Dynamic Autoregulation and Renal Injury in Dahl Rats

Karlsen, Finn Michael; Andersen, Claus B.; Leyssac, P. P.; Holstein‐Rathlou, Niels‐Henrik

doi:10.1161/01.hyp.30.4.975

Cited by 74 publications

(89 citation statements)

References 18 publications

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“…It also modulates tubuloglomerular feedback responsiveness, probably by affecting vascular reactivity to adenosine through modulation of K Ca channel activity (45). Indeed, this hypothesis is consistent with previous observations that the myogenic response (37) and dynamic autoregulation of RBF is impaired in Dahl S rats (14) and that TGF responsiveness is decreased when these rats are fed a HS diet (40).…”

Section: Discussionsupporting

confidence: 89%

Role of 20-HETE in the antihypertensive effect of transfer of chromosome 5 from Brown Norway to Dahl salt-sensitive rats

Williams

Fan

Murphy

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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This study examined whether substitution of chromosome 5 containing the CYP4A genes from Brown Norway rat onto the Dahl S salt-sensitive (SS) genetic background upregulates the renal production of 20-HETE and attenuates the development of hypertension. The expression of CYP4A protein and the production of 20-HETE were significantly higher in the renal cortex and outer medulla of SS.5 BN (chromosome 5-substituted Brown Norway rat) consomic rats fed either a low-salt (LS) or high-salt (HS) diet than that seen in SS rats. The increase in the renal production of 20-HETE in SS.5 BN rats was associated with elevated expression of CYP4A2 mRNA. MAP measured by telemetry rose from 117 Ϯ 1 to 183 Ϯ 5 mmHg in SS rats fed a HS diet for 21 days, but only increased to 151 Ϯ 5 mmHg in SS.5 BN rats. The pressure-natriuretic and diuretic responses were twofold higher in SS.5 BN rats compared with SS rats. Protein excretion rose to 354 Ϯ 17 mg/day in SS rats fed a HS diet for 21 days compared with 205 Ϯ 13 mg/day in the SS.5 BN rats, and the degree of glomerular injury was reduced. Baseline glomerular capillary pressure (Pgc) was similar in SS.5 BN rats (43 Ϯ 1 mmHg) and Dahl S (44 Ϯ 2 mmHg) rats. However, Pgc increased to 59 Ϯ 3 mmHg in SS rats fed a HS diet for 7 days, while it remained unaltered in SS.5 BN rats (43 Ϯ 2 mmHg). Chronic administration of an inhibitor of the synthesis of 20-HETE (HET0016, 10 mg·kg Ϫ1 ·day Ϫ1 iv) reversed the antihypertensive phenotype seen in the SS.5 BN rats. These findings indicate that the transfer of chromosome 5 from the BN rat onto the SS genetic background increases the renal expression of CYP4A protein and the production of 20-HETE and that 20-HETE contributes to the antihypertensive and renoprotective effects seen in the SS.5 BN consomic strain.hypertension; glomerulosclerosis; chromosome 5; Dahl S rats; pressure natriuresis; renal hemodynamics; kidney THE DAHL SALT-SENSITIVE (SS) rat is an inbred genetic model that rapidly develops severe hypertension, proteinuria, glomerulosclerosis, and renal interstitial fibrosis when fed a high salt (HS) diet (4, 7-8, 23, 25, 27, 30, 38, 43). However, the genes and pathways that contribute to the development of hypertension and renal disease have yet to be identified. Previous studies from our laboratory have demonstrated that the pressure natriuretic relationship is impaired in SS rats and that this is associated with increased Cl Ϫ transport in the thick ascending limb of Henle (TALH) (13, 15-16, 29, 44). They also exhibit a deficiency in the renal production of 20-HETE that contributes to the increase in loop Cl Ϫ transport (13,35,44).More recently, Mattson et al. (20) demonstrated that substitution of chromosome 5 from the Brown Norway (BN) rat onto the SS genetic background (SS.5 BN strain) attenuates the development of hypertension and proteinuria in SS.5 BN rats fed a high-salt (HS) diet for 21 days, but the mechanism is unknown. Because the CYP4A genes that produce 20-HETE are located on chromosome 5 and this region has been found to cosegre...

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Section: Discussionsupporting

confidence: 89%

Role of 20-HETE in the antihypertensive effect of transfer of chromosome 5 from Brown Norway to Dahl salt-sensitive rats

Williams

Fan

Murphy

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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“…It must be also emphasized that such intrarenal hemodynamics is confounded or modified by the alterations of other factors, including intrarenal autoregulation mechanism, vascular reactivity, and endothelial function. [41][42][43][44] In conclusion, our data reveal that hypertrophic remodeling without a luminal narrowing at the preglomerular resistance vessels and a permeability defect in filtering at the glomeruli exist in the prehypertensive stage of DS rats. The observed renal structural characteristics may be involved in the genesis of glomerular hypertension in DS rats.…”

