard deviation) plasma level of galectin-3 was 14.7 (4.4) ng/mL. At baseline, galectin-3 was cross-sectionally associated with eGFR (r = -0.31) and urine albumin-to-creatinine ratio (UACR) (r = 0.19). After adjusting for demographics and kidney disease risk factors, there was a significant, graded, and positive association between galectin-3 and incident chronic kidney disease (quartile 4 vs. 1 HR: 1.84, 95% CI: 1.62, 2.09, p for trend <0.001). The association between galectin-3 and incident chronic kidney disease was attenuated but remained significant after accounting for eGFR and UACR (quartile 4 vs. 1 HR: 1.58, 95% CI: 1.39, 1.80, p for trend <0.001). The association was similar by diabetes status (p for interaction = 0.33) and stronger among those with hypertension (p for interaction = 0.004). Conclusion: In this community-based population, higher plasma galectin-3 levels were associated with elevated risk of developing incident chronic kidney disease, particularly among those with hypertension.

Download Full-text

GALECTIN-3 LEVELS IN PATIENTS WITH CONGESTIVE HEART FAILURE NYHA III-IV AND CHRONIC KIDNEY DISEASE

Journal of Hypertension ◽

10.1097/01.hjh.0000572576.82893.b7 ◽

2019 ◽

Vol 37 ◽

pp. e200

Author(s):

V. Podzolkov ◽

N. Dragomiretskaya ◽

A. Kazadaeva ◽

S. Stolbova ◽

E. Shtemplevskay ◽

...

Keyword(s):

Heart Failure ◽

Chronic Kidney Disease ◽

Congestive Heart Failure ◽

Kidney Disease ◽

Galectin 3

Download Full-text

Association of Cardiac Biomarkers With the Kansas City Cardiomyopathy Questionnaire in Patients With Chronic Kidney Disease Without Heart Failure

Journal of the American Heart Association ◽

10.1161/jaha.119.014385 ◽

2020 ◽

Vol 9 (13) ◽

Cited By ~ 1

Author(s):

Sri Lekha Tummalapalli ◽

Leila R. Zelnick ◽

Amanda H. Andersen ◽

Robert H. Christenson ◽

Christopher R. deFilippi ◽

...

Keyword(s):

Heart Failure ◽

Chronic Kidney Disease ◽

Health Status ◽

Kidney Disease ◽

Kansas City ◽

Troponin T ◽

Cardiac Biomarkers ◽

Kansas City Cardiomyopathy Questionnaire ◽

Galectin 3 ◽

Multivariable Adjustment

Background The Kansas City Cardiomyopathy Questionnaire ( KCCQ ) is a measure of heart failure ( HF ) health status. Worse KCCQ scores are common in patients with chronic kidney disease ( CKD ), even without diagnosed heart failure ( HF ). Elevations in the cardiac biomarkers GDF‐15 (growth differentiation factor‐15), galectin‐3, sST2 (soluble suppression of tumorigenesis‐2), hsTnT (high‐sensitivity troponin T), and NT ‐pro BNP (N‐terminal pro‐B‐type natriuretic peptide) likely reflect subclinical HF in CKD . Whether cardiac biomarkers are associated with low KCCQ scores is not known. Methods and Results We studied participants with CKD without HF in the multicenter prospective CRIC (Chronic Renal Insufficiency Cohort) Study. Outcomes included (1) low KCCQ score <75 at year 1 and (2) incident decline in KCCQ score to <75. We used multivariable logistic regression and Cox regression models to evaluate the associations between baseline cardiac biomarkers and cross‐sectional and longitudinal KCCQ scores. Among 2873 participants, GDF‐15 (adjusted odds ratio 1.42 per SD ; 99% CI , 1.19–1.68) and galectin‐3 (1.28; 1.12–1.48) were significantly associated with KCCQ scores <75, whereas sST2, hsTnT, and NT ‐pro BNP were not significantly associated with KCCQ scores <75 after multivariable adjustment. Of the 2132 participants with KCCQ ≥75 at year 1, GDF‐15 (adjusted hazard ratio, 1.36 per SD ; 99% CI , 1.12–1.65), hsTnT (1.20; 1.01–1.44), and NT ‐pro BNP (1.30; 1.08–1.56) were associated with incident decline in KCCQ to <75 after multivariable adjustment, whereas galectin‐3 and sST2 did not have significant associations with KCCQ decline. Conclusions Among participants with CKD without clinical HF , GDF‐15, galectin‐3, NT ‐pro BNP , and hsTnT were associated with low KCCQ either at baseline or during follow‐up. Our findings show that elevations in cardiac biomarkers reflect early symptomatic changes in HF health status in CKD patients.

