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  • 1
    Online Resource
    Online Resource
    Role of 20-HETE in the impaired myogenic and TGF responses of the Af-Art of Dahl salt-sensitive rats
    American Physiological Society ; 2014
    In:  American Journal of Physiology-Renal Physiology Vol. 307, No. 5 ( 2014-09-01), p. F509-F515
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 307, No. 5 ( 2014-09-01), p. F509-F515
    Abstract: The present study examined whether 20-HETE production is reduced in the renal vasculature and whether this impairs myogenic or tubuloglomerular feedback (TGF) responses of the afferent arteriole (Af-Art). The production of 20-HETE was 73% lower in renal microvessels of Dahl salt-sensitive rats (SS) rats than in SS.5 BN rats, in which chromosome 5 from the Brown Norway (BN) rat containing the CYP4A genes was transferred into the SS genetic background. The luminal diameter of the Af-Art decreased by 14.7 ± 1.5% in SS.5 BN rats when the perfusion pressure was increased from 60 to 120 mmHg, but it remained unaltered in SS rats. Administration of an adenosine type 1 receptor agonist (CCPA, 1 μM) reduced the diameter of the Af-Art in the SS.5 BN rats by 44 ± 2%, whereas the diameter of the Af-Art of SS rats was unaltered. Autoregulation of renal blood flow (RBF) and glomerular capillary pressure (PGC ) was significantly impaired in SS rats but was intact in SS.5 BN rats. Administration of a 20-HETE synthesis inhibitor, HET0016 (1 μM), completely blocked the myogenic and adenosine responses in the Af-Art and autoregulation of RBF and PGC in SS.5 BN rats, but it had no effect in SS rats. These data indicate that a deficiency in the formation of 20-HETE in renal microvessels impairs the reactivity of the Af-Art of SS rats and likely contributes to the development of hypertension induced renal injury.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00273.2014
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2014
    detail.hit.zdb_id: 1477287-5
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  • 2
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    A Mutation in γ-Adducin Impairs Autoregulation of Renal Blood Flow and Promotes the Development of Kidney Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Journal of the American Society of Nephrology Vol. 31, No. 4 ( 2020-4), p. 687-700
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 31, No. 4 ( 2020-4), p. 687-700
    Abstract: The genes and mechanisms underlying the association between diabetes or hypertension and CKD risk are unclear. The authors identified a recessive K572Q mutation in γ -adducin ( Add3 ), which encodes a cytoskeletal protein (ADD3), in fawn-hooded hypertensive (FHH) rats—a mutation also reported in Milan normotensive (MNS) rats that develop renal disease. They demonstrated that FHH and Add3 knockout rats had impairments in the myogenic response of afferent arterioles and in renal blood flow autoregulation, which were rescued in Add3 transgenic rats. They confirmed the K572Q mutation’s role in altering the myogenic response in a genetic complementation study that involved crossing FHH and MNS rats. The work is the first to demonstrate that a mutation in ADD3 that causes renal vascular dysfunction also promotes susceptibility to kidney disease. Background The genes and mechanisms involved in the association between diabetes or hypertension and CKD risk are unclear. Previous studies have implicated a role for γ -adducin (ADD3), a cytoskeletal protein encoded by Add3 . Methods We investigated renal vascular function in vitro and in vivo and the susceptibility to CKD in rats with wild-type or mutated Add3 and in genetically modified rats with overexpression or knockout of ADD3. We also studied glomeruli and primary renal vascular smooth muscle cells isolated from these rats. Results This study identified a K572Q mutation in ADD3 in fawn-hooded hypertensive (FHH) rats—a mutation previously reported in Milan normotensive (MNS) rats that also develop kidney disease. Using molecular dynamic simulations, we found that this mutation destabilizes a critical ADD3-ACTIN binding site. A reduction