ErbB4 deletion accelerates renal fibrosis following renal injury

Zeng, Fenghua; Miyazawa, Tomoki; Kloepfer, Lance A.; Harris, Raymond C.

doi:10.1152/ajprenal.00260.2017

Cited by 23 publications

(21 citation statements)

References 35 publications

(47 reference statements)

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“…Liver samples from cryosections were stained with oil red O (ORO). Immunofluorescence staining for macrophages using F4/80 antibody (Bio-Rad, Hercules, CA) was carried out as previously described (31).…”

Section: Methodsmentioning

confidence: 99%

ErbB4 deletion predisposes to development of metabolic syndrome in mice

Zeng

Wang

Kloepfer

et al. 2018

American Journal of Physiology-Endocrinology and Metabolism

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ErbB4, a member of the EGF receptor family, plays a variety of roles in physiological and pathological states. Genetic studies have indicated a link between ErbB4 and type 2 diabetes and obesity, but its role in metabolic syndrome (MetS) has not been reported. In the current study we found that mice with ErbB4 deletion developed MetS after 24 wk on a medium-fat diet (MFD), as indicated by development of obesity, dyslipidemia, hepatic steatosis, hyperglycemia, hyperinsulinemia, and insulin resistance, compared with wild-type mice. ErbB4 deletion mice also exhibited increased amounts of subcutaneous and visceral fat, with increased serum leptin levels, compared with wild-type mice, whereas levels of adiponectin were not significantly different. Histologically, severe inflammation, indicated by F4/80 immunostaining and M1 macrophage polarization, was detected in inguinal and epididymal white adipose tissue in ErbB4 deletion mice. ErbB4 expression decreased during 3T3-L1 preadipocyte differentiation. Administration of neuroregulin 4, a specific ligand for ErbB4, to 3T3-L1 adipocytes had no effect on adipogenesis and lipolysis but significantly inhibited lipogenesis, promoted browning, induced GLUT4 redistribution to the cell membrane, and increased glucose uptake. Neuroregulin 4 also significantly increased glucose uptake in adipocytes isolated from wild-type mice, while these effects were significantly decreased in adipocytes isolated from ErbB4 deletion mice. In conclusion, our results indicate that ErbB4 may play an important role in glucose homeostasis and lipogenesis. ErbB4 deficiency-related obesity and adipose tissue inflammation may contribute to the development of MetS.

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Section: Methodsmentioning

confidence: 99%

ErbB4 deletion predisposes to development of metabolic syndrome in mice

Zeng

Wang

Kloepfer

et al. 2018

American Journal of Physiology-Endocrinology and Metabolism

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“…Kidney fibrosis is the common pathological feature for almost all kinds of chronic kidney diseases, including diabetic kidney and glomerulonephritis, and is strongly related with kidney function decline [ 1 , 2 ]. Kidney fibrosis is characterized by unbalanced extracellular matrix (ECM) metabolism resulting in excessive deposition of matrix component, which returns to impede the function of tubules and glomerulus.…”

Section: Introductionmentioning

confidence: 99%

Specific Inhibitor of Smad3 (SIS3) Attenuates Fibrosis, Apoptosis, and Inflammation in Unilateral Ureteral Obstruction Kidneys by Inhibition of Transforming Growth Factor β (TGF-β)/Smad3 Signaling

Wang

et al. 2018

Med Sci Monit

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BackgroundFibrosis is the common pathological feature in most kinds of chronic kidney disease (CKD). TGF-β/Smads signaling is the master pathway regulating kidney fibrosis pathogenesis, in which Smad3 acts as the integrator of various pro-fibrosis signals. In this study, we analyzed the role of SIS3, a specific inhibitor of Smad3, in mouse unilateral ureteral obstruction (UUO) kidneys.Material/MethodsUUO mice were intraperitoneally injected with 0.2 mg/kg/day or 2 mg/kg/day of SIS3 or control saline for 7 days, followed by analysis of structure injury, fibrosis status, inflammation, apoptosis, and TGF-β/Smads signaling activity.ResultsOur results indicated that SIS3 treatment dosage-dependently relieved the gross structure injury and tubular necrosis in UUO kidneys. Masson staining, immunohistochemistry, and real-time PCR showed significantly decreased extracellular matrix deposition, fibronectin staining intensity, and RNA levels of collagen I and collagen III in SIS3-treated UUO kidneys. SIS3 treatment also suppressed the activation of myofibroblasts, as evidenced by decreased expression levels of α-SMA and vimentin in UUO kidneys. The TGF-β/Smads signaling activity analysis showed that SIS3 inhibited the phosphorylation of Smad3 but not Smad2 and decreased the protein level of TGF-β1, suggesting specific inhibition of the TGF-β/Smad3 pathway in UUO kidneys. Furthermore, SIS3 treatment also ameliorated the increased pro-inflammatory TNF-α and COX2 in UUO kidneys and circulating IL-1β in UUO mice, and inhibited caspase-3 activity and the number of apoptotic cells.ConclusionsSIS3 ameliorated fibrosis, apoptosis, and inflammation through inhibition of TGF-β/Smad3 signaling in UUO mouse kidneys.

