A Maladaptive Role for EP4 Receptors in Podocytes

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112

122

NADPH oxidase (Nox) enzymes are a significant source of reactive oxygen species, which contribute to glomerular podocyte dysfunction. Although studies have implicated Nox1, -2, and -4 in several glomerulopathies, including diabetic nephropathy, little is known regarding the role of Nox5 in this context. We examined Nox5 expression and regulation in kidney biopsies from diabetic patients, cultured human podocytes, and a novel mouse model. Nox5 expression increased in human diabetic glomeruli compared with nondiabetic glomeruli. Stimulation with angiotensin II upregulated Nox5 expression in human podocyte cultures and increased reactive oxygen species generation. siRNA-mediated Nox5 knockdown inhibited angiotensin II-stimulated production of reactive oxygen species and altered podocyte cytoskeletal dynamics, resulting in an Rac-mediated motile phenotype. Because the Nox5 gene is absent in rodents, we generated transgenic mice expressing human Nox5 in a podocyte-specific manner (Nox5 pod+ ). Nox5 pod+ mice exhibited early onset albuminuria, podocyte foot process effacement, and elevated systolic BP. Subjecting Nox5 pod+ mice to streptozotocin-induced diabetes further exacerbated these changes. Our data show that renal Nox5 is upregulated in human diabetic nephropathy and may alter filtration barrier function and systolic BP through the production of reactive oxygen species. These findings provide the first evidence that podocyte Nox5 has an important role in impaired renal function and hypertension. Albuminuria is a clinical marker of kidney dysfunction that arises in most glomerulopathies and is associated with poor prognoses for ESRD, hypertension, and cardiovascular mortality. Changes to the podocyte (e.g., foot process effacement, hypertrophy, detachment, and loss) underlie the development and progression of albuminuria and thereby highlight the critical role for these cells in upholding the glomerular filtration barrier. 1,2 Therefore, identifying factors that induce podocyte injury and loss is essential to understanding the mechanisms of filtration barrier dysfunction. Of the many factors implicated in podocyte dysfunction, excessive production of reactive oxygen species (ROS; oxidative stress) may be particularly important. [3][4][5][6] Although sources of ROS are numerous, the NADPH oxidase (Nox) family of enzymes yields significant superoxide production in the

Section: Albuminuria and Increased Bp In Nox5mentioning

confidence: 99%

Nephropathy and Elevated BP in Mice with Podocyte-Specific NADPH Oxidase 5 Expression

Holterman¹,

Thibodeau²,

Towaij³

et al. 2014

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112

122

“…Among the growing catalog of secretomic mediators of endothelial-podocyte communication, currently identified candidates are predominantly podocyte-derived factors that act on endothelialbound receptors, likely reflecting their requirement to be present in greater abundance to induce their biologic effects when acting contrary to urinary flow. Endothelial-derived regulators of podocyte function may not only be present in relatively low abundance but may also not be restricted to protein-based molecules, with exciting evidence emerging for pivotal effects of both paracrine lipid-mediators 53 and nucleic acids. 54 Over recent years, considerable efforts have been invested in identifying an animal model of diabetic nephropathy that recapitulates human disease.…”

Section: /2mentioning

confidence: 99%

eNOS Deficiency Predisposes Podocytes to Injury in Diabetes

Yuen

Stead

Zhang

et al. 2012

124

130

Endothelial nitric oxide synthase (eNOS) deficiency may contribute to the pathogenesis of diabetic nephropathy in both experimental models and humans, but the underlying mechanism is not fully understood. Here, we studied two common sequelae of endothelial dysfunction in diabetes: glomerular capillary growth and effects on neighboring podocytes. Streptozotocin-induced diabetes increased glomerular capillary volume in both C57BL/6 and eNOS 2/2 mice. Inhibiting the vascular endothelial growth factor receptor attenuated albuminuria in diabetic C57BL/6 mice but not in diabetic eNOS 2/2 mice, even though it inhibited glomerular capillary enlargement in both. In eNOS 2/2 mice, an acute podocytopathy and heavy albuminuria occurred as early as 2 weeks after inducing diabetes, but treatment with either captopril or losartan prevented these effects. In vitro, serum derived from diabetic eNOS 2/2 mice augmented actin filament rearrangement in cultured podocytes. Furthermore, conditioned medium derived from eNOS 2/2 glomerular endothelial cells exposed to both high glucose and angiotensin II activated podocyte RhoA. Taken together, these results suggest that the combined effects of eNOS deficiency and hyperglycemia contribute to podocyte injury, highlighting the importance of communication between endothelial cells and podocytes in diabetes. Identifying mediators of this communication may lead to the future development of therapies targeting endothelial dysfunction in albuminuric individuals with diabetes.

