Extracellular vesicle-packaged ILK from mesothelial cells promotes fibroblast activation in peritoneal fibrosis.

Progressive peritoneal fibrosis and the loss of peritoneal function often emerged in patients undergoing long-term peritoneal dialysis (PD), resulting in PD therapy failure. Varieties of cell-cell communications among peritoneal cells play a significant role in peritoneal fibrogenesis. Extracellular vesicles (EVs) have been confirmed to involve in intercellular communication by transmitting proteins, nucleic acids or lipids. However, their roles and functional mechanisms in peritoneal fibrosis remain to be determined. Using integrative analysis of EV proteomics and single-cell RNA sequencing, we characterized the EVs isolated from PD patient's effluent and revealed that mesothelial cells are the main source of EVs in PD effluent. We demonstrated that transforming growth factor-ß1 (TGF-ß1) can substitute for PD fluid to stimulate mesothelial cells releasing EVs, which in turn promoted fibroblast activation and peritoneal fibrogenesis. Blockade of EVs secretion by GW4869 or Rab27a knockdown markedly suppressed PD-induced fibroblast activation and peritoneal fibrosis. Mechanistically, injured mesothelial cells produced EVs containing high level of integrin-linked kinase (ILK), which was delivered to fibroblast and activated them via p38 MAPK signalling pathway. Clinically, the expression of ILK was up-regulated in fibrotic peritoneum of patients undergoing long-term PD. The percentage of ILK positive EVs in PD effluent correlated with peritoneal dysfunction and the degree of peritoneal damage. Our study highlights that peritoneal EVs mediate communications between mesothelial cells and fibroblasts to initiate peritoneal fibrogenesis. Targeting EVs or ILK could provide a novel therapeutic strategy to combat peritoneal fibrosis.

Proteomic Characterization of Peritoneal Extracellular Vesicles in a Mouse Model of Peritoneal Fibrosis.

Peritoneal fibrosis progression is regarded as a significant cause of the loss of peritoneal function, markedly limiting the application of peritoneal dialysis (PD). However, the pathogenesis of peritoneal fibrosis remains to be elucidated. Tissue-derived extracellular vesicles (EVs) change their molecular cargos to adapt the environment alteration, mediating intercellular communications and play a significant role in organ fibrosis. Hence, we performed, for the first time, four-dimensional label-free quantitative liquid chromatography-tandem mass spectrometry proteomic analyses on EVs from normal peritoneal tissues and PD-induced fibrotic peritoneum in mice. We demonstrated the alterations of EV concentration and protein composition between normal control and PD groups. A total of 2339 proteins containing 967 differentially expressed proteins were identified. Notably, upregulated proteins in PD EVs were enriched in processes including response to wounding and leukocyte migration, which participated in the development of fibrosis. In addition, EV proteins of the PD group exhibited unique metabolic signature compared with those of the control group. The glycolysis-related proteins increased in PD EVs, while oxidative phosphorylation and fatty acid metabolism-related proteins decreased. We also evaluated the effect of cell-type specificity on EV proteins, suggesting that mesothelial cells mainly cause the alterations in the molecular composition of EVs. Our study provided a useful resource for further validation of the key regulator or therapeutic target of peritoneal fibrosis.

Adding/dropping polarization multiplexed cylindrical vector beams with local polarization-matched plasmonic metasurface.

Here we propose a polarization-dependent gradient phase modulation strategy and fabricate a local polarization-matched metasurface to add/drop polarization multiplexed cylindrical vector beams (CVBs). The two orthogonal linear polarization states in CVB multiplexing will represent as radial- and azimuthal-polarized CVBs, which means that we must introduce independent wave vectors to them for adding/dropping the polarization channels. By designing the rotation angle and geometric sizes of a meta-atom, a local polarization-matched propagation phase plasmonic metasurface is constructed, and the polarization-dependent gradient phases were loaded to perform this operation. As a proof of concept, the polarization multiplexed CVBs, carrying 150-Gbit/s quadrature phase shift keying signals, are successfully added and dropped, and the bit error rates approach 1 × 10-6. In addition to representing a route for adding/dropping polarization multiplexed CVBs, other functional phase modulation of arbitrary orthogonal linear polarization bases is expected, which might find potential applications in polarization encryption imaging, spatial polarization shaping, etc.

