Angiotensin II induces nephrin dephosphorylation and podocyte injury: Role of caveolin-1

Ren, Zhigang; Liang, Wei; Chen, Cheng; Yang, Hongxia; Singhal, Pravin C.; Ding, Guohua

doi:10.1016/j.cellsig.2011.09.022

Cited by 63 publications

(61 citation statements)

References 29 publications

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“…Consistently, Ren et al have shown that Cav1 overexpression significantly enhances podocyte apoptosis and nephrin dephosphorylation induced by angiotensin-II in cultured murine podocytes. 16 Therefore, it is a high level of CAV1, rather than a lower level, that negatively affects podocyte health after injury. Intriguingly, caveolae proteins have been implicated in Figure 4.…”

Section: Discussionmentioning

confidence: 99%

Loss of Epithelial Membrane Protein 2 Aggravates Podocyte Injury via Upregulation of Caveolin-1

Wan

Chen

Choi

et al. 2016

Journal of the American Society of Nephrology

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Nephrotic syndrome is a CKD defined by proteinuria with subsequent hypoalbuminemia, hyperlipidemia, and edema caused by impaired renal glomerular filtration barrier function. We previously identified mutations in epithelial membrane protein 2 (EMP2) as a monogenic cause of this disease. Here, we generated an emp2-knockout zebrafish model using transcription activator-like effector nuclease-based genome editing. We found that loss of emp2 in zebrafish upregulated caveolin-1 (cav1), a major component of caveolae, in embryos and adult mesonephric glomeruli and exacerbated podocyte injury. This phenotype was partially rescued by glucocorticoids. Furthermore, overexpression of cav1 in zebrafish podocytes was sufficient to induce the same phenotype observed in emp2 homozygous mutants, which was also treatable with glucocorticoids. Similarly, knockdown of EMP2 in cultured human podocytes resulted in increased CAV1 expression and decreased podocyte survival in the presence of puromycin aminonucleoside, whereas glucocorticoid treatment ameliorated this phenotype. Taken together, we have established excessive CAV1 as a mediator of the predisposition to podocyte injury because of loss of EMP2, suggesting CAV1 could be a novel therapeutic target in nephrotic syndrome and podocyte injury. Nephrotic syndrome (NS) is a CKD defined by nephrotic-range proteinuria caused by disruption of the renal glomerular filtration barrier, resulting in hypoalbuminemia, hyperlipidemia, and edema. Childhood NS, if untreated, is associated with increased risk of life-threatening infections, thromboembolism, lipid abnormalities, and malnutrition. 1 NS is classified by response or nonresponse to a standardized glucocorticosteroid therapy as steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS), respectively. Recent studies of SRNS have identified monogenic causes of SRNS to reside in podocytespecific genes, which if mutated, lead to podocyte dysfunction and defective glomerular filtration barrier. 2 Using the combined approach of homozygosity mapping and whole-exome sequencing, we have previously identified mutations in epithelial membrane protein 2 (EMP2) as a novel monogenic cause for NS. 3 EMP2 was initially identified by its homology with the growth-arrest-specific 3/peripheral myelin protein 22 family 4 and negatively regulates the mRNA and protein levels of CAV1, a major protein component of plasma membrane microdomain caveolae. 5,6 To explore the pathogenic mechanism underlying EMP2 mutations, we have now generated emp2

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Section: Discussionmentioning

confidence: 99%

Loss of Epithelial Membrane Protein 2 Aggravates Podocyte Injury via Upregulation of Caveolin-1

Wan

Chen

Choi

et al. 2016

Journal of the American Society of Nephrology

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“…Cav-1 is a major multifunctional scaf- folding protein of caveolae that serves as a negative or positive modulator of cell signaling pathways by directly interacting with signaling molecules [28,29] . Cav-1 is an important regulatory molecule in the kidneys that is primarily expressed in mesangial cells [17,[30][31][32] , renal proximal tubule cells [33,34] and podocytes [35] . Recently, many studies have demonstrated that the functional connections between cav-1 and ROS play a key role in many diseases.…”

