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  • 1
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    Early onset albuminuria in Dahl rats is a polygenetic trait that is independent from salt loading
    American Physiological Society ; 2003
    In:  Physiological Genomics Vol. 14, No. 3 ( 2003-08-15), p. 209-216
    Details
    In: Physiological Genomics, American Physiological Society, Vol. 14, No. 3 ( 2003-08-15), p. 209-216
    Abstract: The aim of the study was to characterize the genetic basis for the early onset of increased urinary albumin excretion (UAE) observed in the salt-sensitive Dahl rat (SS). We first characterized blood pressures and UAE values in adult SS compared with the spontaneously hypertensive rat (SHR) strain. Blood pressure measurements by radiotelemetry at 14 wk demonstrated similar spontaneous hypertension in both strains on a low-sodium diet containing 0.2% NaCl by weight, whereas UAE was markedly increased in SS compared with SHR (253.07 ± 68.39 vs. 1.65 ± 1.09 mg/24 h, P 〈 0.0001). Analysis of UAE in young animals of both strains fed a low-sodium diet demonstrated that UAE is elevated in SS as early as 4 wk of age ( P 〈 0.0001), when ultrastructural evaluation of glomeruli by electron microscopy appears still normal. At 8 wk SS demonstrated a 280-fold elevated UAE compared with SHR ( P 〈 0.0001). Consequently, to identify quantitative trait loci (QTLs) contributing to salt-independent early manifestation of increased UAE in the SS rat, we performed genome-wide linkage and QTL mapping analysis in a young F 2 population derived from the two contrasting strains. UAE was determined in 539 F 2 animals at 8 wk. We identified seven suggestive or significant UAE QTLs on rat chromosomes (RNO) RNO2, RNO6, RNO8, RNO9, RNO10, RNO11, and RNO19, accounting together for 34% of the overall variance of UAE in this F 2 population. Thus early onset albuminuria in the SS rat is under polygenetic influence and independent from salt loading.
    Type of Medium: Online Resource
    ISSN: 1094-8341 , 1531-2267
    URL: Article
    DOI: 10.1152/physiolgenomics.00053.2003
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2003
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  • 2
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    Renal expression of exchange protein directly activated by cAMP (Epac) 1 and 2
    American Physiological Society ; 2008
    In:  American Journal of Physiology-Renal Physiology Vol. 295, No. 2 ( 2008-08), p. F525-F533
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 295, No. 2 ( 2008-08), p. F525-F533
    Abstract: In the kidney, many physiological processes of ion transport and cellular proliferation are mediated via cAMP, which classically activates protein kinase A (PKA). Recently, however, two new cAMP targets, the exchange protein directly activated by cAMP (Epac) 1 and 2, were identified, which mediate alternative pathways to PKA. To investigate their renal expression, antibodies specifically recognizing Epac1 and Epac2 were generated and used in rat immunohistochemistry with antibodies recognizing aquaporin-1 (AQP1), Tamm-Horsfall protein, Calbindin-D 28K , and AQP2 to mark proximal tubules (PT)/thin descending limbs of Henle's loop (tDLH), thick ascending limbs of Henle's loop (TAL), distal convoluted tubule/connecting tubule (DCT/CNT), and the collecting duct (CD) principal cells, respectively. Epac1 and Epac2 were expressed at the brush border of PT cells but were absent from tDLH cells. In the TAL, Epac1 and Epac2 were expressed throughout the cells with some confinement toward the apical membrane. In the DCT/CNT, Epac1 was confined to the apical region of the cells, whereas Epac2 was mainly expressed in the apical and basolateral regions. In the CD, a dispersed Epac1 expression was found in intercalated cells only (cortical CD), principal and intercalated cells [outer medullary CD (OMCD)], and mainly AQP2-negative cells in the inner medullary CD (IMCD). In contrast, Epac2 expression was at the apical and basolateral membrane of cortical principal cells, dispersed and apical in the OMCD, and in all cells of the IMCD. A similar distribution fo r Epac1/2 was found in the human kidney. The observed expression in different tubular segments suggests a major role for Epac 1/2 in tubular transport physiology and cellular proliferation.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00448.2007
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2008
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  • 3
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    Low plasma carnosinase activity promotes carnosinemia after carnosine ingestion in humans
    American Physiological Society ; 2012
    In:  American Journal of Physiology-Renal Physiology Vol. 302, No. 12 ( 2012-06-15), p. F1537-F1544
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 302, No. 12 ( 2012-06-15), p. F1537-F1544
