Activation of Gαq-Coupled Signaling Pathways in Glomerular Podocytes Promotes Renal Injury

Wang, Liming; Fields, Timothy A.; Pazmino, Kathy; Dai, Qunsheng; Burchette, James L.; Howell, David N.; Coffman, Thomas M.; Spurney, Robert F.

doi:10.1681/asn.2005020167

Cited by 31 publications

(51 citation statements)

References 66 publications

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“…In addition, intraperitoneal injection could lead to tolerance, which prevents the reproduction of MCD model in mice [13]. Wang et al [14] showed that a single epidermal injection of PAN (0.5 mg/g) in mice can generate excess urine protein, thus reproducing the classic rat disease model in mice.…”

Section: Discussionmentioning

confidence: 99%

Bone marrow-derived mesenchymal stem cells ameliorate nephrosis through repair of impaired podocytes

Chen

Wan

Gao

et al. 2017

CIM

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Bone marrow-derived mesenchymal stem cells ameliorate nephrosis through repair of impaired podocytes Abstract Purpose: The purpose of this study was to investigate the effects of bone marrow-derived mesenchymal stem cells (BMSC) on podocytes of puromycin amino nuclear glucoside (PAN) -induced nephrosis in mice.Methods: Mice were randomly divided into Control, PAN and BMSC groups. Mice were injected with PAN (0.5 mg/g weight) via the tail vein. The 24-h urinary protein was obtained after modelling, and urinary protein excretion was determined. The blood and kidney specimens were isolated after the tenth day of modelling. Blood samples were collected for measuring serum creatinine (SCr) and blood urea nitrogen (BUN). A sample of kidney was taken for observing pathological changes through hematoxylin-eosin staining and electron microscopy, and the rest of the kidney was used for detecting the protein and mRNA expression of nephrin, CD2AP, synaptopodin, TRPC6 by real-time quantitative PCR, Western-blot and immunohistochemistry.Results: After PAN injection, podocyte foot process fusion was detected by electron microscopy, and the 24 h urinary protein excretion increased compared with control mice on days 3, 7 and 10 post-PAN injection (P<0.05). Serum albumin decreased compared with control mice after day 10 (P<0.05). The phenomenon of foot process fusion was ameliorated after administration of BMSC, and 24 h urinary protein decreased (P<0.05), while serum albumin increased (P<0.05). Nephrin, CD2AP and synaptopodin in the glomerular slit diaphragm were up-regulated compared to PAN nephropathy model mice (P<0.05) while TRPC6 was down-regulated (P<0.05).Conclusions: Administration of BMSC reduced foot process fusion and urine protein excretion, and protected against podocyte damage caused by PAN.

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Section: Discussionmentioning

confidence: 99%

Bone marrow-derived mesenchymal stem cells ameliorate nephrosis through repair of impaired podocytes

Chen

Wan

Gao

et al. 2017

CIM

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“…15,16 The factors that initiate COX-2 upregulation in podocytes have only recently been investigated. Spurney et al 28 showed that Gq-dependent signaling induces COX-2 expression in cultured podocytes, which was associated with increased PGE 2 synthesis. Our previous work showed that both mechanical stretch and PGE 2 induce COX-2 expression in cultured mouse podocytes.…”

