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  1. Article ; Online: Pro-renin receptor suppresses mitochondrial biogenesis and function via AMPK/SIRT-1/ PGC-1α pathway in diabetic kidney.

    Safia Akhtar / Helmy M Siragy

    PLoS ONE, Vol 14, Iss 12, p e

    2019  Volume 0225728

    Abstract: Abnormal mitochondrial biogenesis and function has been linked to multiple diseases including diabetes. Recently, we demonstrated the role of renal (Pro)renin receptor (PRR) in the dysregulation of mitochondria. We hypothesized that PRR contributes to ... ...

    Abstract Abnormal mitochondrial biogenesis and function has been linked to multiple diseases including diabetes. Recently, we demonstrated the role of renal (Pro)renin receptor (PRR) in the dysregulation of mitochondria. We hypothesized that PRR contributes to the reduction of mitochondrial biogenesis and function in diabetic kidney via PGC-1α/AMPK/SIRT-1 signaling pathway. In vivo and in vitro studies were conducted in C57BL/6 mouse and mouse renal mesangial cells (mRMCs). Control and streptozotocin-induced diabetic mice were injected with scramble or PRR shRNA and followed for a period of eight weeks. PRR mRNA and protein expression increased by 44% and 39% respectively (P<0.05) in kidneys of diabetic mice, and in mRMCs exposed to high glucose by 43 and 61% respectively compared to their respective controls. These results were accompanied by reduced mRNA and protein expressions of PGC-1α (67% and 75%), nuclear respiratory factors (NRF-1, 48% and 53%), mitochondrial transcriptional factor A (mtTFA, 56% and 40%), mitochondrial DNA copy number by 75% (all, P<0.05), and ATP production by 54%, respectively in diabetic kidneys and in mRMCs exposed to high glucose. Compared to non-diabetic control mice, PRR knockdown in diabetic mice and in mRMCs, not only attenuated the PRR mRNA and protein expression but also normalized mRNA and protein expressions of PGC-1α, NRF-1, mtTFA, mitochondrial DNA copy number, and ATP production. Treatment with AMPK inhibitor, Compound C, or SIRT-1 inhibitor, EX-527, alone, or combined with PRR siRNA caused marked reduction of mRNA expression of PGC-1α, NRF-1 and mtTFA, and ATP production in mRMCs exposed to high glucose. In conclusion, our study demonstrated the contribution of the PRR to the reduction of mitochondrial biogenesis and function in diabetic kidney disease via decreasing AMPK/SIRT-1/ PGC-1α signaling pathway.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2019-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Novel regulation of renal gluconeogenesis by Atp6ap2 in response to high fat diet via PGC1-α/AKT-1 pathway

    Safia Akhtar / Silas A. Culver / Helmy M. Siragy

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 10

    Abstract: Abstract Recent studies suggested that renal gluconeogenesis is substantially stimulated in the kidney in presence of obesity. However, the mechanisms responsible for such stimulation are not well understood. Recently, our laboratory demonstrated that ... ...

    Abstract Abstract Recent studies suggested that renal gluconeogenesis is substantially stimulated in the kidney in presence of obesity. However, the mechanisms responsible for such stimulation are not well understood. Recently, our laboratory demonstrated that mice fed high fat diet (HFD) exhibited increase in renal Atp6ap2 [also known as (Pro)renin receptor] expression. We hypothesized that HFD upregulates renal gluconeogenesis via Atp6ap2-PGC-1α and AKT pathway. Using real-time polymerase chain reaction, western blot analysis and immunostaining, we evaluated renal expression of the Atp6ap2 and renal gluconeogenic enzymes, PEPCK and G6Pase, in wild type and inducible nephron specific Atp6ap2 knockout mice fed normal diet (ND, 12 kcal% fat) or a high-fat diet (HFD, 45 kcal% fat) for 8 weeks. Compared with ND, HFD mice had significantly higher body weight (23%) (P < 0.05), renal mRNA and protein expression of Atp6ap2 (39 and 35%), PEPCK (44 and 125%) and G6Pase (39 and 44%) respectively. In addition, compared to ND, HFD mice had increased renal protein expression of PGC-1α by 32% (P < 0.05) and downregulated AKT by 33% (P < 0.05) respectively in renal cortex. Atp6ap2-KO abrogated these changes in the mice fed HFD. In conclusion, we identified novel regulation of renal gluconeogenesis by Atp6ap2 in response to high fat diet via PGC1-α/AKT-1 pathway.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2021-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Angiotensin Type-2 Receptors