SIS3 Alleviates Cisplatin-Induced Acute Kidney Injury by Regulating the LncRNA Arid2-IR-Transferrin Receptor Pathway.

INTRODUCTION: TGF-ß/Smad3 may be involved in the pathogenesis of acute kidney injury (AKI), but its functional role and mechanism of action in cisplatin-induced AKI are unclear. Here, we established a cisplatin-induced AKI mouse model to demonstrate that Smad3 may have roles in cisplatin nephropathy because of its potential effects on tubular epithelial cell (TEC) death and regeneration. METHODS: Using a cisplatin-induced AKI model, the expression levels of lncRNA Arid2-IR were measured by qRT-PCR and the location detected by FISH. Transfected with overexpression of lncRNA Arid2-IR by lentiviral vector in TECs, and the expression of cleaved caspase 3, Bax, Bcl-2, PCNA, p21, p27, transferrin receptor (TFRC), FTH, and FTL were measured by Western blot. Protein molecules bound to lncRNA Arid2-IR were identified by RIP, RNA pull-down assay, mass spectrometry. RESULTS: LncRNA Arid2-IR was significantly downregulated in vivo and in vitro. SIS3 decreased cell apoptosis and promoted cell regeneration by upregulating lncRNA Arid2-IR expression. LncRNA Arid2-IR regulated the cell cycle by decreasing expression of the cyclin-dependent kinase inhibitors p21 and p27. Finally, lncRNA Arid2-IR interacted with the TFRC, and overexpression of lncRNA Arid2-IR increased TFRC expression and decreased FTH and FTL. CONCLUSION: Smad3 regulated lncRNA Arid2-IR via TFRC, thereby regulating the cell cycle, protecting against cell apoptosis, and promoting cell regeneration.

Sofosbuvir and ledipasvir decreased nephrotic syndrome caused by IgA nephropathy with a membranoproliferative pattern of injury in hepatitis C virus-induced cirrhosis: a case report.

Background: Immunoglobulin (Ig) A nephropathy (IgAN) with a membranoproliferative pattern of injury that manifests as nephrotic syndrome (NS) is rarely reported in hepatitis C virus (HCV)-induced cirrhosis. It is not known whether eradication of HCV by direct-acting antiviral (DAA) drugs can lead to remission of proteinuria and improve the long-term prognosis. Case Description: We report the case of a 52-year-old woman with HCV cirrhosis for 10 years. She had undergone splenectomy and cholecystectomy due to complications of liver cirrhosis. The patient presented with NS and was diagnosed by kidney biopsy with IgAN with a membranoproliferative pattern of injury. Twelve-week sofosbuvir and ledipasvir therapy successfully eradicated HCV in this decompensated cirrhosis patient and resulted in partial remission of IgAN. The patient stayed in partial remission for 4 years and had her first relapse with deterioration of portal hypertension and suspected hepatic carcinoma despite a sustained HCV virologic response. We consider the IgAN in this case to be secondary to liver cirrhosis and HCV infection rather than a primary nephropathy. DAA drugs which have no direct reno-protective effect resulted in partial remission of IgAN because they eradicated HCV and improved the liver disorder. Conclusions: Although relapse of IgAN could occur when liver cirrhosis deteriorates, DAA treatment may be considered an alternative for similar patients.

Alteration of N6-Methyladenosine RNA Profiles in Cisplatin-Induced Acute Kidney Injury in Mice.

Aim: To identify the alterations of N6-methyladenosine (m6A) RNA profiles in cisplatin-induced acute kidney injury (Cis-AKI) in mice. Materials and Methods: The total level of m6A and the expression of methyltransferases and demethylases in the kidneys were measured. The profiles of methylated RNAs were determined by the microarray method. Bioinformatics analysis was performed to predict the functions. Results: Global m6A levels were increased after cisplatin treatment, accompanied by the alterations of Mettl3, Mettl14, Wtap, Fto, and Alkbh5. A total of 618 mRNAs and 98 lncRNAs were significantly differentially methylated in response to cisplatin treatment. Bioinformatics analysis indicated that the methylated mRNAs predominantly acted on the metabolic process. Conclusion: M6A epitranscriptome might be significantly altered in Cis-AKI, which is potentially implicated in the development of nephrotoxicity.

