Effects of Angiotensin Receptor Blocker on Phenotypic Alterations of Podocytes in Early Diabetic Nephropathy

Dai, Houyong; Zheng, Min; Tang, Ri‐Ning; Ni, Jie; Ma, Kun-Ling; Li, Qing; Liu, Bi‐Cheng

doi:10.1097/maj.0b013e3182010da9

Cited by 25 publications

(27 citation statements)

References 40 publications

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“…An Akita model of type 1 DN as well as a leptin receptor-deficient db/db mouse model of type 2 DN demonstrated that diseased podocytes lose nephrin expression, become effaced, and detach from the GBM or undergo apoptosis, which all correlate with the appearance of albuminuria [17]. More recently, we demonstrated that podocytes presented with phenotypical change in the early stages of DN and that could be attenuated by irbesartan, an angiotensin II receptor antagonist [18].…”

Section: Discussionmentioning

confidence: 83%

Urinary Podocyte-Associated mRNA profile in Various Stages of Diabetic Nephropathy

Zheng

et al. 2011

PLoS ONE

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BackgroundPodocyte injury and subsequent excretion in urine play a crucial role in the pathogenesis and progression of diabetic nephropathy (DN). Quantification of messenger RNA (mRNA) expression in urinary sediment by real-time PCR is emerging as a noninvasive method of screening DN-associated biomarkers. We hypothesized that the urinary mRNA profile of podocyte-associated molecules may provide important clinical insight into the different stages of diabetic nephropathy.MethodsDN patients (N = 51) and healthy controls (N = 13) were enrolled in this study. DN patients were divided into a normoalbuminuria group (UAE<30 mg/g, n = 17), a microalbuminuria group (UAE 30∼300 mg/g, n = 15), and a macroalbuminuria group (UAE>300 mg/g, n = 19), according to their urinary albumin excretion (UAE). Relative mRNA abundance of synaptopodin, podocalyxin, CD2-AP, α-actin4, and podocin were quantified, and correlations between target mRNAs and clinical parameters were examined.ResultsThe urinary mRNA levels of all genes studied were significantly higher in the DN group compared with controls (p<0.05), and mRNA levels increased with DN progression. Urinary mRNA levels of all target genes positively correlated with both UAE and BUN. The expression of podocalyxin, CD2-AP, α-actin4, and podocin mRNA correlated with serum creatinine (r = 0.457, p = 0.001; r = 0.329, p = 0.01; r = 0.286, p = 0.021; r = 0.357, p = 0.006, respectively). Furthermore, podocalyxin mRNA was found to negatively correlate with eGFR (r = −0.349, p = 0.01).ConclusionThe urinary mRNA profiles of synaptopodin, podocalyxin, CD2-AP, α-actin4, and podocin were found to increase with the progression of DN, which suggested that quantification of podocyte-associated molecules will be useful biomarkers of DN.

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Section: Discussionmentioning

confidence: 83%

Urinary Podocyte-Associated mRNA profile in Various Stages of Diabetic Nephropathy

Zheng

et al. 2011

PLoS ONE

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“…Our previous studies demonstrated that RAS activation and inflammation contributes to the development of renal interstitial fibrosis and cardiac fibrosis via EMT [28-30]. To evaluate the RAS activation in hyperlipidemia mediated renal injury in vivo , we examined the plasma levels and tissue expressions of RAS components in the kidneys.…”

Section: Discussionmentioning

confidence: 99%

Activation of renin-angiotensin system is involved in dyslipidemia-mediated renal injuries in apolipoprotein E knockout mice and HK-2 cells