Section: Discussionmentioning

confidence: 99%

Curcumin attenuates high glucose-induced podocyte apoptosis by regulating functional connections between caveolin-1 phosphorylation and ROS

et al. 2016

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Aim: Caveolin-1 (cav-1) is a major multifunctional scaffolding protein of caveolae. Cav-1 is primarily expressed in mesangial cells, renal proximal tubule cells and podocytes in kidneys. Recent evidence shows that the functional connections between cav-1 and ROS play a key role in many diseases. In this study we investigated whether regulating the functional connections between cav-1 and ROS in kidneys contributed to the beneficial effects of curcumin in treating diabetic nephropathy in vitro and in vivo. Methods: Cultured mouse podocytes (mpc5) were incubated in a high glucose (HG, 30 mmol/L) medium for 24, 48 or 72 h. Male rats were injected with STZ (60 mg/kg, ip) to induce diabetes. ROS generation, SOD activity, MDA content and caspase-3 activity in the cultured cells and kidney cortex homogenate were determined. Apoptotic proteins and cav-1 phosphorylation were analyzed using Western blot analyses. Results: Incubation in HG-containing medium time-dependently increased ROS production, oxidative stress, apoptosis, and cav-1 phosphorylation in podocytes. Pretreatment with curcumin (1, 5, and 10 μmol/L) dose-dependently attenuated these abnormalities in HG-treated podocytes. Furthermore, in HG-containing medium, the podocytes transfected with a recombinant plasmid GFP-cav-1 Y14F (mutation at a cav-1 phosphorylation site) exhibited significantly decreased ROS production and apoptosis compared with the cells transfected with empty vector. In diabetic rats, administration of curcumin (100 or 200 mg/kg body weight per day, ig, for 8 weeks) not only significantly improved the renal function, but also suppressed ROS levels, oxidative stress, apoptosis and cav-1 phosphorylation in the kidneys. Conclusion: Curcumin attenuates high glucose-induced podocyte apoptosis in vitro and diabetic nephropathy in vivo partly through regulating the functional connections between cav-1 phosphorylation and ROS.

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“…If ROS generation continues to worsen, oxidative stress promotes autophagy and apoptosis in podocytes (59,134,251) and mesangial cells (24,189), promotion of profibrotic pathways and glomerulosclerosis, and interruption of the glomerular filtration barrier leading to proteinuria (292). The effects of ROS and RNS on cells of the renal glomerulus are illustrated in Figure 1.…”

Section: Glomerulimentioning

confidence: 99%

Oxidant Mechanisms in Renal Injury and Disease

Ratliff

Abdulmahdi

Pawar

et al. 2016

Antioxidants & Redox Signaling

556

513

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Significance: A common link between all forms of acute and chronic kidney injuries, regardless of species, is enhanced generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) during injury/ disease progression. While low levels of ROS and RNS are required for prosurvival signaling, cell proliferation and growth, and vasoreactivity regulation, an imbalance of ROS and RNS generation and elimination leads to inflammation, cell death, tissue damage, and disease/injury progression. Recent Advances: Many aspects of renal oxidative stress still require investigation, including clarification of the mechanisms which prompt ROS/ RNS generation and subsequent renal damage. However, we currently have a basic understanding of the major features of oxidative stress pathology and its link to kidney injury/disease, which this review summarizes. Critical Issues: The review summarizes the critical sources of oxidative stress in the kidney during injury/ disease, including generation of ROS and RNS from mitochondria, NADPH oxidase, and inducible nitric oxide synthase. The review next summarizes the renal antioxidant systems that protect against oxidative stress, including superoxide dismutase and catalase, the glutathione and thioredoxin systems, and others. Next, we describe how oxidative stress affects kidney function and promotes damage in every nephron segment, including the renal vessels, glomeruli, and tubules. Future Directions: Despite the limited success associated with the application of antioxidants for treatment of kidney injury/disease thus far, preventing the generation and accumulation of ROS and RNS provides an ideal target for potential therapeutic treatments. The review discusses the shortcomings of antioxidant treatments previously used and the potential promise of new ones.

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Angiotensin II induces nephrin dephosphorylation and podocyte injury: Role of caveolin-1

Cited by 63 publications

References 29 publications

Loss of Epithelial Membrane Protein 2 Aggravates Podocyte Injury via Upregulation of Caveolin-1

Loss of Epithelial Membrane Protein 2 Aggravates Podocyte Injury via Upregulation of Caveolin-1

Curcumin attenuates high glucose-induced podocyte apoptosis by regulating functional connections between caveolin-1 phosphorylation and ROS

Oxidant Mechanisms in Renal Injury and Disease

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