    Robert M. Carey / Helmy M. Siragy / John J. Gildea / Susanna R. Keller

    International Journal of Molecular Sciences, Vol 23, Iss 2317, p

    Transducers of Natriuresis in the Renal Proximal Tubule

    2022  Volume 2317

    Abstract: Angiotensin II (Ang II) type-2 receptors (AT 2 R) are expressed in the adult kidney, prominently in renal proximal tubule cells (RPTCs), and play an important role in opposing renal sodium (Na + ) retention induced by Ang II stimulation of Ang II type-1 ... ...

    Abstract Angiotensin II (Ang II) type-2 receptors (AT 2 R) are expressed in the adult kidney, prominently in renal proximal tubule cells (RPTCs), and play an important role in opposing renal sodium (Na + ) retention induced by Ang II stimulation of Ang II type-1 receptor (AT 1 R). Natriuresis induced by AT 1 R blockade is due at least in part to AT 2 R activation and whole body deletion of AT 2 Rs reduces the natriuretic response to increased blood pressure (BP). The major endogenous AT 2 R agonist mediating the natriuretic response is Ang III, the Ang II heptapeptide metabolite generated by aminopeptidase A, and the principal nephron site mediating inhibition of Na + reabsorption by the AT 2 R is the renal proximal tubule (RPT). AT 2 Rs induce natriuresis via a bradykinin, nitric oxide and cyclic GMP (cGMP) signaling cascade. Recent studies demonstrated a key role for protein phosphatase 2A (PP2A) in the AT 2 R-mediated natriuretic response upstream of cGMP. By inducing natriuresis, AT 2 Rs lower BP in the Ang II-infusion model of hypertension. PP2A activation and the natriuretic response to AT 2 R stimulation are defective in spontaneously hypertensive rats, a model of primary hypertension in humans. AT 2 R agonists are candidates for proximal tubule natriuretic agents in Na + and fluid retention disorders.
    Keywords angiotensin receptor ; blood pressure ; natriuresis ; sodium excretion ; renin-angiotensin system ; cyclic GMP ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 290
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: (Pro)renin receptor contributes to renal mitochondria dysfunction, apoptosis and fibrosis in diabetic mice

    Caixia Li / Luis C. Matavelli / Safia Akhtar / Helmy M. Siragy

    Scientific Reports, Vol 9, Iss 1, Pp 1-

    2019  Volume 12

    Abstract: Abstract Recently we demonstrated that increased renal (Pro)renin receptor (PRR) expression in diabetes contributes to development of diabetic kidney disease. However, the exact mechanisms involving PRR activity and diabetic kidney dysfunction are ... ...

    Abstract Abstract Recently we demonstrated that increased renal (Pro)renin receptor (PRR) expression in diabetes contributes to development of diabetic kidney disease. However, the exact mechanisms involving PRR activity and diabetic kidney dysfunction are unknown. We hypothesized that PRR is localized in renal mitochondria and contributes to renal fibrosis and apoptosis through oxidative stress-induced mitochondria dysfunction. Controls and streptozotocin-induced diabetic C57BL/6 mice were injected with scramble shRNA and PRR shRNA and followed for a period of eight weeks. At the end of study, diabetic mice showed increased expressions of PRR and NOX4 in both total kidney tissue and renal mitochondria fraction. In addition, renal mitochondria of diabetic mice showed reduced protein expression and activity of SOD2 and ATP production and increased UCP2 expression. In diabetic kidney, there was upregulation in the expressions of caspase3, phos-Foxo3a, phos-NF-κB, fibronectin, and collagen IV and reduced expressions of Sirt1 and total-FOXO3a. Renal immunostaining revealed increased deposition of PRR, collagen and fibronectin in diabetic kidney. In diabetic mice, PRR knockdown decreased urine albumin to creatinine ratio and the renal expressions of PRR, NOX4, UCP2, caspase3, phos-FOXO3a, phos-NF-κB, collagen, and fibronectin, while increased the renal mitochondria expression and activity of SOD2, ATP production, and the renal expressions of Sirt1 and total-FOXO3a. In conclusion, increased expression of PRR localized in renal mitochondria and diabetic kidney induced mitochondria dysfunction, and enhanced renal apoptosis and fibrosis in diabetes by upregulation of mitochondria NOX4/SOD2/UCP2 signaling pathway.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2019-08-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: High glucose induces podocyte injury via enhanced (pro)renin receptor-Wnt-β-catenin-snail signaling pathway.

