Mode of Proximal Tubule Damage: Differential Cause for the Release of TFF3?

Zwaini, Zinah; Alammari, Dalia Muhammed; Byrne, Sandie; Stover, Cordula M.

doi:10.3389/fimmu.2016.00122

Cited by 7 publications

(7 citation statements)

References 15 publications

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“…Although no definite receptor or binding molecule has been identified, it has been hypothesized that TFF3 may act in a receptor‐mediated manner . The HK‐2 cultured human cell line (proximal tubular epithelial cells) can synthesize and excrete more TFF3 after exposure to damage such as nutrient starvation, hypoxia and immunoglobulin λ light chain . Hypoxia induces the transcription of HIF‐1 and TFF3 mRNA in vitro, and it is known that TFF3 is regulated by HIF‐1α .…”

Section: Discussionmentioning

confidence: 99%

“…23 The HK-2 cultured human cell line (proximal tubular epithelial cells) can synthesize and excrete more TFF3 after exposure to damage such as nutrient starvation, hypoxia and immunoglobulin λ light chain. 24,25 Hypoxia induces the transcription of HIF-1 and TFF3 mRNA in vitro, 26 and it is known that TFF3 is regulated by HIF-1α. 25 The relationship between TFF3 and the molecular mechanisms of fibrosis has not been studied thus far.…”

Section: Discussionmentioning

confidence: 99%

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Renal expression of trefoil factor 3 mRNA in association with tubulointerstitial fibrosis in IgA nephropathy

et al. 2018

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AimTrefoil factor 3 (TFF3) is a small peptide that is involved in mucosal protection. TFF3 is widely expressed in multiple tissues including kidney tissue. Previous studies have reported that the levels of urinary TFF3 are significantly increased in patients with chronic kidney disease. The aim of this study is to detect the TFF3 mRNA in kidney and elucidate the relationship between renal TFF3 mRNA and tubulointerstitial fibrosis in IgA nephropathy (IgAN).MethodsWe investigated the renal mRNA expression of TFF3 by real‐time PCR analysis in biopsy specimens from patients with IgAN, other glomerulonephritis (OGN) and minor glomerular abnormalities (MGA). We also determined the renal localization of TFF3 and the levels of urinary TFF3 by immunostaining and ELISA, respectively.ResultsThe renal TFF3 mRNA expression was significantly associated with the urinary TFF3 secretion and the tubulointerstitial fibrosis score in the IgAN group alone. Immunostaining of the renal specimen of IgAN patients revealed that TFF3 is located in the renal tubular epithelial cells. The locations were almost the same as those that showed uromodulin positivity; specifically, the thick ascending limb (TAL) of the loop of Henle and the early portion of the distal tubule. The urinary TFF3 levels were positively correlated with the levels of urinary biomarkers of tubulointerstitial injury in such patients.ConclusionRenal TFF3 mRNA is associated with renal tubulointerstitial fibrosis in IgAN patients. The TFF3 located in the renal tubular epithelial cells may play a role in the progression of tubulointerstitial fibrosis in IgAN patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Renal expression of trefoil factor 3 mRNA in association with tubulointerstitial fibrosis in IgA nephropathy

et al. 2018

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“…Elevated levels of TFF3 were also found in urine from patients with incident chronic kidney disease as part of a nested case-control study [ 17 ], as well as in serum of patients with CKD stages 1–5 [ 19 , 21 ]. Cultured human proximal tubular epithelial cell line HK-2 can synthesize and excrete TFF3 after exposure to immunoglobulin λ light chain, but not after exposure to fatty acid-free human serum albumin [ 32 ]. The promotor region of human TFF3 has the STAT3 binding site critical for the self-induction of TFF3 [ 33 ] as well as the NF- κ B binding site [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Urine Trefoil Factors as Prognostic Biomarkers in Chronic Kidney Disease

