Unexpected Role of TRPC6 Channel in Familial Nephrotic Syndrome

Winn, Michelle P.; Daskalakis, Nikki; Spurney, Robert F.; Middleton, John

doi:10.1681/asn.2005090962

Cited by 39 publications

(43 citation statements)

References 115 publications

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“…As mentioned, however, prostaglandin and thromboxane receptors are expressed by podocytes 29 ; therefore, podocyte eicosanoid generation could act in an autocrine manner to promote podocyte damage. Indeed, our data suggest that podocytes are capable of generating E-series prostaglandins, which, in turn, could act on Gq-coupled EP1 receptors in podocytes 29 both to stimulate further calcineurin activity and to upregulate COX2. It is possible that this positive feedback loop for stimulating calcineurin activity might have additional adverse consequences, such as promoting podocyte apoptosis by dephosphorylating the proapoptotic protein BAD.…”

Section: Discussionmentioning

confidence: 94%

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Gq-Dependent Signaling Upregulates COX2 in Glomerular Podocytes

Wang

Flannery²,

Rosenberg³

et al. 2008

Journal of the American Society of Nephrology

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Accumulating evidence suggests that upregulation of cyclooxygenase 2 (COX2) in glomerular podocytes promotes podocyte injury. Because Gq signaling activates calcineurin and calcineurin-dependent mechanisms are known to mediate COX2 expression, this study investigated the role of Gq␣ in promoting COX2 expression in podocytes. A constitutively active Gq ␣ subunit tagged with the TAT HIV protein sequence was introduced into an immortalized podocyte cell line by protein transduction. This stimulated inositol trisphosphate production, activated an nuclear factor of activated T cells-responsive reporter construct, and enhanced levels of both COX2 mRNA and protein compared with cells treated with a Gq protein lacking the TAT sequence. Induction of COX2 was associated with increased prostaglandin E 2 production and podocyte death, both of which were attenuated by selective COX2 inhibition. In vivo, levels of COX2 mRNA and protein were significantly enhanced in podocytes from transgenic mice that expressed podocyte-targeted constitutively active Gq␣ compared with nontransgenic littermates. These data suggest that Gq-dependent signaling cascades stimulate calcineurin and, in turn, upregulate COX2 mRNA and protein, increase eicosanoid production, and cause podocyte injury. 19: 210819: -211819: , 200819: . doi: 10.1681 Glomerular podocytes are highly differentiated cells that play a key role in maintaining glomerular permselectivity. [1][2][3] In glomerular diseases, podocyte damage causes proteinuria and progressive loss of kidney function. 2 The underlying mechanisms that predispose podocytes to injury, however, are incompletely understood. Recent studies suggested that upregulation of cyclooxygenase 2 (COX2) in glomerular podocytes promotes podocyte damage. In this regard, COX2 expression in podocytes is increased in diabetic kidney disease, 4 subtotal nephrectomy, 5-9 Thy-1 glomerulonephritis, 10 and human renal allograft rejection, 11 and selective COX2 inhibition reduces renal injury and proteinuria in animal models of diabetes, 12 renal ablation, 5,6,8,9 and salt-sensitive hypertension. 13 More recently, Kennedy et al. 14 demonstrated that mechanical stress induces COX2 expression in cultured podocytes. Moreover, overexpression of COX2 specifically in glomerular podocytes enhances albuminuria and foot process effacement and reduces glomerular nephrin expression in adriamycin nephropathy. 15 These data suggest that COX2 may be an important mediator of renal injury in glomerular disease processes. J Am Soc NephrolCOX2 expression is stimulated, in part, by activation of the serine/threonine phosphatase calcineurin, through activation of nuclear factor of activated T cells (NFAT)-responsive elements in the COX2 promoter. 16 NFAT transcription factors were originally thought to be expressed only in cells of the lymphoid lineage, but abundant evidence now indicates that

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Section: Discussionmentioning

confidence: 94%

“…2,29,[33][34][35][36][37][38][39][40][41][42] These injury-promoting GPCR systems are found in podocytes 2,29 and, thus, may contribute to podocyte injury in disease states, perhaps by upregulating COX2 expression. In this regard, endothelin 1 induces COX2 expression in glomerular mesangial cells by activating NFAT transcription factors.…”

Section: Discussionmentioning

confidence: 99%

Gq-Dependent Signaling Upregulates COX2 in Glomerular Podocytes

Wang

Flannery²,

Rosenberg³

et al. 2008

Journal of the American Society of Nephrology

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“…Current studies show that TRPC6 can interact with G-protein coupled receptors to activate tyrosine kinases, which then promotes influx and intracellular accumulation of calcium ions by regulating cation-dependent phospholipase C channels; thus, implicating TRPC6 in pathophysiology [40][41]. Through plasmid-mediated overexpression of TRPC6 i n p o d o c y t e s , W i g g i n s e t a l .…”

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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“…GPCRs linked to Gq activation play a key role in glomerular diseases including receptors for angiotensin II (AT1), endothelins (ETA), thromboxanes (TP), cysteinyl-leukotrienes, and E-series prostaglandins (EP1) (1,2). These cell surface GPCRs are found in podocytes and regulate pathways involved in cell survival, morphology, motility, and cellular attachment (1)(2)(3)(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%