Creation and Characterization of a Renin Knockout Rat

Moreno, Carol; Hoffman, Mathew; Stodola, Timothy J.; Didier, Daniela N.; Lazar, Jozef; Geurts, Aron M.; North, Paula E.; Jacob, Howard J.; Greene, Andrew S.

doi:10.1161/hypertensionaha.110.163840

Cited by 65 publications

(64 citation statements)

References 28 publications

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“…28 Chromosome 13 contains several critical genes such as genes encoding renin and NADPH subunit p67 phox and several studies utilizing this model illustrate its critical role in BP regulation. [28][29][30][31][32][33] After 3 weeks on a HS diet, MAP was significantly lower in SS. 13 BN rats compared with SS rats, as Figure 1.…”

Section: Enac Plays a Role In Development Of Salt-sensitive Hypertensmentioning

confidence: 97%

Deficiency of Renal Cortical EGF Increases ENaC Activity and Contributes to Salt-Sensitive Hypertension

Pavlov¹,

Levchenko²,

O’Connor³

et al. 2013

Journal of the American Society of Nephrology

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Various stimuli, including hormones and growth factors, modulate epithelial sodium channels (ENaCs), which fine-tune Na + absorption in the kidney. Members of the EGF family are important for maintaining transepithelial Na + transport, but whether EGF influences ENaC, perhaps mediating salt-sensitive hypertension, is not well understood. Here, the ENaC inhibitor benzamil attenuated the development of hypertension in Dahl salt-sensitive rats. Feeding these salt-sensitive rats a high-salt diet led to lower levels of EGF in the kidney cortex and enhanced the expression and activity of ENaC compared with feeding a lowsalt diet. To directly evaluate the role of EGF in the development of hypertension and its effect on ENaC activity, we infused EGF intravenously while continuously monitoring BP of the salt-sensitive rats. Infusion of EGF decreased ENaC activity, prevented the development of hypertension, and attenuated glomerular and renal tubular damage. Taken together, these findings indicate that cortical EGF levels decrease with a high-salt diet in salt-sensitive rats, promoting ENaC-mediated Na + reabsorption in the collecting duct and the development of hypertension. More than 76 million American adults have high BP 1 and the likelihood of developing hypertension significantly increases with age. Nearly 40% of African Americans aged .20 years exhibit hypertension and nearly 70% of these individuals have a form of hypertension that is highly sensitive to salt intake. A reduced ability to maintain sodium homeostasis and normal levels of arterial pressure is a hallmark of all forms of hypertension. 2 In the kidney, discretionary Na + reabsorption in response to endocrine input to the aldosterone-sensitive distal nephron (ASDN) is a determinant of the pressurenatriuresis relationship, which is of fundamental importance in the long-term control of arterial pressure. 2,3 Although sodium transport in ASDN accounts for a small proportion of renal sodium transport (,10%), ENaC activity is the rate-limiting step for this discretionary Na + reabsorption. 4 The Dahl salt-sensitive (SS) rat strain used in this study is a genetic animal model of hypertension and kidney disease that reveals disease traits similar to those observed in humans. This inbred strain exhibits a low-renin, sodium-sensitive form of hypertension that is associated with severe and progressive proteinuria, glomerulosclerosis, and renal interstitial fibrosis. [5][6][7] The EGF and related hormones are multipotent agents [8][9][10][11] involved in regulation of various renal

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Section: Enac Plays a Role In Development Of Salt-sensitive Hypertensmentioning

confidence: 97%

Deficiency of Renal Cortical EGF Increases ENaC Activity and Contributes to Salt-Sensitive Hypertension

Pavlov¹,

Levchenko²,

O’Connor³

et al. 2013

Journal of the American Society of Nephrology

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“…All rats were initially fed a 0.4% NaCl diet (113755; Dyets Inc.). Urine volume, Na + , K + , creatinine, protein, and microalbumin were measured as described previously (49). BP was measured as described previously (49).…”

Section: Methodsmentioning

confidence: 99%

“…Kidneys and hearts were sectioned, mounted on microscope slides, and stained with trichrome. Immunohistochemistry (IHC) was performed using an antibody against alpha-smooth muscle actin using standard IHC methodology (49). Vessel media was calculated by measuring the outer circumference of the vessel minus the inner circumference of the lumen (20 random vessels within the cortex).…”