Yamanari

Sugiyama

Tanaka

et al. 2018

BioMed Research International

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Introduction Trefoil factor family (TFF) peptides are increased in serum and urine in patients with chronic kidney disease (CKD). However, whether the levels of TFF predict the progression of CKD remains to be elucidated. Methods We determined the TFF levels using peptide-specific ELISA in spot urine samples and performed a prospective cohort study. The association between the levels of urine TFFs and other urine biomarkers as well as the renal prognosis was analyzed in 216 CKD patients (mean age: 53.7 years, 47.7% female, 56.9% with chronic glomerulonephritis, and mean eGFR: 58.5 ml/min/1.73 m2). Results The urine TFF1 and TFF3 levels significantly increased with the progression of CKD stages, but not the urine TFF2 levels. The TFF1 and TFF3 peptide levels predicted the progression of CKD ≥ stage 3b by ROC analysis (AUC 0.750 and 0.879, resp.); however, TFF3 alone predicted CKD progression in a multivariate logistic regression analysis (odds ratio 3.854, 95% confidence interval 1.316–11.55). The Kaplan-Meier survival curves demonstrated that patients with a higher TFF1 and TFF3 alone, or in combination with macroalbuminuria, had a significantly worse renal prognosis. Conclusion The data suggested that urine TFF peptides are associated with renal progression and the outcomes in patients with CKD.

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“…The molecular pathways of TFF3 actions are still mysterious, however, cultured cell line of tubular epithelial cells showed overexpression of TFF3 upon exposure to cell damage such as hypoxia. Hypoxia enhances HIF1 as TFF3 transcription in vitro (31). Tubulointerstitial fibrosis is a direct cause of renal ischemia and hypoxia with subsequent increase in TFF3 expression (22).…”

Section: Discussionmentioning

confidence: 99%

Baseline HDAC6 and TFF3 proteins overexpression as prognostic markers of lupus nephritis relapse

2020

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Introduction: Lupus nephritis (LN) is a substantial manifestation of systemic lupus erythematosus (SLE). HDAC6 is overexpressed in various kidney diseases, and its inhibition slows kidney injury progression. Urinary TFF3 increases in chronic kidney diseases (CKDs) and may be associated with patient's outcome.Objectives: This study aimed to examine the relationship between renal HDAC6 and TFF3 proteins expression and with clinicopathologic characteristics and outcome of LN. Patients and Methods: HDAC6 and TFF3 proteins' expression was immunohistochemically detected in 56 cases of LN. They were correlated to patients' age, gender, urinary 24 hours protein and serum creatinine levels at baseline and during follow up. Additionally, they were correlated to LN classes, activity index (AI) and chronicity index (CI) and relapse free survival (RFS). Results: HDAC6 overexpression was significantly associated with serum creatinine and 24 hours proteinuria levels at baseline (P = 0.041 and P =0.026 respectively) and during follow up (P < 0.001). It was associated with AI and CI of class III and IV LN (P = 0.047 and 0.003 respectively). TFF3 overexpression was associated with higher serum creatinine and more proteinuria at baseline (P = 0.015 and 0.001 respectively) and during follow up (P < 0.001). It was significantly associated with higher CI (P = 0.001). Both markers were associated with shorter RFS (P < 0.001). Conclusion: HDAC6 and TFF3 proteins are associated with clinicopathologic features of renal damage in LN. They are reliable predictors of patients' RFS, which makes them good candidates for risk stratification of patients and targeted therapy. ABSTRACT Implication for health policy/practice/research/medical education:Lupus nephritis is a leading cause of CKD, so it is crucial to search for markers that could predict tubulointerstitial injury and patients' relapses. HDAC6 and TFF3 are associated with features of renal damage and early relapse of LN. These effects are due to their capacity to up-regulate BCL2 expression promoting survival of autoreactive B cells as well as stimulation of persistent release of inflammatory cytokines by dendritc cells. Therefore, HDAC6 & TFF3 can be used for prognostic stratification of LN patients. Please cite this paper as: Abdelbary EH, Farouk Ahmed N, Abdelmohsen Ghorab A. Baseline HDAC6 and TFF3 proteins overexpression as prognostic markers of lupus nephritis relapse. J Nephropathol. 2020;9(2):e14.

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Mode of Proximal Tubule Damage: Differential Cause for the Release of TFF3?

Cited by 7 publications

References 15 publications

Renal expression of trefoil factor 3 mRNA in association with tubulointerstitial fibrosis in IgA nephropathy

Renal expression of trefoil factor 3 mRNA in association with tubulointerstitial fibrosis in IgA nephropathy

Urine Trefoil Factors as Prognostic Biomarkers in Chronic Kidney Disease

Baseline HDAC6 and TFF3 proteins overexpression as prognostic markers of lupus nephritis relapse

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