Mesangial Medium from IgA Nephropathy Patients Induces Podocyte Epithelial-to-mesenchymal Transition through Activation of the Phosphatidyl Inositol-3-kinase/Akt Signaling Pathway

Abstract

Background: Podocyte injury plays an important role in glomerulosclerosis in IgA nephropathy (IgAN). Eepithelial-to-mesenchymal transition (EMT) caused by different factors is the main reason for podocyte damage. This study hypothesized that conditioned mesangial medium may induced EMT process of podocytes and thereby lead to glomerular injury or sclerosis. Materials and Methods: Podocytes were incubated in medium from mesangial cells incubated with aggregated IgA1(aIgA1) isolated from IgAN patients. Wortmannin were used to inhibit phosphatidylinositol-3-kinase (PI3-K) in podocytes. Results: Western blot analysis, real-time PCR and confocal fluorescent microscopy demonstrated that reduced expression of P-Cadherin, Zonula occludens-1 (ZO-1) and podocin, increased expression of fibroblast –specific protein (FSP-1), α-smooth muscle action(α-SMA) and desmin in podocytes exposed to medium from mesangial cells incubated with aIgA1 isolated from IgAN patients compared with podocytes cultured in RPMI 1640 medium containing 0.5% fetal bovine serum ( FBS) (p<0.05). Mesangial medium resulted in a greater albumin influx across the podocyte monolayer (p<0.05). Phosphorylation of Akt increased with this medium, as indicated by an increase in the p-Akt/Akt ratio. Treatment with wortmannin partly restored the changes in epithelial and mesenchymal markers and albumin influx. IgAN patients with massive proteinuria showed remarkable α-SMA and FSP-1 expression in podocytes. Conclusion: Our findings indicated that mesangial medium from cells incubated with aIgA1 isolated from IgAN patients induced EMT in podocytes and the PI3-K/ Akt-signaling pathway was involved in the process.

Clinical and pathological analysis of IgA nephropathy with chronic renal failure

“…Recent studies revealed that there existed cross-talk between mesangial cell, podocyte, and tubular cell and they promote disease progression together. [12][13][14] An elegant study showed that segmental glomerulosclerosis and tubular atrophy and interstitial fibrosis were independent predictive factors of end stage renal disease but not mesangial cell proliferation. 15 So, we further speculate that during the progression of IgAN, mesangial cell proliferation is probably the initiating factor, while injury of podocyte and tubular cell are the key elements.…”

Emodin Ameliorates High Glucose Induced-Podocyte Epithelial-Mesenchymal Transition In-Vitro and In-Vivo

“…Recent studies have increasingly demonstrated that podocyte injury plays an important role in the development of DKD [15,16] and emerging evidence suggests that DKD is more a “podocyte disease” [17]. Accumulating evidences suggest that high glucose environment, such as the one observed in diabetes, could be involved in podocytes EMT [18,19,20]. In-vivo study further confirmed that podocyte EMT could be a potential pathway leading to proteinuria in DKD [21].…”

Activation of the Nrf2-ARE Pathway Attenuates Hyperglycemia-Mediated Injuries in Mouse Podocytes

“…Mouse podocytes were provided and cultured as described previously [17,18]. Growth-arrested podocytes were grown in normal glucose (NG; 5 mM), mannitol (MA; 25 mM) and high glucose (HG; 25 mM) medium.…”

“…A BSA permeability assay was used to evaluate the filtration barrier function of podocyte monolayers [18]. Briefly, podocytes (5×10 3 ) were seeded onto collagen-coated trans-well filters (pore size, 3 µm; Corning, New York, NY, USA) and cultured under differentiation conditions.…”