    Caixia Li / Helmy M Siragy

    PLoS ONE, Vol 9, Iss 2, p e

    2014  Volume 89233

    Abstract: Pro)renin receptor (PRR) expression is upregulated in diabetes. We hypothesized that PRR contributes to podocyte injury via activation of Wnt-β-catenin-snail signaling pathway. Mouse podocytes were cultured in normal (5 mM) or high (25 mM) D-glucose for ...

    Abstract (Pro)renin receptor (PRR) expression is upregulated in diabetes. We hypothesized that PRR contributes to podocyte injury via activation of Wnt-β-catenin-snail signaling pathway. Mouse podocytes were cultured in normal (5 mM) or high (25 mM) D-glucose for 3 days. Compared to normal glucose, high glucose significantly decreased mRNA and protein expressions of podocin and nephrin, and increased mRNA and protein expressions of PRR, Wnt3a, β-catenin, and snail, respectively. Confocal microscopy studies showed significant reduction in expression and reorganization of podocyte cytoskeleton protein, F-actin, in response to high glucose. Transwell functional permeability studies demonstrated significant increase in albumin flux through podocytes monolayer with high glucose. Cells treated with high glucose and PRR siRNA demonstrated significantly attenuated mRNA and protein expressions of PRR, Wnt3a, β-catenin, and snail; enhanced expressions of podocin mRNA and protein, improved expression and reorganization of F-actin, and reduced transwell albumin flux. We conclude that high glucose induces podocyte injury via PRR-Wnt-β-catenin-snail signaling pathway.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2014-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: The angiotensin II type 2 receptor and the kidney

    Helmy M Siragy

    Journal of the Renin-Angiotensin-Aldosterone System, Vol

    2010  Volume 11

    Abstract: Recent knowledge demonstrated that the renin-angiotensin system (RAS) functions as a local renal paracrine system. All components of the RAS are present within the kidney and include angiotensinogen, renin, angiotensin I, angiotensin-converting enzymes, ... ...

    Abstract Recent knowledge demonstrated that the renin-angiotensin system (RAS) functions as a local renal paracrine system. All components of the RAS are present within the kidney and include angiotensinogen, renin, angiotensin I, angiotensin-converting enzymes, angiotensin II, the angiotensin II type 1 (AT 1 ) receptor and the angiotensin II type 2 (AT 2 ) receptor. Angiotensin II is the major effector hormone of the RAS and contributes to a variety of renal and cardiovascular physiologic and pathologic mechanisms through stimulation of AT 1 and AT 2 receptors. Angiotensin receptor blockers were developed based on the advanced knowledge of the AT 1 receptor contribution to development of a variety of kidney, vascular and cardiac diseases including but not limited to hypertension, diabetic nephropathy, heart failure, myocardial infarction and atherosclerosis. In contrast, knowledge concerning the role of the AT 2 receptor in health and disease is still emerging. The AT 2 receptor is believed to counterbalance the effects of the AT 1 receptor through influencing cellular differentiation, vasodilation, inhibition of cellular proliferation and hypertrophy, nitric oxide production and natriuresis. Thus, the pursuit of a specific AT 2 receptor agonist is a potentially fruitful area for combating renal and cardiovascular diseases. This review focuses on the role of the AT 2 receptor in the kidney.
    Keywords Medicine (General) ; R5-920
    Subject code 610
    Language English
    Publishing date 2010-03-01T00:00:00Z
    Publisher Hindawi - SAGE Publishing
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Angiotensin type 1 receptor mediates renal production and conversion of prostaglandins E to Fα in conscious diabetic rats

    Peter M Abadir / Helmy M Siragy

    Journal of the Renin-Angiotensin-Aldosterone System, Vol

    2015  Volume 16

    Abstract: Introduction: Previous studies demonstrated that stimulation of angiotensin subtype 1 receptor (AT 1 R) led to increased renal generation of prostaglandins E 2 (PGE 2 ) and renal inflammation. In turn, PGE 2 increases AT 1 R activity. The conversion of ... ...