    Abstract: A polymorphism in the carnosine dipeptidase-1 gene ( CNDP1), resulting in decreased plasma carnosinase activity, is associated with a reduced risk for diabetic nephropathy. Because carnosine, a natural scavenger/suppressor of ROS, advanced glycation end products, and reactive aldehydes, is readily degraded in blood by the highly active carnosinase enzyme, it has been postulated that low serum carnosinase activity might be advantageous to reduce diabetic complications. The aim of this study was to examine whether low carnosinase activity promotes circulating carnosine levels after carnosine supplementation in humans. Blood and urine were sampled in 25 healthy subjects after acute supplementation with 60 mg/kg body wt carnosine. Precooled EDTA-containing tubes were used for blood withdrawal, and plasma samples were immediately deproteinized and analyzed for carnosine and β-alanine by HPLC. CNDP1 genotype, baseline plasma carnosinase activity, and protein content were assessed. Upon carnosine ingestion, 8 of the 25 subjects (responders) displayed a measurable increase in plasma carnosine up to 1 h after supplementation. Subjects with no measurable increment in plasma carnosine (nonresponders) had ∼2-fold higher plasma carnosinase protein content and ∼1.5-fold higher activity compared with responders. Urinary carnosine recovery was 2.6-fold higher in responders versus nonresponders and was negatively dependent on both the activity and protein content of the plasma carnosinase enzyme. In conclusion, low plasma carnosinase activity promotes the presence of circulating carnosine upon an oral challenge. These data may further clarify the link among CNDP1 genotype, carnosinase, and diabetic nephropathy.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00084.2012
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2012
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  • 4
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    Aerobic and resistance training do not influence plasma carnosinase content or activity in type 2 diabetes
    American Physiological Society ; 2015
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 309, No. 7 ( 2015-10-01), p. E663-E669
    Details
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 309, No. 7 ( 2015-10-01), p. E663-E669
    Abstract: A particular allele of the carnosinase gene (CNDP1) is associated with reduced plasma carnosinase activity and reduced risk for nephropathy in diabetic patients. On the one hand, animal and human data suggest that hyperglycemia increases plasma carnosinase activity. On the other hand, we recently reported lower carnosinase activity levels in elite athletes involved in high-intensity exercise compared with untrained controls. Therefore, this study investigates whether exercise training and the consequent reduction in hyperglycemia can suppress carnosinase activity and content in adults with type 2 diabetes. Plasma samples were taken from 243 males and females with type 2 diabetes (mean age = 54.3 yr, SD = 7.1) without major microvascular complications before and after a 6-mo exercise training program [4 groups: sedentary control ( n = 61), aerobic exercise ( n = 59), resistance exercise ( n = 63), and combined exercise training ( n = 60)]. Plasma carnosinase content and activity, hemoglobin (Hb) A 1c , lipid profile, and blood pressure were measured. A 6-mo exercise training intervention, irrespective of training modality, did not decrease plasma carnosinase content or activity in type 2 diabetic patients. Plasma carnosinase content and activity showed a high interindividual but very low intraindividual variability over the 6-mo period. Age and sex, but not Hb A 1c , were significantly related to the activity or content of this enzyme. It can be concluded that the beneficial effects of exercise training on the incidence of diabetic complications are probably not related to a lowering effect on plasma carnosinase content or activity.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    URL: Article
    DOI: 10.1152/ajpendo.00142.2015
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2015
    detail.hit.zdb_id: 1477331-4
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  • 5
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    Genetic predisposition for glomerulonephritis-induced glomerulosclerosis in rats is linked to chromosome 1
    American Physiological Society ; 2008
    In:  Physiological Genomics Vol. 35, No. 2 ( 2008-10), p. 173-181
    Details
    In: Physiological Genomics, American Physiological Society, Vol. 35, No. 2 ( 2008-10), p. 173-181
    Abstract: Genetic factors influence renal disease progression, and several loci have been linked to the spontaneous development of proteinuria and glomerulosclerosis in animal models. However, the role of genetic susceptibility in glomerulonephritis-induced progressive glomerulosclerosis is unknown. In a rat model of mesangial proliferative glomerulonephritis, anti-Thy-1 glomerulonephritis (antiThy1GN), Lewis/Maastricht (Lew/Maa) rats exhibit progression to glomerulosclerosis, whereas in genetically related Lewis/Møllegard (Lew/Moll) rats, glomerular lesions are repaired within 3 wk. The genetic factors underlying this strain-related difference are not known. To identify novel quantitative trait loci (QTL) involved in progression or repair in Lewis rats, 145 female backcross rats [F1(Lew/Maa × Lew/Moll) × Lew/Maa] were studied. After induction of antiThy1GN proteinuria, we determined mesangial activation, the percentage of microaneurysms, and the glomerular damage score for each animal; a genome scan using 187 microsatellite markers was performed. QTL mapping revealed a significant QTL for glomerular damage score on chromosome 1 with a logarithm of odds (LOD) score of 3.9. Homozygosity for Lew/Maa DNA in this region was associated with a higher percentage of damaged glomeruli on day 21. Furthermore, suggestive linkage was found for the percentage of glomeruli with microaneurysms on day 3 on chromosome 1, 6, and 11; for mesangial activation on day 7 on chromosome 18, while proteinuria was suggestively linked to chromosome 5 ( day 0), 4 ( day 3), and 6 ( day 7). This study identifies a QTL on rat chromosome 1 that is significantly linked to progressive glomerulosclerosis after acute glomerulonephritis.