of ADD3 expression in membrane fractions prepared from the kidney and renal vascular smooth muscle cells of FHH rats was associated with the disruption of the F-actin cytoskeleton. Compared with renal vascular smooth muscle cells from Add3 transgenic rats, those from FHH rats had elevated membrane expression of BK α and BK channel current. FHH and Add3 knockout rats exhibited impairments in the myogenic response of afferent arterioles and in renal blood flow autoregulation, which were rescued in Add3 transgenic rats. We confirmed these findings in a genetic complementation study that involved crossing FHH and MNS rats that share the ADD3 mutation. Add3 transgenic rats showed attenuation of proteinuria, glomerular injury, and kidney fibrosis with aging and mineralocorticoid-induced hypertension. Conclusions This is the first report that a mutation in ADD3 that alters ACTIN binding causes renal vascular dysfunction and promotes the susceptibility to kidney disease.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.2019080784
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 2029124-3
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  • 3
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    Impaired myogenic responses of the Af‐Art contributes to chronic kidney disease in Milan Normotensive rats
    Wiley ; 2015
    In:  The FASEB Journal Vol. 29, No. S1 ( 2015-04)
    Details
    In: The FASEB Journal, Wiley, Vol. 29, No. S1 ( 2015-04)
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    URL: Article
    DOI: 10.1096/fsb2.v29.S1
    DOI: 10.1096/fasebj.29.1_supplement.811.17
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 1468876-1
    SSG: 12
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  • 4
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    Abstract 063: Impaired Myogenic Response of the Af-art Contributes to the Increased Susceptibility to Hypertension and Diabetic Induced Renal Disease in Milan Normotensive Rats
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Hypertension Vol. 66, No. suppl_1 ( 2015-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 66, No. suppl_1 ( 2015-09)
    Abstract: Previous studies have indicated that Milan normotensive (MNS) rats are more susceptible to the development of hypertension and diabetic induced renal injury than Milan hypertensive (MHS) rats, but the genes and pathways involved are unknown. MNS also develop proteinuria and chronic kidney disease (CKD) as they age, whereas hypertensive MHS do not. We compared the myogenic response of isolated perfused Af-Art and autoregulation of RBF and glomerular capillary pressure in 6-9 week old MNS and MHS rats. The diameter of Af-Art of MNS rats increased from 14.0 ± 0.5 to 14.2 ± 0.6 μm (n=6) when elevation in perfusion pressure from 60 to 120 mmHg. In contrast, the diameter of the Af-Art decreased significantly from 14.3 ± 0.5 to 11.5 ± 0.6 μm (n=6) in MHS rats. In vivo, RBF increased by 26% when RPP was increased from 100 to 140 mmHg in MNS rats but it remained unchanged in MHS rats. Glomerular capillary pressure rose by 11 mmHg in MNS following the elevation in RPP from 100 to 140 mm Hg but not in MHS rats. Protein excretion increased from 8.9 ± 0.7 to 158.2 ± 23.1 mg/day in MNS rats as the increased in age from 3 to 9 months of age but it did not increase in MHS rats. In com-parison to other strains susceptible and resistant to CKD, we noticed that both MNS and Fawn Hooded hypertensive (FHH) rats that do not autoregulate RBF also share the same sequence variant in the Adducin 3 gene. We performed a genetic complementation study to test whether this mutation might be responsible for the impaired myogenic response in MNS. The diameter of the Af-Art isolated from an F1 cross of MNS & FHH rats increased from 17.2 ± 0.9 to 18.5 ± 0.9 μM (n=5) in response to increase in perfusion pressure and RBF was not efficiently autoregulated in these animals. These data indicate a mutation in Adducin 3 which impairs myogenic response of the Af-Art and increased transmission of pressure to the glomerular capillaries may contribute to the development of CKD in MNS rats similar to what is seen in FHH rats.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.66.suppl_1.063
