Role of Mesangial-Podocytic-Tubular Cross-Talk in IgA Nephropathy

Leung, Joseph C.K.; Lai, Kar Neng; Tang, Sydney C.W.

doi:10.1016/j.semnephrol.2018.05.018

Cited by 35 publications

(33 citation statements)

References 92 publications

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“…In the second condition, there is injury at the proximal tubular cells which results in disturbed absorption of citrate resulting into more excretion of citrate in urine than the first condition. Proximal tubular cell injury also causes IgAN to turn into end stage renal disease (ESRD) rapidly [16]. In this case, the higher citrate level in urine makes IgAN more progressive towards ESRD.…”

Section: Discussionmentioning

confidence: 99%

Urinary Citrate: A Potential Biomarker for IgA Nephropathy

Kumar¹

2020

IJST

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Background: Citrate is filtered by the glomeruli and reabsorbed in tubular cells in kidney. Through this study, we have tried to explore citrate as a diagnostic tool for IgA nephropathy. Methods: We recruited 35 IgA nephropathy (IgAN) patients and 15 healthy controls (HC). 30 ml urine sample collected from each study participant. Solid phase extraction method used for urine purification. Liquid chromatography attached with mass spectrometry (LC-MS/MS) used for the citrate concentration determination. Logistic regression method used for diagnostic model prediction. Findings: Urinary citrate level was higher in IgAN patients by more than two and half times in comparison to HC. We made logistic regression model with citrate, urine protein, estimated glomerular filtration rate (eGFR), urine pH, systolic and diastolic blood pressure as variables. Citrate with urine protein was found to be the best fit statistical model with area under curve 0.77 and sensitivity and specificity more than 0.70 and 0.80, respectively. Applications: Urinary citrate with urine protein can be used for the early prediction of IgAN.

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Section: Discussionmentioning

confidence: 99%

Urinary Citrate: A Potential Biomarker for IgA Nephropathy

Kumar¹

2020

IJST

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“…Despite the restricted deposition of immune complexes in the mesangial area, all renal compartments are injured in IgAN. Murine and human studies have demonstrated that higher Gd-IgA1 serum levels are associated with a stronger mesangial cell response, which translates into more severe glomerular and tubulointerstitial lesions [27,28,29]. Mesangial cell-derived inflammatory and fibrotic mediators (IL-6, MCP-1, TGFβ, TNFα) lead to podocyte dysfunction and their progressive loss and to tubulointerstitial injury [27,28,29].…”

Section: Transitioning From Pathogenesis Of Iga Nephropathy To Promentioning

confidence: 99%

“…Murine and human studies have demonstrated that higher Gd-IgA1 serum levels are associated with a stronger mesangial cell response, which translates into more severe glomerular and tubulointerstitial lesions [27,28,29]. Mesangial cell-derived inflammatory and fibrotic mediators (IL-6, MCP-1, TGFβ, TNFα) lead to podocyte dysfunction and their progressive loss and to tubulointerstitial injury [27,28,29]. This mesangial–podocyte–tubular crosstalk provides the rationale for the spread of initial mesangial injury to the entire nephron and ultimately to progressive loss of renal function [29].…”

Section: Transitioning From Pathogenesis Of Iga Nephropathy To Promentioning

confidence: 99%

“…Mesangial cell-derived inflammatory and fibrotic mediators (IL-6, MCP-1, TGFβ, TNFα) lead to podocyte dysfunction and their progressive loss and to tubulointerstitial injury [27,28,29]. This mesangial–podocyte–tubular crosstalk provides the rationale for the spread of initial mesangial injury to the entire nephron and ultimately to progressive loss of renal function [29].…”

Section: Transitioning From Pathogenesis Of Iga Nephropathy To Promentioning

confidence: 99%

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Has The Time Arrived to Refine The Indications of Immunosuppressive Therapy and Prognosis in IgA Nephropathy?

