Abstract
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-κB/NLRP3 signaling pathway to exert anti-inflammatory effects in a lipopolysaccharide induced proliferation model. Moreover, IgAN rat model was established by bovine serum albumin, CCL4 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-κB nuclear translocation as well as activation of NLRP3 inflammasome, leading to the inhibition of IL-1β 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-κB/NLRP3 pathway, thereby attenuating the renal dysfunction. These findings may provide a new therapeutic target for the treatment of IgAN.
Highlights
IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis, characterized by immune complex deposition, glomerular mesangial cell (GMC) proliferation and extracellular matrix (ECM) deposition (Coppo, 2018)
Studies have shown that HK-2 cells could regulate microenvironment and immune inflammatory response which play a significant role in the repair of renal injury (Hato et al, 2013)
The MTT assay showed that the cell viability of HK-2 cells was decreased by LPS, which was increased after intervention with ZWT-containing serum (ZWTS)
Summary
IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis, characterized by immune complex deposition, glomerular mesangial cell (GMC) proliferation and extracellular matrix (ECM) deposition (Coppo, 2018). The deposition of immune complex can activate mesangial cells, induce cytokines secretion and promote cell proliferation, resulting in inflammation and leading to kidney damage (Zachova et al, 2020). The main clinical manifestations of IgAN are macroscopic hematuria accompanied by proteinuria, severe hypertension and renal insufficiency. Accumulating evidences demonstrated that approximately 30%~40% of patients with IgAN developed into end-stage renal disease (ESRD) within 20 years (Moroni et al, 2019; Chen et al, 2020). The mechanism upon IgAN has not been fully understood, which impedes the design of the specific treatment for the disease. It is essential to uncover appropriate drugs for the IgAN therapy
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