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“…TGF-β is a 25 kDa homodimer prototype of the protein family that regulate cell growth and differentiation, which can stimulate and inhibit cell growth, and is considered to be the main switch in the pathogenesis of organ fibrosis (26). Renal fibrosis is a common pathological feature of almost all types of chronic renal diseases, which is closely related to the decline of renal function (27). Renal fibrosis is mainly caused by the formation of tissue scar by activating TGF-β1/ Smads signaling pathway (28).…”

Section: Discussionmentioning

confidence: 99%

Associations between the concentrations of CD68, TGF‑β1, renal injury index and prognosis in glomerular diseases

2020

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The present study aimed to investigate the association between the concentrations of CD68, TGF-β1, renal injury index and prognosis in glomerular diseases. Altogether 218 patients with glomerular diseases admitted to Weifang People's Hospital from January, 2014 to March, 2017 were used as the study group. A total of 100 healthy individuals who visited Weifang People's Hospital for a physical examination during the same time period were used as the control group. The levels of CD68 in peripheral blood obtained from the 2 groups of subjects were detected by flow cytometry, and the expression of TGF-β1 in serum was detected by enzyme-linked immunosorbent assay (ELISA). The concentrations of CD68 and TGF-β1 between the 2 groups were compared. The correlation between the concentrations of CD68, TGF-β1 and renal injury indexes in the study group was analyzed, as well as prognostic significance. The diagnostic value of CD68 and TGF-β1 in patients with glomerular disease was analyzed using a ROC curve, and the recovery of the patients was observed. The serum concentrations of CD68 and TGF-β1 in the study group were higher than those in the control group (P<0.05). The concentrations of CD68 and TGF-β1 in the study group positively correlated with the renal injury indexes, such as blood urea nitrogen (BUN), serum creatinine (SCR), uric acid (UA) and the 24-h urinary protein quantity (P<0.05). ROC curve analysis revealed that the area under the curve of CD68 and TGF-β1 as regards the diagnostic value in patients with glomerular disease was 0.808 and 0.738, respectively, while the area under the combined detection curve was 0.866. Multivariate unconditional logistic regression analysis revealed that the clinical classification and the concentrations of CD68 and TGF-β1 were independent prognostic factors in the study group. On the whole, the findings of the present study demonstrate that clinical classification, and the CD68 and TGF-β1 concentrations are independent prognostic factors for patients with glomerular disease. CD68 and TGF-β1 have certain value in the diagnosis of glomerular diseases, and may thus be used as predictors of the diagnosis and recovery of glomerular disease.

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ErbB4 deletion accelerates renal fibrosis following renal injury

Cited by 23 publications

References 35 publications

ErbB4 deletion predisposes to development of metabolic syndrome in mice

ErbB4 deletion predisposes to development of metabolic syndrome in mice

Specific Inhibitor of Smad3 (SIS3) Attenuates Fibrosis, Apoptosis, and Inflammation in Unilateral Ureteral Obstruction Kidneys by Inhibition of Transforming Growth Factor β (TGF-β)/Smad3 Signaling

Associations between the concentrations of CD68, TGF‑β1, renal injury index and prognosis in glomerular diseases

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ErbB4 deletion accelerates renal fibrosis following renal injury

Cited by 23 publications

References 35 publications

ErbB4 deletion predisposes to development of metabolic syndrome in mice

ErbB4 deletion predisposes to development of metabolic syndrome in mice

Specific Inhibitor of Smad3 (SIS3) Attenuates Fibrosis, Apoptosis, and Inflammation in Unilateral Ureteral Obstruction Kidneys by Inhibition of Transforming Growth Factor β (TGF-β)/Smad3 Signaling

Associations between the concentrations of CD68, TGF‑&beta;1, renal injury index and prognosis in glomerular diseases

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Associations between the concentrations of CD68, TGF‑β1, renal injury index and prognosis in glomerular diseases