Inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induced hypertension in mice.

BACKGROUND AND PURPOSE: Inflammasomes are multimeric complexes that facilitate caspase-1-mediated processing of the pro-inflammatory cytokines IL-1ß and IL-18. Clinical hypertension is associated with renal inflammation and elevated circulating levels of IL-1ß and IL-18. Therefore, we investigated whether hypertension in mice is associated with increased expression and/or activation of the inflammasome in the kidney, and if inhibition of inflammasome activity reduces BP, markers of renal inflammation and fibrosis. EXPERIMENTAL APPROACH: Wild-type and inflammasome-deficient ASC(-/-) mice were uninephrectomized and received deoxycorticosterone acetate and saline to drink (1K/DOCA/salt). Control mice were uninephrectomized but received a placebo pellet and water. BP was measured by tail cuff; renal expression of inflammasome subunits and inflammatory markers was measured by real-time PCR and immunoblotting; macrophage and collagen accumulation was assessed by immunohistochemistry. KEY RESULTS: 1K/DOCA/salt-induced hypertension in mice was associated with increased renal mRNA expression of inflammasome subunits NLRP3, ASC and pro-caspase-1, and the cytokine, pro-IL-1ß, as well as protein levels of active caspase-1 and mature IL-1ß. Following treatment with 1K/DOCA/salt, ASC(-/-) mice displayed blunted pressor responses and were also protected from increases in renal expression of IL-6, IL-17A, CCL2, ICAM-1 and VCAM-1, and accumulation of macrophages and collagen. Finally, treatment with a novel inflammasome inhibitor, MCC950, reversed hypertension in 1K/DOCA/salt-treated mice. CONCLUSIONS AND IMPLICATIONS: Renal inflammation, fibrosis and elevated BP induced by 1K/DOCA/salt treatment are dependent on inflammasome activity, highlighting the inflammasome/IL-1ß pathway as a potential therapeutic target in hypertension.

Acute pressure-natriuresis relationship following withdrawal of chronic noradrenaline infusion.

1. Pathological changes to the kidney, such as vascular remodelling, have been found in several models of hypertension and may contribute to the maintenance of hypertension or confer susceptibility to redeveloping hypertension after the original prohypertensive stimulus is withdrawn. 2. To investigate whether noradrenaline-induced hypertension induces persistent, functionally important changes to the kidney, the acute pressure-natriuresis relationship was characterized in anaesthetized rats under controlled neural and hormonal conditions following chronic (14 days) intravenous infusion of noradrenaline (48 microg/kg per h) or vehicle (0.04 mg/mL ascorbic acid and 0.156 mg/mL NaH2PO4 2 H2O in 10 IU/mL heparinized saline). 3. Conscious mean arterial pressure was significantly elevated by infusion of noradrenaline at 48 microg/kg per h (+10 +/- 2 mmHg at Day 14; P < 0.01 vs vehicle group). The acute relationships between arterial pressure and renal blood flow, glomerular filtration rate, Na+ excretion and urine flow were not significantly different between the noradrenaline- and vehicle-infused rats immediately after termination of noradrenaline infusion. 4. In summary, chronic intravenous noradrenaline infusion did not cause persistent changes in renal function, indicating that, in contrast with many models of hypertension, this model does not induce underlying prohypertensive changes to the kidney.

Sex differences in postnatal growth and renal development in offspring of rabbit mothers with chronic secondary hypertension.

Previously, we demonstrated that adult blood pressure was increased in offspring of rabbit mothers with chronic secondary renal hypertension. Our study identified sex-specific differences in the programming of hypertension, with female, not male, offspring, having increased blood pressure at 30 wk of age. The aim of this study was to characterize the maternal hypertension during pregnancy to determine potential programming stimuli. Further, we examined the impact of chronic maternal hypertension on offspring birth weight, nephron number, and renal noradrenaline content (as an index of renal innervation density). Three groups of mothers and their offspring were studied: two-kidney, one-wrap (2K-1W, n = 9 mothers) hypertensive, two-kidney, two-wrap (2K-2W, n = 8) hypertensive, and a sham-operated group (n = 9). Mean arterial blood pressure was increased by approximately 20 mmHg throughout pregnancy in both hypertensive groups compared with sham mothers (P(G) < 0.001). Plasma renin activity (PRA; P(G) < 0.05) and aldosterone (P(G) < 0.05) levels were increased during gestation in the 2K-1W, but not the 2K-2W mothers. Birth weight was increased by approximately 20% in offspring of both groups of hypertensive mothers (P(T) < 0.001), though this was associated with a reduction in litter size. Renal noradrenaline content was increased ( approximately 40%, P < 0.05) at 5 wk of age in female 2K-1W offspring compared with sham offspring. Glomerular number was not reduced in female offspring of either group of hypertensive mothers; however, glomerular tuft volume was reduced in female 2K-2W offspring (P < 0.05), indicative of a reduction in glomerular filtration surface area. In conclusion, the two models of renal hypertension produced differential effects on the offspring. The impact of a stimulated maternal renin-angiotensin system in the 2K-1W model of hypertension may influence development of the renal sympathetic nerves and contribute to programming of adult hypertension.