Section: Discussionmentioning

confidence: 99%

A Maladaptive Role for EP4 Receptors in Podocytes

Stitt-Cavanagh¹,

Faour²,

Takami³

et al. 2010

Journal of the American Society of Nephrology

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Inhibition of p38 mitogen-activated protein kinase and cyclooxygenase-2 reduces albuminuria in models of chronic kidney disease marked by podocyte injury. Previously, we identified a feedback loop in podocytes whereby an in vitro surrogate for glomerular capillary pressure (i.e., mechanical stretch) along with prostaglandin E 2 stimulation of its EP4 receptor induced cyclooxygenase-2 in a p38-dependent manner. Here we asked whether stimulation of EP4 receptors would exacerbate glomerulopathies associated with enhanced glomerular capillary pressure. We generated mice with either podocyte-specific overexpression or depletion of the EP4 receptor (EP4 podϩ and EP4 podϪ/Ϫ , respectively). Glomerular prostaglandin E 2 -stimulated cAMP levels were eightfold greater for EP4 podϩ mice compared with nontransgenic (non-TG) mice. In contrast, EP4 mRNA levels were Ͼ50% lower, and prostaglandin E 2 -induced cAMP synthesis was absent in podocytes isolated from EP4 podϪ/Ϫ mice. Non-TG and EP4 podϩ mice underwent 5/6 nephrectomy and exhibited similar increases in systolic BP (ϩ25 mmHg) by 4 weeks compared with sham-operated controls. Two weeks after nephrectomy, the albumin-creatinine ratio of EP4 podϩ mice (3438 g/mg) was significantly higher than that of non-TG mice (773 g/mg; P Ͻ 0.0001). Consistent with more severe renal injury, the survival rate for nephrectomized EP4 podϩ mice was significantly lower than that for non-TG mice (14 versus 67%). In contrast, 6 weeks after nephrectomy, the albumin-creatinine ratio of EP4 podϪ/Ϫ mice (753 g/mg) was significantly lower than that of non-TG mice (2516 g/mg; P Ͻ 0.05). These findings suggest that prostaglandin E 2 , acting via EP4 receptors contributes to podocyte injury and compromises the glomerular filtration barrier.

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“…We used male mice because female mice are relatively resistant. Previous studies successfully induced PAN nephrosis in mice after a high dosage (500 mg/kg subcutaneously), 34 after a high-cholesterol diet, 35 or with multiple doses (20 mg/kg subcutaneously or 90 mg/kg intraperitoneally). 36,37 We found that PAN led to an increase in UAE associated with foot process effacement and a reduction in podocin and ZO-1 mRNA expression.…”

Section: Discussionmentioning

confidence: 99%

Activation of Adenosine 2A Receptors Preserves Structure and Function of Podocytes

Awad

Rouse

Liu

et al. 2008

Journal of the American Society of Nephrology

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Adenosine 2A receptor (A 2A R) activation was recently shown to be renoprotective in diabetic nephropathy. A 2A R are found in glomeruli and have been shown to associate with the podocyte cytoskeletal protein ␣-actinin-4, but the effect of their activation on podocyte structure and function is unknown. Podocyte injury was induced in C57BL/6 mice with puromycin aminonucleoside, and the selective A 2A R agonist ATL313 was found to attenuate the resulting albuminuria and foot process fusion. The selective A 2A R antagonist ZM241385 reversed the effects of ATL313. In vitro, A 2A R mRNA and protein were expressed in a conditionally immortalized podocyte cell line, and A 2A R-like immunoreactivity co-localized with the actin cytoskeleton. Treatment with ATL313 also blocked the increased podocyte permeability to albumin and disruption of the actin cytoskeleton that accompanied puromycin aminonucleosideinduced injury in vitro. ATL313 was ineffective, however, in the presence of the A 2A R antagonist and in A 2A R-deficient podocytes. It was concluded that A 2A R activation reduces glomerular proteinuria, at least in part, by preserving the normal structure of podocyte foot processes, slit diaphragms, and actin cytoskeleton.

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Activation of Gαq-Coupled Signaling Pathways in Glomerular Podocytes Promotes Renal Injury

Cited by 31 publications

References 66 publications

Bone marrow-derived mesenchymal stem cells ameliorate nephrosis through repair of impaired podocytes

Bone marrow-derived mesenchymal stem cells ameliorate nephrosis through repair of impaired podocytes

A Maladaptive Role for EP4 Receptors in Podocytes

Activation of Adenosine 2A Receptors Preserves Structure and Function of Podocytes

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