Section: Tomoda Et Al Renovascular Structure In Dahl Salt-sensitive Ratssupporting

confidence: 52%

Renal Structural Properties in Prehypertensive Dahl Salt-Sensitive Rats

et al. 2000

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Abstract-In 10-to 12-week-old Dahl salt-sensitive (DS) and salt-resistant (DR) rats fed a 0.3% salt diet (nϭ10 in each group), flow-pressure and pressure-glomerular filtration rate (F-P and P-GFR, respectively) relationships were established for maximally vasodilated perfused kidneys. From these relationships, 3 indices of vascular structural properties were estimated: slope of F-P (minimal renal vascular resistance reflecting overall luminal dimensions of preglomerular and postglomerular vasculature), slope of P-GFR (glomerular filtration capability against pressure), and threshold pressure for beginning filtration at P-GFR (preglomerular-to-postglomerular vascular resistance ratio). Thereafter, maximal renal vascular resistance was determined to assess wall-to-lumen ratios of the resistance vessels in half of each group. In the remainder, the kidneys were perfusion-fixed for histological analysis. Mean arterial pressure did not differ between the DS and DR rats. There were no significant differences in the slopes of F-P between the 2 groups. In contrast, the slope of P-GFR was significantly lower (33%) in DS rats than in DR rats, although the DS kidneys began filtering at a threshold pressure similar to that of the DR kidneys. Thus, in DS rats, there were no abnormalities in luminal dimensions at preglomerular and postglomerular vascular segments, but the kidney filtration capacity decreased at any given increase in pressure. Maximal vascular resistance was greater in DS than in DR rats, a finding compatible with the histological appearance, which showed vascular hypertrophy with little, if any, vascular narrowing in the interlobular arteries of DS rats. In conclusion, hypertrophic remodeling without vascular narrowing at preglomerular resistance vessels and structural defects in filtering at the glomeruli could occur in prehypertensive DS rats. (Hypertension. 2000;36:68-72.)Key Words: renal artery Ⅲ rats, Dahl Ⅲ kidney Ⅲ remodeling Ⅲ hypertension, sodium-dependent O n the basis of intrarenal hemodynamic data in various hypertensive animal models, it is recognized that in models of salt-induced hypertension, including Dahl saltsensitive (DS) rats and deoxycorticosterone-salt rats, intraglomerular pressure is elevated compared with models of spontaneous (ie, non-salt-induced) hypertension, such as the spontaneously hypertensive rat(s) (SHR). 1-6 Because intraglomerular hypertension plays an important role in the genesis of glomerular injuries, 7 it might be responsible for the early onset and rapid progression of hypertensive renal damages that are found in association with salt-induced hypertension in animals and humans. 8 -13 Accordingly, from the viewpoint of cardiovascular protection, it is clinically important to elucidate the precise mechanisms causing intraglomerular hypertension in salt-induced hypertension.In hypertension, it is well known that resistance vessels become thicker or encroach into the lumen (ie, vascular hypertrophy or vascular remodeling) in the kidneys as well as in other vascular beds...

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“…In addition, we measured the ability of autoregulatory responses, which was significantly lower in DS rat kidneys. The autoregulatory response is reported to be significantly decreased in DS rats 31 and remnant kidney rats, a model of progressive renal damage. 32 The renal autoregulatory response is coordinated by two mechanisms: myogenic response and tubulo-glomerular feedback.…”

Section: Ds-h Ds-l Ds-h-tel Ds-h-mentioning

confidence: 98%

Telmisartan improves endothelial dysfunction and renal autoregulation in Dahl salt-sensitive rats

et al. 2009

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Hypertensive vascular disorders are characterized by endothelial dysfunction. Loss of renal autoregulation causes glomerular hypertension. However, the relationship between the autoregulatory response and glomerular damage has not been well examined. We examined the contributions of uncoupled endothelial nitric oxide synthase (eNOS) in hypertensive renal disease, and the relationship between the degree of autoregulation impairment and glomerular injury. We also investigated the effects of telmisartan on eNOS coupling and renal autoregulation. Male Dahl salt-sensitive hypertensive (DS) rats (14-week old) fed an 8% salt diet were used to examine endothelial dysfunction and impaired renal autoregulation caused by glomerular hypertension. Some DS rats were treated with telmisartan (3.0 mg kg À1 day À1 ), an angiotensin receptor blocker, for 2 weeks. Increased superoxide production and decreased nitric oxide production, as detected by fluorescent indicator perfusion methods, were observed in the glomeruli and arterioles of hypertensive DS rats. Telmisartan improved the imbalance of superoxide and nitric oxide in the glomeruli and arterioles. Decreased serum tetrahydrobiopterin levels and coupled eNOS seen in the DS rat kidney were improved with telmisartan treatment. The endothelial relaxation reaction was impaired in DS rat aortic arteries. Autoregulatory capacity in response to step changes in perfusion pressure was also impaired in DS rat kidney. Treatment with telmisartan improved these abnormalities. Endothelial dysfunction in the glomeruli and impaired renal autoregulation, which may cause glomerular sclerosis, were observed in DS rat kidney. Telmisartan treatment improves these dysfunctions in hypertensive renal disease.

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Dynamic Autoregulation and Renal Injury in Dahl Rats

Cited by 74 publications

References 18 publications

Role of 20-HETE in the antihypertensive effect of transfer of chromosome 5 from Brown Norway to Dahl salt-sensitive rats

Role of 20-HETE in the antihypertensive effect of transfer of chromosome 5 from Brown Norway to Dahl salt-sensitive rats

Renal Structural Properties in Prehypertensive Dahl Salt-Sensitive Rats

Telmisartan improves endothelial dysfunction and renal autoregulation in Dahl salt-sensitive rats

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