Renal vascular resistance properties and glomerular protection in early established SHR hypertension.

OBJECTIVE: To characterize the in vivo vascular properties of the spontaneously hypertensive rat (SHR) renal vascular bed by examining vascular conductance/resistance responsiveness to vasoactive agents in vivo and determining whether the filtration surface area of glomerular capillaries is reduced. DESIGN AND METHODS: in vivo renal blood flow responses to intrarenally administered angiotensin II, phenylephrine and acetylcholine were compared in 10-week-old SHR and Wistar-Kyoto (WKY) rats using a wide range of doses from near threshold to near maximal effect. Unbiased stereological techniques and high-resolution light microscopy were used to estimate the surface area and length of glomerular capillaries, and evidence of capillary damage. RESULTS: The SHR renal bed demonstrated significantly enhanced dose-vascular resistance responses to vasoconstrictors. For vascular conductance and calculated radius of resistance vessels, the SHR curves were significantly lower across the full dilator-constrictor range examined, but the dose-related changes were similar to those of WKY rats. There were only modest enhancements of the renal blood flow responses in the SHR, evident only when renal blood flow was reduced by more than 50% SHR and WKY rats did not differ in mean glomerular capillary surface area (0.13+/-0.02 mm2 and 0.14+/-0.02 mm2, respectively) or length (5.76+/-0.85 mm and 5.48+/-0.90 mm, respectively) nor was there evidence of glomerular capillary damage in either strain. CONCLUSIONS: The renal vascular bed of the SHR in vivo exhibits reduced vascular conductance across a wide vasomotor range, compatible with findings in other vascular beds. We have further shown no evidence of reduced glomerular capillary surface area or damage. These findings are compatible with the hypothesis that the reduced conductance of the SHR pre-glomerular vasculature increases the aorta-capillary pressure gradient thus protecting the glomerular capillaries from systemic hypertension at this age.

Renomedullary interstitial cell lipid droplet content is increased in spontaneously hypertensive rats and by low salt diet.

OBJECTIVE: To compare the volumes of renomedullary interstitial cell (RMIC) lipid droplets (putative source of vasodepressor substance) in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats on high and low salt diets as an indication of whether the renomedullary vasodepressor system of the SHR is defective. METHODS: Ten-week-old male SHR and WKY rats received a low (0.05% w/w) or high salt (5.0%) diet for 21 days. Conscious mean arterial pressure (MAP) was measured and the renal papilla perfusion fixed with a high osmolarity fixative. Using electron microscopic stereological techniques, the volume density of lipid in RMIC (VVLipid,RMIC) and the total volumes of lipid (VLipid) and RMIC (VRMIC) in papilla were measured. RESULTS: MAP of SHR (high 155 +/- 3 mmHg; low 151 +/- 3 mmHg) was significantly greater than WKY rats (high 126 +/- 2 mmHg; low 129 +/- 2 mmHg; P< 0.001), however salt diet had no significant effect on MAP. The VLipid of rats on the low salt diet was approximately 2.5 times greater than in rats on the high salt diet (P < 0.01). SHR had significantly greater VLipid than WKY rats irrespective of salt diet (P< 0.05; SHR-low 0.245 +/- 0.031 mm3, SHR-high 0.093 +/- 0.007 mm3; WKY-low 0.126 +/- 0.032 mm3, WKY-high 0.051 +/- 0.020 mm3). Similar differences were seen for VVLipid,RMIC, however VRMIC was not different between rat strains or salt diet groups. CONCLUSIONS: SHR and WKY rats responded similarly to the altered salt diets, and SHR demonstrated greater volumes of stored RMIC lipid droplets irrespective of the level of salt intake. These results indicate that SHR hypertension is not due to a deficiency in the amount of lipid droplets, the putative source of the renomedullary vasodepressor substance and that the renomedullary vasodepressor system of the SHR is capable of responding normally to the physiological stimulus of altered salt intake.