A retrospective cohort study on the pathology and outcomes of type 2 diabetic patients with renal involvement.

OBJECTIVE: To investigate the association of clinical and histological characteristics and the development of ESRD in T2DM patients with renal involvement. METHODS: We conducted a retrospective analysis of clinical and pathologic data from T2DM patients who underwent renal biopsy (n = 120). RESULTS: The mean age, duration of diabetes, and eGFR were 50.9 ± 11.2 years, 92.8 ± 41.3 months, 55.1 ± 42.3 mL/min/1.73 m2, respectively. Among these patients, 57 (47.5%) were diagnosed with diabetic nephropathy (DN), and 63 (52.5%) with non-diabetic renal disease (NDRD). The most common subtype of NDRD is membranous nephropathy. Compared with the NDRD group, the DN group had a longer duration of diabetes, worse renal function, and a higher proportion of diabetic retinopathy. Kaplan-Meier analysis showed that the 5-year renal survival rate of the DN group was only 41%, whereas that of the NDRD group was 84%. ESRD was defined as eGFR below 15 mL/min/1.73 m2. After multivariate adjustment, the risk of ESRD in DN patients was 3.81 times higher than that in NDRD patients. According to Glomerular Class, the 5-year renal survival rate of type IIA, IIB, III, and IV in the DN group was 88, 56, 28, and 15%, respectively. Kaplan-Meier analysis showed that there was a significant difference in renal survival among different glomerular classes or different interstitial fibrosis and tubular atrophy (IFTA) scores. But Cox proportional hazards analysis indicated that only IFTA score (HR 2.75, 95% CI 1.37-5.51, P = 0.001), but not the glomerular class (HR 1.21, 95% CI 0.73-2.00, P = 0.465), could predict renal outcome when adjusting for multivariate. CONCLUSION: The prognosis of DN patients is significantly worse than that of NDRD patients. Compared with glomerular lesions, tubulointerstitial lesions were associated with higher risk for renal death in DN patients.

The influence of cardiac valvular calcification on all-cause and cardiovascular mortality in maintenance hemodialysis patients.

OBJECTIVE: To investigate the effect of cardiac valve calcification (CVC) on all-cause and cardiovascular mortality in maintenance hemodialysis (MHD) patients. METHODS: A retrospective cohort study was conducted in 183 long-term hemodialysis patients with complete follow-up data from January 1, 2012, to December 30, 2015. The baseline data between CVC and non-CVC groups were compared. Kaplan-Meier method was used to analyze all-cause and cardiovascular mortality. The effect of CVC on prognosis was analyzed using the Cox proportional hazard regression model and subgroup analysis. RESULTS: Among 183 patients under hemodialysis, 104 (56.8%) were males, with an average age of 56.1 ± 17.0 years and 68 (37.2%) were complicated with valvular calcification. The median follow-up period was 30.8 months. All-cause and cardiovascular mortality were 50% vs. 14.8% and 25% vs. 7.0% in the CVC and non-CVC groups, respectively (P < 0.05). Kaplan-Meier indicated that differences in all-cause and cardiovascular mortality were statistically significant between the two groups (P < 0.001). Cox regression analysis showed that CVC significantly increased all-cause (hazards ratio [HR] 2.161 [1.083-4.315]) and cardiovascular mortality (3.435 [1.222-9.651]) after adjusting for multiple factors. Meanwhile, CVC also increases the incidence of new-onset cardiovascular events. Subgroup analysis revealed that all-cause and cardiovascular mortality were significantly higher in patients with aortic valve calcification (AVC) than in patients with mitral valve calcification (MVC). Multivariate calibration showed that AVC increased the risk of cardiovascular death (HR 5.486 [1.802-16.702]) (P < 0.05), whereas MVC did not. By further comparing the echocardiographic data of the two groups, the incidence of LVH and pulmonary hypertension in the AVC group was significantly higher than that in the MVC group. CONCLUSION: Valve calcification increases the risk of all-cause and cardiovascular mortality in MHD patients, also new-onset cardiovascular events, and aortic valve calcification contributes more to the risk of cardiovascular mortality.