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 2094210-2
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  • 5
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    Genetic basis of the impaired renal myogenic response in FHH rats
    American Physiological Society ; 2013
    In:  American Journal of Physiology-Renal Physiology Vol. 304, No. 5 ( 2013-03-01), p. F565-F577
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 304, No. 5 ( 2013-03-01), p. F565-F577
    Abstract: This study examined the effect of substitution of a 2.4-megabase pair (Mbp) region of Brown Norway (BN) rat chromosome 1 (RNO1) between 258.8 and 261.2 Mbp onto the genetic background of fawn-hooded hypertensive (FHH) rats on autoregulation of renal blood flow (RBF), myogenic response of renal afferent arterioles (AF-art), K + channel activity in renal vascular smooth muscle cells (VSMCs), and development of proteinuria and renal injury. FHH rats exhibited poor autoregulation of RBF, while FHH.1BN congenic strains with the 2.4-Mbp BN region exhibited nearly perfect autoregulation of RBF. The diameter of AF-art from FHH rats increased in response to pressure but decreased in congenic strains containing the 2.4-Mbp BN region. Protein excretion and glomerular and interstitial damage were significantly higher in FHH rats than in congenic strains containing the 2.4-Mbp BN region. K + channel current was fivefold greater in VSMCs from renal arterioles of FHH rats than cells obtained from congenic strains containing the 2.4-Mbp region. Sequence analysis of the known and predicted genes in the 2.4-Mbp region of FHH rats revealed amino acid-altering variants in the exons of three genes: Add3, Rbm20, and Soc-2. Quantitative PCR studies indicated that Mxi1 and Rbm20 were differentially expressed in the renal vasculature of FHH and FHH.1BN congenic strain F. These data indicate that transfer of this 2.4-Mbp region from BN to FHH rats restores the myogenic response of AF-art and autoregulation of RBF, decreases K + current, and slows the progression of proteinuria and renal injury.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00404.2012
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2013
    detail.hit.zdb_id: 1477287-5
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  • 6
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    Impaired myogenic response of the afferent arteriole contributes to the increased susceptibility to renal disease in Milan normotensive rats
    Wiley ; 2017
    In:  Physiological Reports Vol. 5, No. 3 ( 2017-02)
    Details
    In: Physiological Reports, Wiley, Vol. 5, No. 3 ( 2017-02)
    Abstract: Milan normotensive ( MNS ) rats are more susceptible to the development of renal disease than Milan hypertensive ( MHS ) rats, but the genes and pathways involved are unknown. This study compared the myogenic response of isolated perfused afferent arterioles (Af‐Art) and autoregulation of renal blood flow ( RBF ) and glomerular capillary pressure (Pgc) in 6–9‐week‐old MNS and MHS rats. The diameter of the Af‐Art of MHS rats decreased significantly from 14.3 ± 0.5 to 11.5 ± 0.6  μ m when perfusion pressure was elevated from 60 to 120 mmHg. In contrast, the diameter of Af‐Art of MNS rats did not decrease. RBF was well autoregulated in MHS rats, but it increased by 26% in MNS rats. Pgc rose by 11 mmHg when renal perfusion pressure ( RPP ) was increased from 100 to 140 mmHg in MNS but not in MHS rats. Protein excretion increased from 10 ± 1 to 245 ± 36 mg/day in MNS rats as they aged from 3 to 11 months but it did not increase in MHS rats. We also compared the development of proteinuria in MNS and MHS rats following the induction of diabetes with streptozotocin. Protein excretion rose from 16 ± 3 to 234 ± 43 mg/day in MNS rats, but it remained unaltered in MHS rats. These data indicate that the myogenic response of the Af‐art is impaired in MNS rats and increased transmission of pressure to the glomerulus may contribute to renal injury in MNS rats similar to what is seen in fawn‐hooded hypertensive and Dahl salt‐sensitive rats.