Angiotensin II infused intrarenally causes preglomerular vascular changes and hypertension.

The effects on the renal vasculature and on arterial blood pressure of chronic infusion of low doses of angiotensin II (Ang II) into the renal artery were studied. Sprague Dawley rats were infused continuously with Ang II (0.5, 1.5, or 4.5 ng. kg(-1). min(-1)) or vehicle into the right renal artery (contralateral nephrectomy). Intrarenal Ang II infusion for 25 days produced dose-dependent rises (P:<0.001) in awake mean arterial pressure (111+/-1, 119+/-5, and 130+/-3 mm Hg in rats receiving 0.5, 1.5, and 4.5 ng. kg(-1). min(-1) Ang II, respectively) compared with 105+/-1 mm Hg (vehicle). Renal vessel lumen characteristics were assessed with an established, maximally dilated, isosmotic perfused kidney preparation. This revealed a small dose-dependent right shift in the pressure-flow relation (P=0.05), as well as a dose-dependent right shift and a dose-dependent reduction in the slope of the pressure-glomerular filtration rate relation (P=0.04 and 0.03, respectively). The effects of Ang II infusion on arterial pressure were not affected by the timing of the contralateral nephrectomy but were reduced when the contralateral kidney remained in situ. Acute losartan administration (10 mg/kg IV bolus) produced similar effects on arterial pressure in rats infused with vehicle or Ang II (4.5 ng. kg(-1). min(-1)) for 14 days, P=0.89), indicating the lack of systemic spillover of Ang II. Intraperitoneal Ang II (0.5, 1.5, or 4.5 ng. kg(-1). min(-1) for 25 days) had no effect on arterial pressure. Thus, chronic intrarenal infusion of low doses of Ang II resulted in changes in the renal vasculature compatible with dose-related structural reductions in the lumen diameter of preglomerular vessels and produced dose-related increases in arterial pressure.

Renovascular hypertension: structural changes in the renal vasculature.

Experimental narrowing of the main renal artery to produce hypertension increases the aorta-glomerular capillary pressure difference and vascular resistance. This article examines the hypothesis that hypertension also may be caused by structural changes that narrow intrarenal blood vessels, similarly increasing preglomerular vascular resistance and the aortic-glomerular capillary pressure gradient. There is evidence of both wall hypertrophy and lumen narrowing of the preglomerular arteries in spontaneously hypertensive rats, with increased preglomerular resistance and aortic-glomerular capillary pressure difference. We have also attempted to induce structural changes in renal-preglomerular vessels experimentally by infusing angiotensin II at low doses (0.5 to 4.5 ng/kg per minute) into the renal artery of Sprague-Dawley rats and greyhound dogs for up to 4 weeks. This angiotensin II infusion produced apparent dose-related effects on preglomerular vessel structure and hypertension. The possibility that hypertension may be induced by structural changes in preglomerular resistance vessel walls, by simulation of the hemodynamic effects of main renal artery stenosis, deserves further investigation.

Perindopril treatment affects both preglomerular renal vascular lumen dimensions and in vivo responsiveness to vasoconstrictors in spontaneously hypertensive rats.

We have previously shown that chronic treatment with angiotensin-converting enzyme inhibition (ACEI) did not reverse hypertrophy of the renal arterial wall in spontaneously hypertensive rats (SHR). In this study we determined the effects of perindopril on the functional properties of the renal vasculature in vivo and on its resistance to flow at maximal dilatation in vitro, a measure of vessel lumen diameter. Two groups of SHR were studied: untreated or treated with perindopril (3 mg/kg per day) in their drinking water from 4 weeks of age. At 10 weeks, (1) vessel lumen characteristics were assessed using a maximally dilated in vitro isolated kidney perfusion and (2) the renal vasoconstrictor responses to bolus doses of vasoactive agents (angiotensin II and phenylephrine) administered into the renal artery were measured in vivo (anesthetized rats). Mean arterial pressure was significantly lower in conscious SHR treated with perindopril (132+/-2 versus 97+/-2 mm Hg, P<.001). In vitro, the pressure-flow relationship and the pressure-glomerular filtration rate relationship were both shifted significantly to the left (P<.001). The perindopril-treated kidneys began filtering at a significantly lower threshold perfusion pressure than nontreated controls (P<.001). In vivo, renal vasoconstrictor responses to increasing doses of both vasoconstrictor agents were significantly less marked in the perindopril-treated SHR than in untreated SHR (P<.05). Thus, chronic ACEI increased average renal vessel lumen diameter in SHR, predominantly in preglomerular vessels, and reduced renal vasoconstrictor responsiveness in vivo, findings compatible with remodeling of the preglomerular vasculature around a greater lumen.

