BN phenome: detailed characterization of the cardiovascular, renal, and pulmonary systems of the sequenced rat

Kwitek, Anne E.; Jacob, Howard J.; Baker, John E.; Dwinell, Melinda R.; Forster, H. V.; Greene, Andrew S.; Kunert, Mary Pat; Lombard, Julian H.; Mattson, David L.; Pritchard, Kirkwood A.; Roman, Richard J.; Tonellato, Peter J.; Cowley, Allen W.

doi:10.1152/physiolgenomics.00288.2005

Cited by 38 publications

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“…Blood was obtained at the moment of tissue collection by heart puncture after fasting overnight. Measurement of plasma glucose, serum cholesterol, and triglyceride concentrations were performed by Marshfield Laboratories (Marshfhield, WI) as described previously (8). Plasma glucose levels were measured by standard procedures as described (4).…”

Section: Blood Analysismentioning

confidence: 99%

Mitochondrial DNA Variant for Complex I Reveals a Role in Diabetic Cardiac Remodeling

Savitha

Vásquez‐Vivar

Migrino

et al. 2012

Journal of Biological Chemistry

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Background: Mitochondrial dysfunction may influence myocardial remodeling in diabetes.Results: Impaired respiratory complex activity and energy depletion without mitochondrial uncoupling was identified in a new conplastic rat model of diabetes. Conclusion: mtDNA mutations are a risk factor for developing myocardial dysfunction in diabetes. Significance: Identifying mtDNA background is important for recognizing patients at risk for heart diseases.Myocardial remodeling and dysfunction are serious complications of type 2 diabetes mellitus (T2DM). Factors controlling their development are not well established. To specifically address the role of the mitochondrial genome, we developed novel conplastic rat strains, i.e. strains with the same nuclear genome but a different mitochondrial genome. The new animals were named T2DN mtFHH and T2DN mtWistar , where the acronym T2DN denotes their common nuclear genome (type 2 diabetic nephropathy (T2DN) rats) and mtFHH or mtWistar the origin of their mitochondria, Fawn Hooded Hypertensive (FHH) or Wistar rats, respectively. The T2DN mtFHH and T2DN mtWistar showed a similar progression of diabetes as determined by HbA1c, cholesterol, and triglycerides with normal blood pressure, thus enabling investigation of the specific role of the mitochondrial genome in cardiac function without the confounding effects of obesity or hypertension found in other models of diabetes. Echocardiographic analysis of 12-week-old animals showed no abnormalities, but at 12 months of age the T2DN mtFHH showed left ventricular remodeling that was verified by histology. Decreased complex I and complex IV but not complex II activity within the electron transport chain was found only in T2DN mtFHH , which was not explained by differences in protein content. Decreased cardiac ATP levels in T2DN mtFHH were in agreement with a lower ATP synthetic capacity by isolated mitochondria. Together, our data provide experimental evidence that mtDNA sequence variations have an additional role in energetic heart deficiency. The mitochondrial DNA background may explain the increased susceptibility of certain T2DM patients to develop myocardial dysfunction. Type 2 diabetes mellitus (T2DM)2 is a complex and heterogeneous disorder with a prevalence nearing epidemic proportions worldwide. Myocardial dysfunction and heart failure are serious complications developing in many cases independently of coronary artery disease and hypertension. It is considered that molecular alterations at the myocyte level may be a key factor in the development of myocardial dysfunction. The pathogenesis of ventricular dysfunction has been examined previously in genetic animal models of T2DM (1-3). Because these models present with a variety of metabolic disorders, it has been impossible to isolate the influence of intrinsic mitochondrial impairments in disease mechanisms.A new rat model of type 2 diabetes mellitus was developed by crossing diabetic male Goto-Kakizaki (GK) rats with female Fawn Hooded Hypertensive (FHH) rats (4). This new T2DM rat ...