Low serum uric acid levels increase the risk of all-cause death and cardiovascular death in hemodialysis patients.

BACKGROUND: Elevated serum uric acid (SUA) is associated with increased cardiovascular (CV) and all-cause mortality risk in the general population, but the impact of UA on mortality in hemodialysis patients is still controversial. The aim of the study was to explore the relationship between SUA and all-cause mortality and CV mortality in hemodialysis patients. METHODS: This retrospective, observational cohort study included 210 HD patients with a mean age of 56.6 ± 16.6 years. All demographic and laboratory data were recorded at baseline. The Kaplan-Meier method and Cox proportional hazard regression model were used to examine the association between SUA and all-cause mortality and CV mortality in HD patients. RESULTS: With 420 µmol/L (20th percentile) and 644 µmol/L (80th percentile) as the boundary points, the patients were divided into three groups. After a median follow-up of 49.8 months, 68 (32.4%) all-cause deaths and 34 (16.2%) CV deaths were recorded. The Kaplan-Meier method showed that with a decrease in SUA, all-cause mortality (log rank χ2 = 15.61, p = .000), and CV mortality (log rank χ2=14.28, p = .000) increased. Each 100 µmol/L increase in SUA was associated with lower all-cause mortality with an hazard ratio (HR) of 0.792 (0.645-0.972) and lower CV mortality with an HR of 0.683 (0.505-0.924) after adjusting for age, sex, and complications. Compared to the lowest quartile, all-cause mortality [HR 0.351(0.132-0.934), p = .036] and CV mortality [HR 0.112 (0.014-0.925), p = .042] were lower in the highest SUA quartile. CONCLUSION: A lower SUA level in HD patients was associated with a higher risk of all-cause mortality and CV mortality. Moreover, higher SUA concentrations may be cardioprotective in HD patients.

Sirt3 modulates fatty acid oxidation and attenuates cisplatin-induced AKI in mice.

Fatty acid oxidation (FAO) dysfunction is one of the important mechanisms of renal fibrosis. Sirtuin 3 (Sirt3) has been confirmed to alleviate acute kidney injury (AKI) by improving mitochondrial function and participate in the regulation of FAO in other disease models. However, it is not clear whether Sirt3 is involved in regulating FAO to improve the prognosis of AKI induced by cisplatin. Here, using a murine model of cisplatin-induced AKI, we revealed that there were significantly FAO dysfunction and extensive lipid deposition in the mice with AKI. Metabolomics analysis suggested reprogrammed energy metabolism and decreased ATP production. In addition, fatty acid deposition can increase reactive oxygen species (ROS) production and induce apoptosis. Our data suggested that Sirt3 deletion aggravated FAO dysfunction, resulting in increased apoptosis of kidney tissues and aggravated renal injury. The activation of Sirt3 by honokiol could improve FAO and renal function and reduced fatty acid deposition in wide-type mice, but not Sirt3-defective mice. We concluded that Sirt3 may regulate FAO by deacetylating liver kinase B1 and activating AMP-activated protein kinase. Also, the activation of Sirt3 by honokiol increased ATP production as well as reduced ROS and lipid peroxidation through improving mitochondrial function. Collectively, these results provide new evidence that Sirt3 is protective against AKI. Enhancing Sirt3 to improve FAO may be a potential strategy to prevent kidney injury in the future.

Expansion of Monocytic Myeloid-Derived Suppressor Cells in Patients Under Hemodialysis Might Lead to Cardiovascular and Cerebrovascular Events.