Angiotensin II antagonism and pre-glomerular arterial wall dimensions in the kidney of the spontaneously hypertensive rat.

The effects of the angiotensin II type 1 receptor antagonist TCV-116 on the wall dimensions of the interlobular and arcuate arteries have been studied. SHR rats were treated with TCV-116 between 4 and 10 weeks, at which time their kidneys were perfusion-fixed and examined using stereological techniques. TCV-116 reduced arterial pressure and left ventricle/body weight ratio, but did not reduce renal arterial wall dimensions. For both arcuate and interlobular arteries, wall density/kidney ratio was significantly greater in the TCV-116 treated SHR than in untreated SHR and wall:lumen ratio was also significantly greater for the interlobular arteries in the TCV-116 treated rats. These findings are similar to those obtained previously using enalapril, and indicate that hypertrophy of the walls of these intra-renal arteries is not secondary to the elevated arterial pressure, unlike in other vascular beds.

Structural changes in the renal vasculature in the spontaneously hypertensive rat: no effect of angiotensin II blockade.

1. There is strong evidence for a renal basis to the development of hypertension in the spontaneously hypertensive rat (SHR). Alterations of the SHR renal vasculature, including the glomerulus, may be involved in the initiation and maintenance of hypertension in this animal model. 2. The arterial walls of pre-glomerular vessels of the SHR are hypertrophied compared with WKY vessels. Unlike other vascular beds in the SHR, this hypertrophy is independent of angiotensin II (AngII). 3. Glomerular number and volume are similar between SHR and the normotensive Wistar-Kyoto (WKY) rats. These results provide no support for the theory that a reduced filtration surface area within the kidneys of the SHR contributes to the elevated blood pressure in these animals. 4. Intrarenal hypertrophy may have similar haemodynamic consequences to clipping of the main renal artery, as in Goldblatt hypertension. Further analysis of the role of pre-glomerular arterial hypertrophy is warranted to determine its involvement in the initiation and maintenance of hypertension in the SHR.

Glomerular dimensions in spontaneously hypertensive rats: effects of AT1 antagonism.

OBJECTIVE: A reduction in glomerular number and/or size has been implicated in the development of hypertension. This study investigated whether differences in glomerular number and/or size occur during the development of hypertension in the spontaneously hypertensive rat (SHR) and whether angiotensin II is responsible for any glomerular differences. METHODS: SHR (n=6) and Wistar-Kyoto (WKY) rats (n=6) were administered the angiotensin II type I receptor antagonist TCV-116 from 4 to 10 weeks of age. At 10 weeks of age, the kidneys from these rats and those from untreated SHR (n=6) and WKY rats (n=6) controls were perfusion fixed at physiological pressures and analysed using unbiased stereological techniques. RESULTS: There were no significant differences in glomerular number, glomerular volume or total glomerular volume between SHR and WKY rats. Treatment of SHR with TCV-116 significantly lowered systolic blood pressure but had no significant effect on glomerular number or volume or total glomerular volume. Treatment of WKY rats with TCV-116 reduced systolic blood pressure, body weight, glomerular volume and total glomerular volume; however, total glomerular volume per body weight of treated WKY rats was not significantly different from that of untreated WKY rats. CONCLUSION: There were no differences in glomerular number or volume in SHR compared with WKY rats at 10 weeks of age. We therefore conclude that glomerular changes are not responsible for the development of hypertension in SHR. Angiotensin II, via the type 1 receptor, does not contribute to glomerular growth during the development of hypertension in the SHR.

Structural changes in the renal vasculature in the spontaneously hypertensive rat: no effect of angiotensin II blockade.