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Section: Blood Analysismentioning

confidence: 99%

Mitochondrial DNA Variant for Complex I Reveals a Role in Diabetic Cardiac Remodeling

Savitha

Vásquez‐Vivar

Migrino

et al. 2012

Journal of Biological Chemistry

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“…Mattson et al (26) have previously done a strain comparison of BN and FHH renal parameters and reported that BN rats are more resistant to the development of proteinuria and renal injury than FHH rats and that substitution of chromosome 1 from BN to FHH rats ameliorates renal injury in FHH.1BN consomic rats. Similarly, a study comparing BN to 10 other normotensive and hypertensive rat strains found that albumin and protein excretion, blood urea nitrogen (BUN), and plasma creatinine are significantly lower in BN than in FHH and Dahl S rats (23). Moreover, the BN rat was simply used as a donor strain for the 2.4-Mbp region of interest on RNO1.…”

Section: F573 Impaired Mr In Fhhmentioning

confidence: 99%

Genetic basis of the impaired renal myogenic response in FHH rats

Burke

Pabbidi

Fan

et al. 2013

American Journal of Physiology-Renal Physiology

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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 ϩ 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 ϩ 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 ϩ current, and slows the progression of proteinuria and renal injury. kidney; glomerulosclerosis; chronic renal failure; renal hemodynamics THE FAWN-HOODED HYPERTENSIVE (FHH) rat is a genetic model of hypertension (33) that develops proteinuria, glomerulosclerosis (21,30,37,47), and chronic kidney disease (22,(25)(26)(41)(42). We have previously reported that the development of proteinuria and glomerular injury in FHH rats is associated with an impaired autoregulation of renal blood flow (RBF), glomerular filtration rate (GFR), and glomerular capillary pressure (Pgc) (24,40,43,48). Genetic cosegregation studies identified five quantitative trait loci (QTLs) linked to the development of proteinuria in F2 crosses of FHH and AugustCopenhagen inbred (ACI) rats (4 -5, 36). The rat chromosome (RN) regions are Rf-1 and Rf-2 on RNO1, Rf-3 on RNO3, Rf-4 on RNO14, and Rf-5 on RNO17. The Rf-1 QTL is of particular interest in that it lies within a region that is homologous to an area on human chromosome 10 linked to the development of diabetic nephropathy (19) and end-stage renal disease (18). More recent studies identified a G-to-A mutation in the start codon of Rab38, a gene in the Rf-2 QTL that influences protein trafficking and contributes to the development of proteinuria in FHH rats (32). However, the genes in the Rf-1 region that contribute to the development of proteinuria and renal disease in FHH rats and the mechanisms involved are unknown.We have previously reported that substitution of a 99.4-megabase pair (Mbp) reg...

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“…For example, Brown Norway (BN) rats exhibit more resistance to myocardial IR injury than does the Dahl saltsensitive (SS) strain (3). Moreover, introgression of BN chromosome 6 into an SS background (SS 6BN ) conferred significant cardioprotection (17). In other words, one or more genes on chromosome 6 with or without linkage to other chromosomes may be responsible for higher IR tolerance.…”

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Genetically determined mitochondrial preservation and cardioprotection against myocardial ischemia-reperfusion injury in a consomic rat model

Nabbi

Gadicherla

Kersten

et al. 2014

Physiological Genomics

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BN phenome: detailed characterization of the cardiovascular, renal, and pulmonary systems of the sequenced rat

Abstract: Editor-in-Chief, Physiological Genomics. BN phenome: detailed characterization of the cardiovascular, renal, and pulmonary systems of the sequenced rat.

Cited by 38 publications

References 28 publications

Mitochondrial DNA Variant for Complex I Reveals a Role in Diabetic Cardiac Remodeling

Mitochondrial DNA Variant for Complex I Reveals a Role in Diabetic Cardiac Remodeling

Genetic basis of the impaired renal myogenic response in FHH rats

Genetically determined mitochondrial preservation and cardioprotection against myocardial ischemia-reperfusion injury in a consomic rat model

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