    Type of Medium: Online Resource
    ISSN: 2051-817X , 2051-817X
    URL: Article
    DOI: 10.14814/phy2.13089
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 2724325-4
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  • 7
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    Abstract MP14: A K572Q Mutation in Gamma-adducin Is Responsible for the Impaired Myogenic Response and Autoregulation of Renal and Cerebral Blood Flow in FHH Rats
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Hypertension Vol. 66, No. suppl_1 ( 2015-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 66, No. suppl_1 ( 2015-09)
    Abstract: The FHH rat is a genetic model of hypertension induced CKD, but the genes and pathways involved are unknown. We recently reported that the myogenic response of the renal and cerebral arteries is impaired in FHH rats and it was restored in a FHH.1BN congenic strain in which a small region of Chr. 1 containing 15 genes, including gamma-Adducin (Add3), from BN rats was transferred into the FHH background. We further identified a K572Q mutation in Add3 in FHH versus FHH.1BN rat. The present study examined the contribution of Add3 to the impaired myogenic reactivity using Add3 transgenic and KO rats. The diameter of the middle cerebral artery (MCA) decreased by 20-30% in SD, FHH.1BN and FHH.Add3 transgenic rats when perfusion pressure was increased from 40 to 140 mmHg. In contrast, the MCA of FHH and SD.Add3 knockout rats did not constrict. The myogenic response of the MCA is also impaired in MNS rats that share the same mutation in Add3 as in FHH rat and this phenotype was complemented in a F1 cross of FHH and MNS strain. Autoregulation of CBF was impaired in FHH rats and rose by 99 ± 7% when MAP was increased from 100 to 190 mmHg and was restored in FHH.Add3 and FHH.1BN rats. Similarly, the diameter of Af-art of FHH, MNS and a F1 cross of FHH and MNS rat increased in response to increase in perfusion pressure but decreased in FHH.1BN rats that have wild type Add3. FHH rats exhibited impaired autoregulation of RBF in comparison with FHH.1BN rats. Pgc estimated from the stopflow pressure increased by 20 mmHg in FHH rats when RPP was increased from 100 to 140 mmHg versus only 4 mmHg in the congenic strain. FHH rats developed severe renal injury and proteinuria rose from 37 ± 2 to 260 ± 32 mg/day as they aged from 12 to 21 weeks, but rose by a significant lesser extent in FHH.1BN and FHH.Add3 rats. BK current in VSMC isolated from the MCA was 5-fold higher in FHH vs. FHH.1BN rats. Administration of IBTX normalized the elevated BK channel current and restored the myogenic response in FHH rats but it had little effect in FHH.1BN. These results indicate that the K572Q mutation in Add3 plays a causal role in the impaired myogenic response and autoregulation of renal and cerebral circulation in FHH rats and may contribute to the development of renal and cerebral end organ damage with aging and after the onset of hypertension.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.66.suppl_1.mp14
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 2094210-2
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  • 8
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    Abstract 067: Genetic Complementation Establishes That a K572Q Mutation in Gamma-adducin Plays a Causal Role in Renal Microvascular Dysfunction in FHH and MNS Rats
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Hypertension Vol. 70, No. suppl_1 ( 2017-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 70, No. suppl_1 ( 2017-09)
    Abstract: The Fawn-Hooded hypertensive (FHH) rat is a genetic model of hypertension-induced renal disease. However, the causal genes and pathways involved are unclear. We previously reported that the transfer of a small region in Chr. 1 of Brown-Norway (BN) rats which contains 15 genes, including gamma-Adducin (Add3), into the FHH background restores renal microvascular function and attenuates the development of proteinuria in FHH rats. Our further work identified a K572Q mutation in Add3 in FHH rats as a potential candidate variant in the pathogenesis of renal disease. The present study examined the role of Add3 in the impaired myogenic response of the afferent artery (Af-art) and autoregulation of renal blood flow (RBF) using transgenic and KO rats. RBF increased by 21.5 ± 3.0% in SD. Add3 KO rats (n=7) when mean arterial pressure (MAP) was increased from 100 to 150 mmHg. In contrast, RBF only increased by 3.5 ± 0.9% in wildtype SD rats (n=13). The diameters of the renal Af-art decreased by 12.9 ± 0.8% in SD rats when perfusion pressure was increased from 60 to 120 mmHg, but it increased in SD.Add3 KO