Background: The specific mechanism of cardiovascular and cerebrovascular vasculopathy in the context of end-stage renal disease has not been elucidated. In the present study, we investigated the clinical impact of myeloid-derived suppressor cells (MDSCs) on hemodialysis patients and their mechanism of action. Methods: MDSCs were tested among 104 patients undergoing hemodialysis and their association with overall survival (OS) and cardiovascular and cerebrovascular events was determined. Results: Hemodialysis patients presented a significantly higher level of monocytic MDSCs (M-MDSCs) compared to healthy controls. M-MDSC were tested 3 months after first testing among 103 hemodialysis patients, with one patient not retested due to early death. The repeated results of M-MDSC levels were consistent with the initial results. Patients with persistent high level of M-MDSCs presented decreased OS, as well as increased stroke and acute heart failure events. As illustrated by multivariate Cox regression, M-MDSC was an independent predictor for OS and stroke events of hemodialysis patients. T cell proliferations were significantly abrogated by hemodialysis-related M-MDSCs in a dose-dependent manner. Besides, M-MDSCs presented higher levels of CXCR4 and VLA-4 compared to monocytes, which indicated their enhanced capability to be recruited to atherosclerotic lesions. The expression of arginase I and activity of arginase was also significantly raised in hemodialysis-related M-MDSCs. Human coronary arterial endothelial cells (HCAECs) presented increased capability to migration by coculture with M-MDSCs, compared with monocyte group. Arginase inhibitor and L-arginine abrogated the immune suppressive function and induction of HCAECs migration of hemodialysis related M-MDSC. Plasma IFN-γ, TNF-α and IL-6 were elevated in hemodialysis patients compared with healthy control. M-MDSC level was positively related to IL-6 level among hemodialysis patients. The plasma of hemodialysis patients induced M-MDSCs significantly compared with plasma from health donors. Besides, IL-6 neutralizing antibody significantly abrogated the induction. Neutralizing antibody of IFN-γ and TNF-α partially decreased the generation of arginase of the induced M-MDSC. Conclusions: M-MDSCs were elevated in ESRD patients under hemodialysis, and they exhibited a strong association with the risk of cardiovascular and cerebrovascular diseases. Hemodialysis related M-MDSC presented enhanced recruitment to atherosclerotic lesions, promoted the migration of endothelial cells through exhaustion of local L-arginine.

Circular RNA expression profiles in cisplatin-induced acute kidney injury in mice.

Aim: This study was carried out to identify the expression profile and role of circRNAs in cisplatin-induced acute kidney injury (AKI). Materials & methods: In this study, an AKI model was established in cisplatin-treated mice, and the expression of circRNAs was profiled by next-generation sequencing. The differential expression levels of selected circRNAs were determined by quantitative real-time polymerase chain reaction. Bioinformatics analysis was conducted to predict the functions. Results: In total, 368 circRNAs were detected to be differentially expressed in response to cisplatin treatment. Bioinformatics analysis indicated that the parental genes of the differentially expressed circRNAs were predominantly implicated in the cell and cell part, cellular process and cancer pathways. Conclusion: CircRNAs might be differentially expressed in AKI, which are potentially involved in pathophysiology of cisplatin-induced nephrotoxicity.

Advanced glycation end products induce glomerular endothelial cell hyperpermeability by upregulating matrix metalloproteinase activity.

The present study aimed to investigate the effects of advanced glycation end­products (AGEs) on the permeability of glomerular endothelial cells (GEnCs) and determine whether enhanced permeability was due to degradation of tight junction (TJ) complexes by matrix metalloproteinases (MMPs). Cultured monolayers of GEnCs were exposed to AGEs at different doses and treatment durations in the presence or absence of the organic MMP­2/9 inhibitor (2R)­2­((4­biphenyl sulfony­l)amino)­3­phenylproprionic acid) (BiPs). Expression of the TJ proteins occludin and claudin­5 was determined by western blot analysis and immunofluorescence, while the permeability of the GEnCs was measured using transendothelial electrical resistance and by diffusion of 4 kDa fluorescein isothiocyanate (FITC)­dextran. The activities of MMP­2 and MMP­9 were assayed using gelatin zymography. The results indicated that AGE­treated cultures significantly reduced occludin and claudin­5 immunoreactivity. Similarly, the surface expression of these proteins was significantly reduced and rows of TJs which normally connect endothelial cells became discontinuous or fractured following AGE exposure. Disruption of TJs was accompanied by significantly reduced transendothelial resistance and hyperpermeability to FITC­dextran. Treatment with AGEs evoked a dose­ and time­dependent upregulation of MMP­2 and MMP­9. However, co­administration of AGEs and BiPS, an inhibitor of MMP­2/MMP­9, inhibited the downregulation of occludin and claudin­5, with a concomitant reversal of GEnC monolayer hyperpermeability. In conclusion, AGEs promoted glomerular hyperpermeability in vitro by the MMP­mediated disruption of TJs. Chronic elevation of endothelial cell AGEs in diabetes mellitus may contribute to glomerular hyperpermeability by inducing the overexpression of MMPs, which degrade TJs, leading to proteinuria.

