A New Vision of IgA Nephropathy: The Missing Link

Sallustio, Fabio; Curci, Claudia; Di Leo, Vincenzo; Gallone, Anna; Pesce, Francesco; Gesualdo, Loreto

doi:10.3390/ijms21010189

Cited by 39 publications

(55 citation statements)

References 100 publications

(118 reference statements)

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“…Mesangial cell is activated when immune complexes come into glomerulus. After that, excessive cell proliferation and cytokines release trigger kidney injury (Sallustio et al, 2019). To elucidate the underlying protective mechanism of ZWT treatment in IgAN.…”

Section: Zwt Regulated Secretion Of Exosomes Which Affected Nf-kb/nlmentioning

confidence: 99%

Zhen-Wu-Tang Protects IgA Nephropathy in Rats by Regulating Exosomes to Inhibit NF-κB/NLRP3 Pathway

et al. 2020

Front. Pharmacol.

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Immunoglobulin A nephropathy (IgAN) is one of the most frequent kinds of primary glomerulonephritis characterized by IgA immune complexes deposition and glomerular proliferation. Zhen-wu-tang (ZWT), a well-known traditional Chinese formula has been reported to ameliorate various kidney diseases. However, its pharmacological mechanism remains unclear. Exosomes have been described in diverse renal diseases by mediating cellular communication but rarely in the IgAN. The purpose of the present study is to explore whether the underlying mechanisms of the effect of ZWT on IgAN is correlated to exosomes. Our results demonstrated that in human renal tubular epithelial cells (HK-2) stimulated by lipopolysaccharide, exosomes are obviously released after ZWT-containing serum treatment especially with 10% ZWT. In addition, once released, HK-2-derived exosomes were uptaked by human mesangial cells (HMC), which impeded the activation of NF-kB/NLRP3 signaling pathway to exert anti-inflammatory effects in a lipopolysaccharide induced proliferation model. Moreover, IgAN rat model was established by bovine serum albumin, CCL 4 mixed solution and LPS. We found that 10% ZWT could significantly promote the release of exosomes from HK-2 and inhibit HMC proliferation to improve inflammation. Thus HK-2-derived exosomes treated with 10% ZWT (ZWT-EXO) were administered to the rats by tail vein injection. Our results showed that ZWT-EXO decreased the levels of 24 h proteinuria, urinary erythrocyte, IgA deposition in glomerulus and renal pathological injury which ameliorated the kidney damage. In addition, ZWT was able to dramatically promote secretion of exosomes in renal tissues while blocked NF-kB nuclear translocation as well as activation of NLRP3 inflammasome, leading to the inhibition of IL-1b and caspase-1. In conclusion, our study reveal that ZWT has protective effects on IgAN by regulating exosomes secretion to inhibit the activation of NF-kB/NLRP3 pathway, thereby attenuating the renal dysfunction. These findings may provide a new therapeutic target for the treatment of IgAN.

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Section: Zwt Regulated Secretion Of Exosomes Which Affected Nf-kb/nlmentioning

confidence: 99%

Zhen-Wu-Tang Protects IgA Nephropathy in Rats by Regulating Exosomes to Inhibit NF-κB/NLRP3 Pathway

et al. 2020

Front. Pharmacol.

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“…An updated vision of the IgAN points to the need to consider this pathology as an entity closely linked to environmental factors, lifestyle, and diet. In addition to the strong association established with genetic factors, there are data on the possible influence of local pathogens with the development of this glomerulonephritis, especially with parasitic helminth infections [6, 7]. The discovery of new pathogenic mechanisms, especially the role of complement, forces us to change the vision of this entity with the need for an individualized approach with personalized therapy.…”

Section: Introduction Iga Nephropathy Overviewmentioning

confidence: 99%

A Personalized Update on IgA Nephropathy: A New Vision and New Future Challenges

Gutiérrez

Carvaca-Fontán

Luzardo

et al. 2020

Nephron

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IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world among patients undergoing renal biopsy. Approximately 30% of patients with IgAN develop end-stage kidney disease 20 years after renal biopsy. It is a glomerulopathy with a very broad clinical presentation, making it difficult to stratify and treat. IgAN is characterized by dysregulation of the immune system, which causes an abnormal synthesis of IgA1 that is deglycosylated causing its mesangial deposition. IgAN pathogenesis is incompletely understood; the current multi-hit hypothesis of IgAN pathogenesis does not explain the range of glomerular inflammation and renal injury associated with mesangial IgA deposition. Although associations between IgAN and glomerular and circulating markers of complement activation are established, the mechanism of complement activation and contribution to glomerular inflammation and injury are not defined. On the other hand, the renal-gut connection can also play an important role in the pathogenesis of IgAN with possible therapeutic implications. In order to standardize the histological findings, the Oxford Classification has allowed clarifying renal lesions that confer potential risk of progression. Currently, except for the blockade of the renin-angiotensin-aldosterone system, no other therapies are available in clinical setting for the treatment of IgAN, although the range of new drugs under investigation is extensive. The incorporation in the next trials of clinical parameters such as the amount of hematuria and histological lesions may allow more personalized therapeutic approaches. To summarize, in recent years, several important efforts have taken place in the understanding of IgAN, but still, further studies are warranted to elucidate the best therapeutic strategies according to the risk to improve the prognosis of this entity.

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“…Furthermore, the decreased expression level of the molecular chaperone Cosmc in B cells of patients with IgAN is associated with the number of B cells and the abnormal glycosylation of IgA1 in IgAN (5)(6)(7)(8). However, the production of IgA1 with low galactosylation in IgAN may be the result of B cell defect, and the activity of C1GalT1 is decreased in B cells (9). This is consistent with the observation that an increasing number of poly IgA1 (pIgA1) plasma cells are found in the bone marrow and tonsils of patients with IgAN with the inactivation of C1GalT1 of B cells, and the increase in IgA1 synthesis of these plasma cells in spontaneous culture is also observed (10,11).…”

Section: Introductionmentioning

confidence: 99%

T lymphocytes in IgA nephropathy (Review)

Tang

et al. 2020

Exp Ther Med

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Immunoglobulin A nephropathy (IgAN), the most common primary glomerulonephritis worldwide, is the main cause of end-stage renal disease. IgAN is characterized by the accumulation of immune complexes in the circulation, which contain abnormal levels of IgA. IgAN primarily results from galactose-deficient IgA1 (Gd-IgA1) and Gd-IgA1 deposition in the renal mesangium, causing local proliferation and matrix expansion. Gd-IgA1 has been confirmed as one of the key effectors in the pathogenesis of IgAN, but the origin of Gd-IgA1 is not clear. Recent studies have shown that Gd-IgA1 deposition could be the result of mucosally primed plasma cells and is associated with T cell dysregulation. T cells contribute to the IgA response and play an important role in the development of IgAN. In the present review, the latest discoveries regarding the role of T lymphocytes in the pathogenesis of IgAN have been summarized. Understanding these advances will allow novel therapeutic strategies for the treatment of IgAN.

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A New Vision of IgA Nephropathy: The Missing Link

Cited by 39 publications

References 100 publications

Zhen-Wu-Tang Protects IgA Nephropathy in Rats by Regulating Exosomes to Inhibit NF-κB/NLRP3 Pathway

Zhen-Wu-Tang Protects IgA Nephropathy in Rats by Regulating Exosomes to Inhibit NF-κB/NLRP3 Pathway

A Personalized Update on IgA Nephropathy: A New Vision and New Future Challenges

T lymphocytes in IgA nephropathy (Review)

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