“…This pathway may work in parallel with enhanced thromboxane production and TP receptor activation. 6 The findings of Stitt-Cavanaugh et al 9 raise several questions for future exploration and scrutiny. For example, which signaling pathways linked to the EP4 receptors are responsible for its action in glomerular disease?…”

mentioning

confidence: 98%

“…6 These findings are consistent with older studies showing efficacy of thromboxane synthase inhibitors and TP receptor antagonists in experimental models such as adriamycin nephropathy 7 and murine lupus nephritis. 8 In this issue of JASN, Stitt-Cavanagh et al 9 implicate another prostanoid pathway in glomerular disease: Prostaglandin E 2 (PGE 2 ) acting through its EP4 receptor. This finding is surprising from at least two perspectives.…”

mentioning

confidence: 99%

See 1 more Smart Citation

The EP4 Receptor for Prostaglandin E2 in Glomerular Disease

Sparks¹,

Coffman²

2010

Prostanoids generated by the metabolism of arachidonic acid through the cyclooxygenase (COX) pathway have diverse functions in health and disease. 1 The kidney is prominent among the physiologic systems affected by these ubiquitous mediators. Along with effects to modulate renal blood flow, GFR, and sodium excretion, prostanoids affect the function of the glomerular filtration barrier. This is illustrated by clinical studies showing that nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit COX enzymes, attenuate the levels of proteinuria in patients with glomerular diseases. 2,3 Because NSAIDs block production of all prostanoids, the specific prostanoids influencing glomerular function in this setting cannot be discerned. Moreover, because NSAIDs frequently cause adverse effects in patients with kidney disease, including acute deterioration in GFR and exacerbation of hypertension, this approach to antiproteinuric therapy has limited applications.In experimental models of glomerular disease, a number of studies have indicated beneficial effects of more specific pharmacologic inhibitors that block individual prostanoid synthetic pathways or receptors. More recently, this issue has been explored using modern molecular genetics. For example, Harris and associates 4,5 showed that overexpression of the inducible COX isoform, COX2, in podocytes of transgenic mice enhances susceptibility to glomerular injury caused by adriamycin or puromycin. This was due, at least in part, to exaggerated production of thromboxane A 2 and activation of the thromboxane-prostanoid (TP) receptor. 6 These findings are consistent with older studies showing efficacy of thromboxane synthase inhibitors and TP receptor antagonists in experimental models such as adriamycin nephropathy 7 and murine lupus nephritis. 8 In this issue of JASN, Stitt-Cavanagh et al. 9 implicate another prostanoid pathway in glomerular disease: Prostaglandin E 2 (PGE 2 ) acting through its EP4 receptor. This finding is surprising from at least two perspectives. First, in the studies of Harris and associates, deletion of EP4 receptors from podocytes had no effect on proteinuria and kidney injury in mice also overexpressing COX2. 6 Second, the EP4 receptor has long been considered to have beneficial and protective effects in kidney disease and hypertension.Once COX and PGE synthases form PGE 2 through the successive metabolism of arachidonic acid, it elicits its biological effects through a family of G protein-coupled receptors. These receptors, by convention designated EP (for E-prostanoid) receptors, are divided into four distinct pharmacologic classes: EP1 through 4. 10,11 The EP4 receptor signals through Gs proteins and adenylyl cyclase. 11 Because of the linkage between enhanced formation of cAMP and relaxation of bronchial and vascular smooth muscle, the EP4 receptor has been classically considered a relaxant receptor. 11 In the kidney, vasodilator actions of PGE 2 , likely mediated by the EP4 receptor, are linked to protection of renal blood flow during sta...