Update on endothelins - biology and clinical implications

Hunley, Tracy E.; Kon, Valentina

doi:10.1007/s004670100631

Cited by 46 publications

(38 citation statements)

References 80 publications

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“…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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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: 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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“…Common to these GPCR systems is activation of PLC through G␣q (13)(14)(15)(16)(17)(18). To determine whether G␣q plays a key role in progression of glomerular diseases, we expressed a constitutively active G␣q in glomerular podocytes using the mouse nephrin promoter (29,30).…”

Section: Discussionmentioning

confidence: 99%

“…These injury-promoting GPCR systems are found in podocytes (2) and, thus, may contribute to podocyte injury in disease states. Although the signaling pathways that are activated by these GPCR are diverse (13)(14)(15)(16)(17)(18), common to all of these receptor systems is activation of phospholipase C (PLC) through G␣q (13)(14)(15)(16)(17)(18). Activation of PLC generates the second messengers diacyl glycerol (DAG) and inositol phosphates (IP).…”

mentioning

confidence: 99%

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

Wang

Fields²,

Pazmino³

et al. 2005

Journal of the American Society of Nephrology

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The glomerular podocyte plays a key role in maintaining the integrity of the glomerular filtration barrier. This function may be regulated by activation of cell surface G protein-coupled receptors (GPCR). Studies suggest that podocytes express GPCR that are implicated in the pathogenesis of glomerular diseases. Common to these GPCR systems is activation of phospholipase C through the Gq ␣-subunit (G␣q). For investigating the role of G␣q-coupled signaling pathways in promoting renal injury in podocytes, a constitutively active G␣q subunit (G␣qQ>L) was expressed in glomerular podocytes using the mouse nephrin promoter. Transgenic (TG) mice demonstrated albuminuria as well as a decrease in both kidney mass and nephron number. By light microscopy, a portion of the TG mice had glomerular abnormalities, including focal to diffuse hypercellularity and segmental sclerosis. Consistent with injury-promoting effects of G␣qQ>L, there was a significant reduction in podocalyxin mRNA as well as nephrin mRNA and protein levels in glomeruli from TG mice compared with non-TG controls. Expression of the transgene also seemed to increase susceptibility to glomerular injury, because treatment with puromycin aminonucleoside enhanced proteinuria in TG mice compared with non-TG littermate controls (4.2 ؎ 1.0 [TG] versus 1.6 ؎ 0.3 [non-TG] mg/24 h; P ‫؍‬ 0.0161). Thus, activation of G␣q in glomerular podocytes caused alterations in glomerular histomorphology, albuminuria, decreased nephron mass, and reduced glomerular expression of both nephrin and podocalyxin as well as enhanced susceptibility to glomerular damage induced by puromycin aminonucleoside. It is speculated that G␣q-coupled signaling cascades may be important effector pathways mediating renal injury.

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“…Although the signaling pathways that are activated by these GPCR are diverse, common to all of these receptor systems is activation of PLC␤ through G proteins that belong to the Gq family (71,72,(77)(78)(79)(80). Although the precise mechanisms are incompletely understood, Gq-coupled receptors are potent activators of TRPC6 (4,31,35,62,81).…”

Section: Plc-coupled Receptors On Podocytesmentioning

confidence: 99%