    Type of Medium: Online Resource
    ISSN: 1094-8341 , 1531-2267
    URL: Article
    DOI: 10.1152/physiolgenomics.00268.2007
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2008
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  • 6
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    Does low serum carnosinase activity favor high-intensity exercise capacity?
    American Physiological Society ; 2014
    In:  Journal of Applied Physiology Vol. 116, No. 5 ( 2014-03-01), p. 553-559
    Details
    In: Journal of Applied Physiology, American Physiological Society, Vol. 116, No. 5 ( 2014-03-01), p. 553-559
    Abstract: Given the ergogenic properties of β-alanyl-L-histidine (carnosine) in skeletal muscle, it can be hypothesized that elevated levels of circulating carnosine could equally be advantageous for high-intensity exercises. Serum carnosinase (CN1), the enzyme hydrolyzing the dipeptide, is highly active in the human circulation. Consequently, dietary intake of carnosine usually results in rapid degradation upon absorption, yet this is less pronounced in subjects with low CN1 activity. Therefore, acute carnosine supplementation before high-intensity exercise could be ergogenic in these subjects. In a cross-sectional study, we determined plasma CN1 activity and content in 235 subjects, including 154 untrained controls and 45 explosive and 36 middle- to long-distance elite athletes. In a subsequent double-blind, placebo-controlled, crossover study, 12 men performed a cycling capacity test at 110% maximal power output (CCT 110%) following acute carnosine (20 mg/kg body wt) or placebo supplementation. Blood samples were collected to measure CN1 content, carnosine, and acid-base balance. Both male and female explosive athletes had significantly lower CN1 activity (14% and 21% lower, respectively) and content (30% and 33% lower, respectively) than controls. Acute carnosine supplementation resulted only in three subjects in carnosinemia. The CCT 110% performance was not improved after carnosine supplementation, even when accounting for low/high CN1 content. No differences were found in acid-base balance, except for elevated resting bicarbonate following carnosine supplementation and in low CN1 subjects. In conclusion, explosive athletes have lower serum CN1 activity and content compared with untrained controls, possibly resulting from genetic selection. Acute carnosine supplementation does not improve high-intensity performance.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    URL: Article
    DOI: 10.1152/japplphysiol.01218.2013
    RVK:
    WA 15000
    RVK:
    XA 52094
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2014
    detail.hit.zdb_id: 1404365-8
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    SSG: 31
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  • 7
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    Curcumin inhibits cystogenesis by simultaneous interference of multiple signaling pathways: in vivo evidence from a Pkd1 -deletion model
    American Physiological Society ; 2011
    In:  American Journal of Physiology-Renal Physiology Vol. 300, No. 5 ( 2011-05), p. F1193-F1202
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 300, No. 5 ( 2011-05), p. F1193-F1202
    Abstract: Autosomal dominant polycystic kidney disease (ADPKD) caused by mutations in either the PKD1 or PKD2 gene is a major cause of end-stage renal failure. A number of compounds targeting specific signaling pathways were able to inhibit cystogenesis in rodent models and are currently being tested in clinical trials. However, given the complex signaling in ADPKD, an ideal therapy would likely have to comprise several pathways at once. Therefore, multitarget compounds may provide promising therapeutic interventions for the treatment of ADPKD. To test this hypothesis, we treated Pkd1-deletion mice with diferuloylmethane (curcumin), a compound without appreciable side effects and known to modulate several pathways that are also altered in ADPKD, e.g., mammalian target of rapamycin (mTOR) and Wnt signaling. After conditional inactivation of Pkd1, mTOR signaling was indeed elevated in cystic kidneys. Interestingly, also activation of signal transducers and activator of transcription 3 (STAT3) strongly correlated with cyst progression. Both pathways were effectively inhibited in vitro by curcumin. Importantly, Pkd1-deletion mice that were treated with curcumin and killed at an early stage of PKD displayed improved renal histology and reduced STAT3 activation, proliferation index, cystic index, and kidney weight/body weight ratios. In addition, renal failure was significantly postponed in mice with severe PKD. These data suggest that multitarget compounds hold promising potential for safe and effective treatment of ADPKD.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00419.2010