rats. The myogenic response of the Af-art in FHH rats was markedly impaired and increased by 8 ± 1.2% when the pressure was increased by from 60 to120 mmHg. The myogenic response was restored, and the diameters of the Af-art decreased by 12 ± 0.7% and 7 ± 1.0% in FHH. 1 BN congenic rats (n=27) and FHH.Add3 transgenic rats that express wt-Add3. RBF increased by 35.1 ± 3.0% when MAP was increased from 100 to 150 mmHg in FHH rats (n=15) versus 7.5 ± 1.7% and 6.0+ 1.3% in FHH.1 BN or a F1 cross of FHH and FHH.1 BN rats (n=8) and FHH.Add3 transgenic rats. The myogenic response of Af-art and autoregulation of RBF were also impaired in MNS rats (n=6) that carry the same K572Q mutation in Add3 as FHH rats. These phenotypes were complemented in a F1 cross of FHH and MNS rats (n=7), but the myogenic response and autoregulation of RBF were restored in an F1 cross of FHH and FHH.1 BN rats with one copy of wt-Add3. These results indicate that the recessive K572Q mutation of Add3 in FHH and MNS rats plays a causal role in renal microvascular dysfunction, which may contribute to the development of chronic kidney disease induced by hypertension in these models.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.70.suppl_1.067
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 2094210-2
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  • 9
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    Knockout of Dual-Specificity Protein Phosphatase 5 Protects Against Hypertension-Induced Renal Injury
    American Society for Pharmacology & Experimental Therapeutics (ASPET) ; 2019
    In:  Journal of Pharmacology and Experimental Therapeutics Vol. 370, No. 2 ( 2019-08), p. 206-217
    Details
    In: Journal of Pharmacology and Experimental Therapeutics, American Society for Pharmacology & Experimental Therapeutics (ASPET), Vol. 370, No. 2 ( 2019-08), p. 206-217
    Type of Medium: Online Resource
    ISSN: 0022-3565 , 1521-0103
    URL: Article
    DOI: 10.1124/jpet.119.258954
    Language: English
    Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
    Publication Date: 2019
    detail.hit.zdb_id: 1475023-5
    SSG: 15,3
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  • 10
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    Abstract 39: Cyp4a1 Transgenic Rats Generated Using Sleeping Beauty Transposon System Restores the Impaired Myogenic Responses in the Afferent Arteriole of Dahl S Rats
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Hypertension Vol. 62, No. suppl_1 ( 2013-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 62, No. suppl_1 ( 2013-09)
    Abstract: We have reported that the production of 20-HETE is reduced in the renal vasculature of Dahl S rats and that myogenic and TGF responses of afferent arteries (Af-Art) are impaired in Dahl S rats. In this study we generated CYP4A1 transgenic rats in the Dahl S inbred strain background utilizing the enhanced Sleeping Beauty (SB100X) transposon system to determine if upregulation of 20-HETE production can restore vascular reactivity and oppose the development of renal injury. Fertilized eggs collected from female Dahl S rats were microinjected with a transposon vector harboring the rat CYP4A1 cDNA under the control of the ubiquitous CAG promoter along with SB100X transposase mRNA to produce transgenic founders. Heterozygous founders were backcrossed to Dahl S rats, transgene insertion sites were identified by Ligation Mediated PCR and sequencing, and the progeny were brother-sister mated to derive homozygous transgenic lines. The expression of CYP4A protein was significantly elevated and the production of 20-HETE was 3-fold higher in the renal outer medullary tissue of CYP4A1 transgenic (n=17) compared to Dahl S rats (n=17). 20-HETE production was 10-fold higher in renal microvessels of CYP4A1 transgenic animals than Dahl S rats. (0.2±0.3, n=22 versus 1.9±0.1 pmol/mg/min, n=14). The luminal diameter of the Af-Art decreased significantly from 15.9 ± 0.6 to 14.1 ± 0.5 μm in CYP4A1 transgenic rats (n=5) when the perfusion pressure was increased from 60 to 120 mmHg, whereas it remained unaltered in Dahl S rats (from 19.4 ± 2.3 to 20.6 ± 5.6 μm, n=22). These studies further support the view that a deficiency in the formation of 20-HETE in the renal microcirculation contributes to the marked susceptibility of Dahl S rats to develop of hypertension and diabetic induced renal injury, and the new CYP4A1 transposon transgenic rat model may be useful for determining the mechanisms involved.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.62.suppl_1.A39
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 2094210-2
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