    Abstract Introduction: Previous studies demonstrated that stimulation of angiotensin subtype 1 receptor (AT 1 R) led to increased renal generation of prostaglandins E 2 (PGE 2 ) and renal inflammation. In turn, PGE 2 increases AT 1 R activity. The conversion of PGE 2 to the less active metabolite prostaglandin F 2α (PGF 2α ) via 9-ketoreductase interrupts this feedback loop. The effects of diabetes on the interface between AT 1 R, PGE 2 and PGF 2α are not well established. We hypothesized that in diabetes, an aberrant AT 1 R activity enhances the biosynthesis of PGE 2 and impairs the activity of PGE 9-ketoreductase, leading to accumulation of PGE 2 . Materials and methods: Using microdialysis technique, we monitored renal interstitial fluid levels of angiotensin II (Ang II), PGE 2 and PGF 2α in control and AT 1 R blocker, valsartan, treated diabetic rats ( N =8 each). We utilized the PGF 2α to PGE 2 ratio as indirect measure of PGE 9-ketoreductase activity. Results: Diabetes increased renal interstitial fluid levels of Ang II, PGE 2 and PGF 2α . PGF 2α /PGE 2 ratio increased by the third week, but declined by the sixth week of diabetes. Valsartan reduced PGE 2 and PGF 2α levels and increased Ang II and the conversion of PGE 2 to PGF 2α . Conclusion: Our results suggest that in diabetes, AT 1 R increases PGE 2 generation and reduces conversion of PGE 2 to PGF 2 α with the progression of diabetes.
    Keywords Medicine (General) ; R5-920
    Subject code 616
    Language English
    Publishing date 2015-12-01T00:00:00Z
    Publisher Hindawi - SAGE Publishing
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: (Pro)Renin receptor mediates obesity-induced antinatriuresis and elevated blood pressure via upregulation of the renal epithelial sodium channel.

    Syed S Quadri / Silas Culver / Nrupama Ramkumar / Donald E Kohan / Helmy M Siragy

    PLoS ONE, Vol 13, Iss 8, p e

    2018  Volume 0202419

    Abstract: Recent studies have demonstrated that the renal (pro)renin receptor (PRR) regulates expression of the alpha subunit of the epithelial sodium channel (α-ENaC). In this study we hypothesized that the renal PRR mediates high fat diet (HFD)-induced sodium ... ...

    Abstract Recent studies have demonstrated that the renal (pro)renin receptor (PRR) regulates expression of the alpha subunit of the epithelial sodium channel (α-ENaC). In this study we hypothesized that the renal PRR mediates high fat diet (HFD)-induced sodium retention and elevated systolic blood pressure (SBP) by enhancing expression of the epithelial sodium channel (α-ENaC). In our study we used a recently developed inducible nephron specific PRR knockout mouse. Mice (n = 6 each group) were allocated to receive regular diet (RD, 12 kcal% fat) or a high-fat diet (HFD, 45 kcal% fat) for 10 weeks. Body weight (BW), SBP, urine volume (UV) and urine sodium (UNaV), as well as renal interstitial Angiotensin II (Ang II), and renal medullary expression of PRR, p-SGK-1, α-ENaC were monitored in RD and HFD mice with or without PRR knockout. At baseline, there were no significant differences in BW, BP, UV or UNaV between different animal groups. At the end of the study, HFD mice had significant increases in SBP, BW, and significant reductions in UV and UNaV. Compared to RD, HFD significantly increased mRNA and protein expression of PRR, α-ENaC, p-SGK-1, and Ang II. Compared to HFD alone, PRR knockout mice on HFD had reduced mRNA and protein expression of PRR, p-SGK-1, and α-ENaC, as well as increased UV, UNaV and significantly reduced SBP. RIF Ang II was significantly increased by HFD and did not change in response to PRR knockout. We conclude that obesity induced sodium retention and elevated SBP are mediated by the PRR-SGK-1- α-ENaC pathway independent of Ang II.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2018-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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