Obrișcă

Sinescu

Ismail

et al. 2019

JCM

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Immunoglobulin A nephropathy (IgAN) is the most frequent glomerular disease worldwide and a leading cause of end-stage renal disease. Particularly challenging to the clinician is the early identification of patients at high risk of progression, an estimation of the decline in renal function, and the selection of only those that would benefit from additional immunosuppressive therapies. Nevertheless, the pathway to a better prognostication and to the development of targeted therapies in IgAN has been paved by recent understanding of the genetic and molecular basis of this disease. Merging the data from the Oxford Classification validation studies and prospective treatment studies has suggested that a disease-stratifying algorithm would be appropriate for disease management, although it awaits validation in a prospective setting. The emergence of potential noninvasive biomarkers may assist traditional markers (proteinuria, hematuria) in monitoring disease activity and treatment response. The recent landmark trials of IgAN treatment (STOP-IgAN and TESTING trials) have suggested that the risks associated with immunosuppressive therapy outweigh the benefits, which may shift the treatment paradigm of this disease. While awaiting the approval of the first therapies for IgAN, more targeted and less toxic immunotherapies are warranted. Accordingly, the targeting of complement activation, the modulation of mucosal immunity, the antagonism of B-cell activating factors, and proteasomal inhibition are currently being evaluated in pilot studies for IgAN treatment.

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“…Studies over the past decades have indicated that circulating glycosylated IgA1 binds to autoantibodies and forms immune complexes that deposit in the mesangium, resulting in activated resident cells and local inflammation (Novak et al, 2018). More evidence have shown that mesangialderived mediators contribute to the pathogenesis of tubulointerstitial damage and podocyte injury via mesangialpodocytic-tubular crosstalk (Leung et al, 2018). Genome-wide association studies have also demonstrated that genetic components are implicated in disease pathogenesis and identified several susceptibility genes and loci associated with immune regulation (Zhang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Spleen Tyrosine Kinase Inhibition Ameliorates Tubular Inflammation in IgA Nephropathy

Yiu

Chan

et al. 2021

Front. Physiol.

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Spleen tyrosine kinase (Syk) is a non-receptor tyrosine kinase involved in signal transduction in a variety of immune responses. It has been demonstrated that Syk plays a pathogenic role in orchestrating inflammatory responses and cell proliferation in human mesangial cells (HMC) in IgA nephropathy (IgAN). However, whether Syk is involved in tubular damage in IgAN remains unknown. Using human kidney biopsy specimens, we found that Syk was activated in renal tubules of biopsy-proven IgAN patients with an increase in total and phosphorylated levels compared to that from healthy control subjects. In vitro, cultured proximal tubular epithelial cells (PTECs) were stimulated with conditioned medium prepared from human mesangial cells incubated with polymeric IgA (IgA-HMC) from patients with IgAN or healthy control. Induction of IL-6, IL-8, and ICAM-1 synthesis from cultured PTECs incubated with IgA-HMC conditioned medium was significantly suppressed by treatment with the Syk inhibitor R406 compared to that from healthy control. Furthermore, R406 downregulated expression of phosphorylated p65 NF-κB and p-42/p-44 MAPK, and attenuated TNF-α-induced cytokine production in PTECs. Taken together, our findings suggest that Syk mediates IgA-HMC conditioned medium-induced inflammation in tubular cells via activation of NF-κB and p-42/p-44 MAPK signaling. Inhibition of Syk may be a potential therapeutic approach for tubulointerstitial injury in IgAN.

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Role of Mesangial-Podocytic-Tubular Cross-Talk in IgA Nephropathy

Cited by 35 publications

References 92 publications

Urinary Citrate: A Potential Biomarker for IgA Nephropathy

Urinary Citrate: A Potential Biomarker for IgA Nephropathy

Has The Time Arrived to Refine The Indications of Immunosuppressive Therapy and Prognosis in IgA Nephropathy?

Spleen Tyrosine Kinase Inhibition Ameliorates Tubular Inflammation in IgA Nephropathy

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