High glucose induces activation of the local renin­angiotensin system in glomerular endothelial cells.

Activation of the intrarenal renin­angiotensin system (RAS), which has been identified in podocytes and mesangial cells, is a novel mechanism in the progression of diabetic kidney disease (DKD). The present study aimed to identify the local RAS in glomerular endothelial cells (GEnCs). Rat GEnCs were stimulated by culture medium containing 30 mmol/l glucose for 12, 24, 48 and 72 h. Angiotensin II (Ang II) concentrations in cell lysates and culture media were examined by ELISA and mRNA levels of angiotensinogen and renin in cell lysates were analyzed by quantitative polymerase chain reaction. Ang II type 1 receptor (AT1R), Ang II type 2 receptor (AT2R), renin and angiotensinogen levels in cell lysates were determined by western blot analysis. Localization of intracellular AT1R, AT2R, angiotensinogen and renin was identified by confocal immunofluorescence microscopy. Consequently, high glucose (HG) increased intracellular and extracellular Ang II levels. Captopril and chymostatin (inhibitor of chymase, an enzyme that converts Ang I to Ang II) were able to antagonize HG­induced Ang II generation. Moreover, HG increased angiotensinogen production in GEnCs and reduced renin mRNA expression without altering renin protein production. However, HG decreased AT1R levels and resulted in AT2R shifting from the nuclear to perinuclear region in GEnCs. In conclusion, HG activated the intracellular RAS in rat GEnCs and the underlying mechanism may involve angiotensin­converting enzyme (ACE) and non­ACE pathways. The effects of HG on GEnCs may also involve the substrate and receptors of Ang II.

Simvastatin alleviates hyperpermeability of glomerular endothelial cells in early-stage diabetic nephropathy by inhibition of RhoA/ROCK1.

BACKGROUND: Endothelial dysfunction is an early sign of diabetic cardiovascular disease and may contribute to progressive diabetic nephropathy (DN). There is increasing evidence that dysfunction of the endothelial tight junction is a crucial step in the development of endothelial hyperpermeability, but it is unknown whether this occurs in glomerular endothelial cells (GEnCs) during the progression of DN. We examined tight junction dysfunction of GEnCs during early-stage DN and the potential underlying mechanisms. We also examined the effect of simvastatin (3-Hydroxy-3-methylglutaryl CoA reductase inhibitor) on dysfunction of the tight junctions of cultured GEnCs and in db/db mice with early-stage DN. METHODS: We assessed the expression of occludin and ZO-1, two major components of the tight junction complex, in cultured rat GEnCs treated with high glucose and in 12 week-old db/db mice with early-stage DN. We also investigated activation of RhoA/ROCK1 signaling, GEnC permeability, and renal function of the mice. RESULTS: High glucose suppresses occludin expression and disrupts occludin/ZO-1 translocation in GEnCs. These changes were associated with increased permeability to albumin and activation of RhoA/ROCK1 signaling. Occludin and ZO-1 dysregulation also occurred in the glomeruli of mice with early-stage DN, and these abnormalities were accompanied by albuminuria and activation of RhoA/ROCK1 in isolated glomeruli. Simvastatin prevented high glucose or hyperglycemia-induced dysregulation of occludin and ZO-1 by inhibition of RhoA/ROCK1 signaling in cultured GEnCs and in db/db mice with early-stage DN. CONCLUSION: Our results indicate that activation of RhoA/ROCK1 by high glucose disrupts the expression and translocation of occludin/ZO-1 and that simvastatin alleviates occludin/ZO-1 dysregulation and albuminuria by suppressing RhoA/ROCK1 signaling during early-stage DN. These results suggest a potential therapeutic strategy for preventing the onset of albuminuria in early-stage DN.

Mesangial medium from IgA nephropathy patients induces podocyte epithelial-to-mesenchymal transition through activation of the phosphatidyl inositol-3-kinase/Akt signaling pathway.

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.