Effect of Add1 gene transfer on blood pressure in reciprocal congenic strains of Milan rats

Tripodi, Grazia; Florio, Monica; Ferrandi, Mara; Modica, Rossana; Zimdahl, Heike; Hübner, Norbert; Ferrari, Paolo; Bianchi, Giuseppe

doi:10.1016/j.bbrc.2004.09.079

Cited by 31 publications

(27 citation statements)

References 29 publications

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“…Compared with MNS rats, the NA congenic substrain showed a significant increase of SBP (Table 1). Conversely, the NB congenic substrain showed SBP levels similar to those of MNS rats (Table 1) (Tripodi et al, 2004;Ferrandi et al, 2010b). The prolonged oral treatment with rostafuroxin (100 mg/kg per day for 8 weeks, starting from weaning) reduced SBP in MHS and NA rats, but was inactive in MNS rats (Table 1), confirming previous data (Ferrandi et al, 2010a).…”

Section: Rat Modelssupporting

confidence: 85%

“…Two congenic substrains were studied: NA (carrying the mutant 316Y a-adducin from MHS) and NB (carrying the mutant 529R b-adducin from MHS). NA congenic rats, but not NB, significantly raise SBP compared with MNS (Tripodi et al, 2004).…”

Section: Animal Modelsmentioning

confidence: 79%

“…Congenic rat strains were obtained from MHS and MNS rats, as previously described (Tripodi et al, 2004). The donor strain was the MHS and the receiving genetic background was the MNS.…”

Section: Animal Modelsmentioning

confidence: 99%

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Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

Ferrandi

Molinari

Rastaldi

et al. 2014

J Pharmacol Exp Ther

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Glomerulopathies are important causes of morbidity and mortality. Selective therapies that address the underlying mechanisms are still lacking. Recently, two mechanisms, mutant b-adducin and ouabain, have been found to be involved in glomerular podocytopathies and proteinuria through nephrin downregulation. The main purpose of the present study was to investigate whether rostafuroxin, a novel antihypertensive agent developed as a selective inhibitor of Src-SH2 interaction with mutant adducinand ouabain-activated Na,K-ATPase, may protect podocytes from adducin-and ouabain-induced effects, thus representing a novel pharmacologic approach for the therapy of podocytopathies and proteinuria caused by the aforementioned mechanisms. To study the effect of rostafuroxin on podocyte protein changes and proteinuria, mice carrying mutant b-adducin and ouabain hypertensive rats were orally treated with 100 mg/kg per day rostafuroxin. Primary podocytes from congenic rats carrying mutant a-adducin or b-adducin (NB) from Milan hypertensive rats and normal rat podocytes incubated with 10 29 M ouabain were cultured with 10 29 M rostafuroxin. The results indicated that mutant b-adducin and ouabain caused podocyte nephrin loss and proteinuria in animal models. These alterations were reproduced in primary podocytes from NB rats and normal rats incubated with ouabain. Treatment of animals, or incubation of cultured podocytes with rostafuroxin, reverted mutant b-adducin-and ouabain-induced effects on nephrin protein expression and proteinuria. We conclude that rostafuroxin prevented podocyte lesions and proteinuria due to mutant b-adducin and ouabain in animal models. This suggests a potential therapeutic effect of rostafuroxin in patients with glomerular disease progression associated with these two mechanisms.

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Section: Rat Modelssupporting

confidence: 85%

Section: Animal Modelsmentioning

confidence: 79%

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Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

Ferrandi

Molinari

Rastaldi

et al. 2014

J Pharmacol Exp Ther

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“…Details about gene transfer in reciprocal congenic strains of Milan rats have been published earlier. 9 All the procedures followed were in accordance with the guidelines of our institution (Medical School, University of Brescia). The rats were housed two to a cage in a room in which the temperature was controlled between 23 and 25 1C, and a 12-h light/dark cycle was maintained.…”

Section: Methodsmentioning

confidence: 99%

Functional alterations of mesenteric small resistance arteries in Milan hypertensive and normotensive rats

et al. 2009

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The Milan hypertensive rat strain (MHS) is a genetic strain in which cardiovascular phenotypes seem to be dependent, at least in part, on adducin gene polymorphisms. The aim of our study was to evaluate the structure, contractile responses and endothelium-dependent vasodilation in mesenteric small resistance arteries in 12-week-old MHS, (n¼7), age-matched Milan normotensive rats (MNS, n¼7) and congenic strains in which the DNA segments carrying the a-adducin locus from the MHS have been introgressed into the MNS (MNA, n¼7). Systolic blood pressure (tail cuff) and left ventricular weight to body weight were measured. Mesenteric small arteries were dissected and mounted on a micromyograph; the media:lumen ratio was then calculated. Concentration-response curves to acetylcholine and to norepinephrine (NE) were created. Systolic blood pressure was significantly increased in the MHS and MNA strains compared with the MNS. No significant difference in mesenteric small resistance artery structure was observed among the groups; however, a slightly more elevated media:lumen ratio was observed in MNA compared with the MNS. In contrast, left ventricular weight to body weight was significantly increased and ACH-induced dilatation was significantly impaired in the MHS and in MNA compared with MNS. The concentration-response curve to NE in the MHS showed significantly reduced sensitivity to NE; however, maximum contraction was increased in the MHS vs. the other groups. The MHS presents cardiac (but not vascular) remodeling, endothelial dysfunction and a peculiar contractile response to NE, compared with the other groups. The systolic blood pressure increase and trend to vascular remodeling in MNA support the pathogenic role of a-adducin.

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“…There have been a number of studies that have utilized reciprocal congenic strains to investigate the genetic basis of various diseases, including hypertension (3,13,14,58,62), stroke (49), ethanol sensitivity (44), arthritis susceptibility (48), and proteinuria and glomerulosclerosis (63). In some instances, the reciprocal congenic strains demonstrated comparable effects on the phenotype, whereas in other studies the effect observed between the reciprocal strains was not comparable.…”

Section: Discussionmentioning

confidence: 99%

Investigating the effect of genetic background on proteinuria and renal injury using two hypertensive strains

Packard

Saad²,

Gunning³

et al. 2009

American Journal of Physiology-Renal Physiology

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Effect of Add1 gene transfer on blood pressure in reciprocal congenic strains of Milan rats

Cited by 31 publications

References 29 publications

Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

Functional alterations of mesenteric small resistance arteries in Milan hypertensive and normotensive rats

Investigating the effect of genetic background on proteinuria and renal injury using two hypertensive strains

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