Download Full-text

Chronic effects of repeated low-dose cisplatin treatment in mouse kidneys and renal tubular cells

AJP Renal Physiology ◽

10.1152/ajprenal.00385.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. F1582-F1592 ◽

Cited By ~ 5

Author(s):

Ying Fu ◽

Juan Cai ◽

Fanghua Li ◽

Zhiwen Liu ◽

Shaoqun Shu ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Low Dose ◽

Interstitial Fibrosis ◽

Cell Model ◽

Repeated Treatment ◽

Renal Tubular Cells ◽

Acute Kidney Disease ◽

Atubular Glomeruli ◽

Renal Tubular

Cisplatin is a commonly used chemotherapeutic drug for cancer treatment, but its nephrotoxicity may lead to the deterioration of renal function. Previous work has been focused on cisplatin-induced acute kidney disease, whereas the mechanism of chronic kidney disease after cisplatin chemotherapy is largely unknown. In the present study, we have characterized the mouse model of chronic kidney defects induced by repeated low-dose cisplatin treatment. We have also established a relevant cell culture model. In the animal model, C57 mice were given weekly injection of 8 mg/kg cisplatin for 4 wk. This led to a sustained decline of kidney function. These mice showed loss of kidney mass, interstitial fibrosis, continued activation of inflammatory cytokines, and appearance of atubular glomeruli. In the cell model, the BUMPT mouse proximal tubular cell line was treated four times with 1–2 μM cisplatin, resulting in low levels of apoptosis and the expression of fibrosis proteins and profibrotic factors. These data suggest that repeated treatment with low-dose cisplatin causes long-term renal pathologies with characteristics of chronic kidney disease.

Download Full-text

Uric acid-induced phenotypic transition of renal tubular cells as a novel mechanism of chronic kidney disease

AJP Renal Physiology ◽

10.1152/ajprenal.00560.2012 ◽

2013 ◽

Vol 304 (5) ◽

pp. F471-F480 ◽

Cited By ~ 113

Author(s):

Eun-Sun Ryu ◽

Mi Jin Kim ◽

Hyun-Soo Shin ◽

Yang-Hee Jang ◽

Hack Sun Choi ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Uric Acid ◽

Kidney Disease ◽

Organic Anion ◽

Mesenchymal Transition ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Renal Tubular ◽

Phenotypic Transition ◽

E Cadherin

Recent experimental and clinical studies suggest a causal role of uric acid in the development of chronic kidney disease. Most studies have focused on uric acid-induced endothelial dysfunction, oxidative stress, and inflammation in the kidney. The direct effects of uric acid on tubular cells have not been studied in detail, and whether uric acid can mediate phenotypic transition of renal tubular cells such as epithelial-to-mesenchymal transition (EMT) is not known. We therefore investigated whether uric acid could alter E-cadherin expression and EMT in the kidney of hyperuricemic rats and in cultured renal tubular cells (NRK cells). Experimental hyperuricemia was associated with evidence of EMT before the development of significant tubulointerstitial fibrosis at 4 wk, as shown by decreased E-cadherin expression and an increased α-smooth muscle actin (α-SMA). Allopurinol significantly inhibited uric acid-induced changes in E-cadherin and α-SMA with an amelioration of renal fibrosis at 6 wk. In cultured NRK cells, uric acid induced EMT, which was blocked by the organic anion transport inhibitor probenecid. Uric acid increased expression of transcriptional factors associated with decreased synthesis of E-cadherin (Snail and Slug). Uric acid also increased the degradation of E-cadherin via ubiquitination, which is of importance since downregulation of E-cadherin is considered to be a triggering mechanism for EMT. In conclusion, uric acid induces EMT of renal tubular cells decreasing E-cadherin synthesis via an activation of Snail and Slug as well as increasing the degradation of E-cadherin.

Download Full-text

Aortic Aneurysms, Chronic Kidney Disease and Metalloproteinases

Biomolecules ◽

10.3390/biom11020194 ◽

2021 ◽

Vol 11 (2) ◽

pp. 194

Author(s):

Michele Andreucci ◽

Michele Provenzano ◽

Teresa Faga ◽

Ashour Michael ◽

Gemma Patella ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Proteolytic Enzymes ◽

Aortic Aneurysms ◽

Matrix Deposition ◽

Renal Tubular Cells ◽

Increased Risk ◽

Inflammatory Stimuli ◽

A Disintegrin And Metalloproteinase ◽

Renal Tubular

Metalloproteinases (MPs) are proteolytic enzymes involved in extracellular matrix deposition, regulation of cellular signals of inflammation, proliferation, and apoptosis. Metalloproteinases are classified into three families: Matrix-MPs (MMPs), A-Disintegrin-and-Metalloprotease (ADAMs), and the A-Disintegrin-and-Metalloproteinase-with-Thrombospondin-1-like-Domains (ADAMTS). Previous studies showed that MPs are involved in the development of aortic aneurysms (AA) and, concomitantly, in the onset of chronic kidney disease (CKD). CKD has been, per se, associated with an increased risk for AA. The aim of this review is to examine the pathways that may associate MPs with CKD and AA. Several MMPs, such as MMP-2, -8, -9, and TIMP-1 have been shown to damage the AA wall and to have a toxic effect on renal tubular cells, leading to fibrosis. Similarly, ADAM10 and 17 have been shown to degrade collagen in the AA wall and to worsen kidney function via pro-inflammatory stimuli, the impairment of the Renin-Angiotensin-Aldosterone System, and the degradation of structural proteins. Moreover, MMP-2 and -9 inhibitors reduced aneurysm growth and albuminuria in experimental and human studies. It would be important, in the future, to expand research on MPs from both a prognostic, namely, to refine risk stratification in CKD patients, and a predictive perspective, likely to improve prognosis in response to targeted treatments.

Download Full-text