1. There is strong evidence for a renal basis to the development of hypertension in the spontaneously hypertensive rat (SHR). Alterations of the SHR renal vasculature, including the glomerulus, may be involved in the initiation and maintenance of hypertension in this animal model. 2. The arterial walls of pre-glomerular vessels of the SHR are hypertrophied compared with WKY vessels. Unlike other vascular beds in the SHR, this hypertrophy is independent of angiotensin II (AngII). 3. Glomerular number and volume are similar between SHR and the normotensive Wistar-Kyoto (WKY) rats. These results provide no support for the theory that a reduced filtration surface area within the kidneys of the SHR contributes to the elevated blood pressure in these animals. 4. Intrarenal hypertrophy may have similar haemodynamic consequences to clipping of the main renal artery, as in Goldblatt hypertension. Further analysis of the role of pre-glomerular arterial hypertrophy is warranted to determine its involvement in the initiation and maintenance of hypertension in the SHR.

Enalapril does not prevent renal arterial hypertrophy in spontaneously hypertensive rats.

Angiotensin-converting enzyme inhibitors prevent the development of vessel wall hypertrophy in some vascular beds in spontaneously hypertensive rats (SHR), but their effects on hypertrophy of renal arterial vessels have not been studied. We therefore used stereological techniques to study wall and lumen dimensions of the interlobular (cortical radial) and arcuate arteries in the kidneys of SHR (n = 7), SHR treated from 4 to 10 weeks of age with enalapril (25 to 30 mg/kg per day; SHR-E, n = 7), and Wistar-Kyoto rats (WKY, n = 7). All kidneys were perfusion-fixed at 10 weeks. Systolic blood pressure was 199 +/- 9, 139 +/- 11, and 156 +/- 8 mm Hg in the SHR, SHR-E, and WKY groups, respectively. For the interlobular arteries, the volume density of artery wall, wall-to-lumen ratio, and wall thickness in the untreated SHR were significantly greater than in the WKY (0.84 +/- 0.09 versus 0.69 +/- 0.07 x 10(-3), 0.75 +/- 0.20 versus 0.53 +/- 0.08, and 13.6 +/- 3.3 versus 10.6 +/- 0.8 microns, respectively), but values in the SHR-E were similar to those in the untreated SHR (1.10 +/- 0.20 x 10(-3), 0.88 +/- 0.22, and 14.0 +/- 2.6 microns, respectively). For the arcuate arteries, wall thickness and volume density were significantly greater in SHR than WKY (17.3 +/- 3.0 versus 13.9 +/- 1.7 microns and 1.63 +/- 0.51 versus 1.14 +/- 0.27 x 10(-3), respectively), and values in the SHR-E (15.7 +/- 1.7 microns and 1.69 +/- 0.50 x 10(-3), respectively) were not significantly different from those in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Pre-glomerular structural changes in the renal vasculature in hypertension.

This paper reviews the evidence for the occurrence of hypertrophy of the renal arterial vessels in experimental and human hypertension. In spontaneously hypertensive rats (SHR), the walls of the interlobar, arcuate and interlobular arteries appear to be hypertrophied in both the "pre-hypertensive phase" and in established hypertension. The lumen diameter of the afferent arteriole in SHR is reduced, but this is probably not due to wall hypertrophy. The renal arterial hypertrophy is not reversed by chronic angiotensin converting enzyme inhibition in SHR, in contrast to findings in other vascular beds. Renal arterial hypertrophy also occurs in other forms of hypertension including in the kidney contralateral to a renal artery stenosis, and in hypertension following sino-aortic denervation. Whilst it is not possible to document changes in wall dimensions of intrarenal arteries during the development of human hypertension, renal haemodynamic abnormalities currently attributed to renal vasoconstriction in early human hypertension are also compatible with renal arterial hypertrophy. These abnormalities include increased resting renal vascular resistance and augmented renal vascular resistance responses to vasoconstrictor agents. It is argued that hypertrophy of renal vasculature to increase pre-glomerular resistance will have dual effects: it will increase total peripheral resistance (the kidneys account for about 20% of total peripheral resistance), and it will effect renal haemodynamics distally in a manner similar to narrowing of the main renal artery. It remains to be shown experimentally whether renal arterial hypertrophy could be the primary cause of some forms of hypertension.