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2011
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  • 8
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    Genetic linkage of albuminuria and renal injury in Dahl salt-sensitive rats on a high-salt diet: comparison with spontaneously hypertensive rats
    American Physiological Society ; 2004
    In:  Physiological Genomics Vol. 18, No. 2 ( 2004-07-08), p. 218-225
    Details
    In: Physiological Genomics, American Physiological Society, Vol. 18, No. 2 ( 2004-07-08), p. 218-225
    Abstract: Our aim was to study the effects of high-salt diet on the genetics of albuminuria and renal injury in the Dahl salt-sensitive (SS) rat. We compared SS with salt-resistant spontaneously hypertensive rats (SHR) and with genetically related salt-sensitive stroke-prone SHR (SHRSP). Moreover, we performed genome-wide linkage analysis to identify quantitative trait loci (QTL) contributing to salt-induced renal injury in an F 2 population derived from SS and SHR ( n = 230). In response to high-salt diet SS and SHRSP developed a striking increase in systolic blood pressure, urinary albumin excretion (UAE), and renal damage indices compared with SHR. Both SHRSP and SS developed severe glomerulosclerosis, whereas microangiopathy, tubulointerstitial fibrosis, and inflammation were more pronounced in SHRSP. We detected two QTL with significant linkage to UAE on rat chromosomes (RNO) 6 and 19. Comparison with the recently identified salt-independent UAE QTL in young animals revealed that the UAE QTL on RNO6 is unique to high-salt conditions, whereas RNO19 plays a significant role during both low- and high-salt conditions. Some F 2 animals demonstrated severe microangiopathy and tubulointerstitial injury, which exceeded the degree observed in the parental SS strain. Three loci demonstrated suggestive linkage to these phenotypes on RNO3, RNO5, and RNO20, whereas no linkage to glomerular damage was found. Further analyses at these loci indicated that the severity of renal injury was attributable to the SHR allele. Our data suggest that the SHR genetic background confers greater susceptibility for the development of microangiopathy and tubulointerstitial injury in salt-sensitive hypertension than the SS background.
    Type of Medium: Online Resource
    ISSN: 1094-8341 , 1531-2267
    URL: Article
    DOI: 10.1152/physiolgenomics.00068.2004
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2004
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  • 9
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    Induction of albuminuria and kidney damage in SHR by transfer of chromosome 8 from Munich Wistar Frömter rats
    American Physiological Society ; 2012
    In:  Physiological Genomics Vol. 44, No. 1 ( 2012-01), p. 110-116
    Details
    In: Physiological Genomics, American Physiological Society, Vol. 44, No. 1 ( 2012-01), p. 110-116
    Abstract: Inbred Munich Wistar Frömter [MWF/FubRkb (RGD:724569), MWF] rats develop progressive albuminuria with age that is under polygenetic influence. We previously identified a major albuminuria quantitative trait locus (QTL) on rat chromosome (RNO)8 in MWF. To test the independent role of QTL(s) for albuminuria development on RNO8, we generated a consomic SHR-Chr 8 MWF /Rkb (SHR-8 MWF ) strain by transferring RNO8 from MWF into the albuminuria-resistant background of the spontaneously hypertensive rat [SHR/FubRkb (RGD:631696; SHR)]. Young male MWF, SHR, and SHR-8 MWF were sham-operated or unilaterally nephrectomized (Nx) at 6 wk and followed up to 24 wk of age, respectively. Systolic blood pressure was significantly lower in SHR-8 MWF Sham compared with SHR Sham (−19.4 mmHg, P = 0.03) at 24 wk. In contrast, transfer of MWF-RNO8 into SHR induced a significant elevation of urinary albumin excretion (UAE) between weeks 12 and 24 in SHR-8 MWF compared with SHR Sham animals ( P 〈 0.0001, respectively). Nx resulted in a significant increase in UAE in both strains during follow-up ( P 〈 0.0001, respectively), with significant higher values in SHR-8 MWF compared with SHR ( P 〈 0.005, respectively). Renal structural changes as determined by glomerulosclerosis (GSI) and tubulointerstitial damage index (TDI) were significantly higher in consomic animals either at Sham (TDI) or Nx (GSI) conditions ( P 〈 0.05, respectively). These data confirm the independent role of MWF QTL(s) on RNO8 for both albuminuria and structural kidney damage. Moreover, this study shows for the first time the induction of albuminuria by transferring one or more albuminuria QTL into a resistant recipient background in a consomic rat strain.
    Type of Medium: Online Resource
    ISSN: 1094-8341 , 1531-2267
    URL: Article
    DOI: 10.1152/physiolgenomics.00123.2011
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2012
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