Changxian

et al. 2013

Lipids Health Dis

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BackgroundDyslipidemia and activation of renin-angiotensin system (RAS) contribute to the progression of chronic kidney disease (CKD). This study investigated possible synergistic effects of intrarenal RAS activation with hyperlipidemia in renal injuries.MethodsApolipoprotein knockout mice were fed with normal chow diet (control) or high fat diet (HF group) for eight weeks. Human proximal tubular epithelial cell line (HK-2) was treated without (control) or with cholesterol (30 μg/ml) plus 25-hydroxycholesterol (1 μg/ml) (lipid group) for 24 hours. The plasma lipid profile and RAS components were determined by clinical biochemistry assay and radiommunoassay, respectively. Collagen deposition in kidneys was evaluated by Masson-staining. The gene and protein expressions of molecules involved in RAS components and biomarkers of epithelial mesenchymal transition (EMT) were examined by real-time PCR, immunochemical staining, and Western blot.ResultsThe mice fed with high-fat diet showed significant hyperlipidemia with collagen deposition in renal tubular interstitium compared to controls. The plasma levels of renin, angiotensin I, and angiotensin II were no difference in two groups. However, the kidneys of HF group showed up-regulated RAS components, which were positively associated with increased plasma levels of triglyceride, total cholesterol, and LDL. These effects were further confirmed by in vitro studies. Lipid loading induced HK-2 cells underwent EMT, which was closely associated with the increased expressions of intracellular RAS components.ConclusionsLocal RAS activation was involved in hyperlipidemia-mediated renal injuries, suggesting that there are synergistic effects resulting from RAS activation with hyperlipidemia that accelerates the progression of CKD.

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“…The degree of glomerular staining was counted according to the positively stained glomerular areas expressed as a percentage of total areas [Adamczak et al, 2003;Dai et al, 2011]: 0: no lesions; 1þ: 1-25%; 2þ: 26-50%; 3þ: 51-75%; 4þ: 76-100%. A total of 4 mm sections were stained for periodic acid-Schiff staining (PAS) or Masson's trichrome and examined by light microscopy in a blinded manner.…”

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

Protection of CTGF Antibody Against Diabetic Nephropathy in Mice Via Reducing Glomerular β‐Catenin Expression and Podocyte Epithelial‐Mesenchymal Transition

Dai

Cao

et al. 2017

J of Cellular Biochemistry

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Despite substantial progress in medical care, the morbidity rate of diabetic nephropathy (DN) remains high in patients with diabetes. Evidence suggests that connective tissue growth factor (CTGF) induced podocyte injury may contribute to DN and CTGF inhibition could reduce albuminuria. However, to date the mechanisms involved in the effect of CTGF on podocyte injury have not been fully understood. The aim of this study is to investigate the effects of therapeutic CTGF antibody on glomerular β-catenin expression and podocyte epithelial-mesenchymal transition (EMT) in diabetic mice. C57BL/6J mice were randomly divided into three groups as the following: the control, DN, and DN treated by CTGF antibody group. DN was induced by a single intraperitoneal injection of streptozotocin and then CTGF antibody was administrated three times per week for 8 weeks. Urinary albumin excretion, mesangial proliferation and matrix deposition, and β-catenin expression in glomeruli at mRNA and protein level were all increased in DN mice compared to that in the control. Besides, the development of EMT in podocytes from diabetic mice, demonstrated by the downregulation of nephrin and upregulation of desmin in glomeruli, was detected. Furthermore, blocking CTGF by specific antibody reduced albuminuria, prevented the overexpression of CTGF, as well as β-catenin, in glomeruli and subsequently ameliorated podocyte EMT in DN mice. In summary, this study suggested that CTGF antibody protected podocytes against injury in DN mice by reducing β-catenin overexpression and preventing podocyte EMT, which might provide new insight into the mechanism of CTGF inhibition in the treatment of DN. J. Cell. Biochem. 118: 3706-3712, 2017. © 2017 Wiley Periodicals, Inc.

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Effects of Angiotensin Receptor Blocker on Phenotypic Alterations of Podocytes in Early Diabetic Nephropathy

Cited by 25 publications

References 40 publications

Urinary Podocyte-Associated mRNA profile in Various Stages of Diabetic Nephropathy

Urinary Podocyte-Associated mRNA profile in Various Stages of Diabetic Nephropathy

Activation of renin-angiotensin system is involved in dyslipidemia-mediated renal injuries in apolipoprotein E knockout mice and HK-2 cells

Protection of CTGF Antibody Against Diabetic Nephropathy in Mice Via Reducing Glomerular β‐Catenin Expression and Podocyte Epithelial‐Mesenchymal Transition

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