Section: Methodsmentioning

confidence: 99%

Mutation of Plekha7 attenuates salt-sensitive hypertension in the rat

Endres

Priestley²,

Palygin³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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PLEKHA7 (pleckstrin homology domain containing family A member 7) has been found in multiple studies as a candidate gene for human hypertension, yet functional data supporting this association are lacking. We investigated the contribution of this gene to the pathogenesis of salt-sensitive hypertension by mutating Plekha7 in the Dahl salt-sensitive (SS/JrHsdMcwi) rat using zincfinger nuclease technology. After four weeks on an 8% NaCl diet, homozygous mutant rats had lower mean arterial (149 ± 9 mmHg vs. 178 ± 7 mmHg; P < 0.05) and systolic (180 ± 7 mmHg vs. 213 ± 8 mmHg; P < 0.05) blood pressure compared with WT littermates. Albumin and protein excretion rates were also significantly lower in mutant rats, demonstrating a renoprotective effect of the mutation. Total peripheral resistance and perivascular fibrosis in the heart and kidney were significantly reduced in Plekha7 mutant animals, suggesting a potential role of the vasculature in the attenuation of hypertension. Indeed, both flow-mediated dilation and endothelium-dependent vasodilation in response to acetylcholine were improved in isolated mesenteric resistance arteries of Plekha7 mutant rats compared with WT. These vascular improvements were correlated with changes in intracellular calcium handling, resulting in increased nitric oxide bioavailability in mutant vessels. Collectively, these data provide the first functional evidence that Plekha7 may contribute to blood pressure regulation and cardiovascular function through its effects on the vasculature.H ypertension is a complex disease that is characterized by increased blood pressure, renal damage, and vascular dysfunction which collectively increase risk of atherosclerosis, stroke, heart disease, and renal failure in one-quarter of all adults worldwide (1-3). Because there is strong evidence of heritability in hypertension (2, 4, 5), considerable effort has been put toward identifying novel candidate genes and their molecular mechanisms. Genome-wide association studies (GWAS) have identified many potential hypertension loci, which shed light on the genetic complexity of this disease (5-8) but have provided little mechanistic insight. As such, validation and elucidation of the functional roles and disease mechanisms for these gene candidates are the next important challenges (4).Because hypertension is a complex disease (i.e., multiple variants of small effect sizes contributing to disease risk), we hypothesized candidate gene targeting on a genetically sensitized background would reveal functional role(s) of genetic disease modifiers. The Dahl salt-sensitive (SS) rat is an inbred genetic model of salt-sensitive hypertension that displays hypertensioninduced renal damage, cardiac hypertrophy and vascular dysfunction (9-11). These phenotypes are induced by exposing SS rats to a high-salt diet, which results in rapid induction of hypertensive phenotypes that closely resemble salt-induced hypertension seen in humans (12-15). Knockout of specific genes in this disease model using zinc-finger nuclease (ZFN...

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“…5 Confirmation of the dominant role of renin in Ang II formation was provided by studies of renin (and prorenin) gene knockout mice and rats, which have undetectable plasma levels of Ang I, and the effects of renin (and prorenin) deficiency in humans. [6][7][8] Further evidence is provided by the marked suppression of plasma Ang I and Ang II levels by renin inhibitors. [9][10] Although serine proteases may contribute to Ang peptide formation at tissue sites of inflammation, 1 the available evidence indicates that nonrenin pathways of Ang formation are clearly unable to compensate for renin deficiency or inhibition.…”

Section: The Role Of Reninmentioning

confidence: 99%

Angiotensin II generation in vivo: does it involve enzymes other than renin and angiotensin-converting enzyme?

Campbell

2012

J Renin Angiotensin Aldosterone Syst

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Creation and Characterization of a Renin Knockout Rat

Cited by 65 publications

References 28 publications

Deficiency of Renal Cortical EGF Increases ENaC Activity and Contributes to Salt-Sensitive Hypertension

Deficiency of Renal Cortical EGF Increases ENaC Activity and Contributes to Salt-Sensitive Hypertension

Mutation of Plekha7 attenuates salt-sensitive hypertension in the rat

Angiotensin II generation in vivo: does it involve enzymes other than renin and angiotensin-converting enzyme?

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