Subtle Renal Injury Is Likely a Common Mechanism for Salt-Sensitive Essential Hypertension

Johnson, Richard J.; Rodríguez‐Iturbe, Bernardo; Nakagawa, Takahiko; Kang, Duk Hee; Feig, Daniel I.; Herrera-Acosta, Jaime

doi:10.1161/01.hyp.0000154784.14018.5f

Cited by 87 publications

(65 citation statements)

References 64 publications

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“…This has raised the possibility that the primary defect in the disease may, in most individuals, be a result of subtle renal injury rather than a genetic polymorphism (55). Indeed, many linkage studies have been unrewarding (5).…”

Section: Genetics and Hypertensionmentioning

confidence: 99%

How does salt retention raise blood pressure?

Blaustein¹,

Zhang²,

Ling³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

129

121

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A critical question in hypertension research is: How is long-term blood pressure controlled? Excessive NaCl ingestion or NaCl retention by the kidneys and the consequent tendency toward plasma volume expansion lead to hypertension. Nevertheless, the precise mechanisms linking salt to high blood pressure are unresolved. The discovery of endogenous ouabain, an adrenocortical hormone, provided an important clue. Ouabain, a selective Na ϩ pump inhibitor, has cardiotonic and vasotonic effects. Plasma endogenous ouabain levels are significantly elevated in Ϸ40% of patients with essential hypertension and in animals with several forms of salt-dependent hypertension. Also, prolonged ouabain administration induces hypertension in rodents. Mice with mutant Na ϩ pumps or Na/Ca exchangers (NCX) and studies with a ouabain antagonist and an NCX blocker are revealing the missing molecular mechanisms. These data demonstrate that ␣ 2 Na ϩ pumps and NCX1 participate in long-term regulation of vascular tone and blood pressure. Pharmacological agents or mutations in the ␣ 2 Na ϩ pump that interfere with the action of ouabain on the pump, and reduced NCX1 expression or agents that block NCX all impede the development of salt-dependent or ouabain-induced hypertension. Conversely, nanomolar ouabain, reduced ␣ 2 Na ϩ pump expression, and smooth muscle-specific overexpression of NCX1 all induce hypertension. Furthermore, ouabain and reduced ␣ 2 Na ϩ pump expression increase myogenic tone in isolated mesenteric small arteries in vitro, thereby tying these effects directly to the elevation of blood pressure. Thus, endogenous ouabain, and vascular ␣ 2 Na ϩ pumps and NCX1, are critical links between salt and hypertension. New pharmacological agents that act on these molecular links have potential in the clinical management of hypertension.ouabain; Na ϩ pump; Na/Ca exchanger; Ca 2ϩ ; myogenic tone HYPERTENSION, DEFINED AS A diastolic blood pressure (BP) Ն 90 mmHg and/or systolic BP Ն 140 mmHg, is endemic in Westernized societies. This is a very important public health issue because hypertension is a major risk factor for premature death and disability from heart attack, heart failure, stroke, and many other afflictions (16,59). In the United States, alone, Ϸ20% of the population (i.e., Ϸ50 million individuals) are hypertensive; moreover, more than half of all individuals over the age of 60 years have hypertension. In a small fraction of cases, the hypertension is due to specific causes, such as renal vascular disease or excessive secretion of aldosterone (primary aldosteronism) or catecholamines (pheochromocytoma). The vast majority (Ϸ90%) of patients, however, have elevated BP of unknown cause; hence the terms, primary or essential hypertension. The immediate cause for the elevated BP in nearly all chronic hypertensive persons is excessive narrowing of the small (resistance) arteries. Nevertheless, a key question in any discussion of hypertension is: What specific mechanisms actually lead to the abnormal arterial constriction and elevation ...

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Section: Genetics and Hypertensionmentioning

confidence: 99%

How does salt retention raise blood pressure?

Blaustein¹,

Zhang²,

Ling³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

129

121

View full text Add to dashboard Cite

show abstract

“…HYPERTENSION IS THE MOST COMMON chronic disorders worldwide and secondary forms of hypertension are found in 5-10% of the hypertensive population, of which most can be linked to renal disease (24). In humans, as well as in experimental models of salt-sensitive hypertension, there is a growing body of evidence pointing at a close relationship between nitric oxide (NO) deficiency and development of hypertension (37).…”

mentioning

confidence: 99%

Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals

Carlström¹,

Brown²,

Edlund³

et al. 2008

American Journal of Physiology-Renal Physiology

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Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals. Am J Physiol Renal Physiol 294: F362-F370, 2008. First published November 21, 2007 doi:10.1152/ajprenal.00410.2007.-Hydronephrotic animals develop renal injury and hypertension, which is associated with an abnormal tubuloglomerular feedback (TGF). The TGF sensitivity is coupled to nitric oxide (NO) in the macula densa. The involvement of reduced NO availability in the development of hypertension in hydronephrosis was investigated. Hydronephrosis was induced by ureteral obstruction in young rats. Blood pressure and renal excretion were measured in adulthood, under different sodium conditions, and before and after chronic administration of either N G -nitro-L-arginine methyl ester (L-NAME) or L-arginine. Blood samples for ADMA, SDMA, and L-arginine analysis were taken and the renal tissue was used for histology and determination of NO synthase (NOS) proteins. TGF characteristics were determined by stop-flow pressure technique before and after administration of 7-nitroindazole (7-NI) or L-arginine. Hydronephrotic animals developed salt-sensitive hypertension, which was associated with pressure natriuresis and diuresis. The blood pressure response to L-NAME was attenuated and L-arginine supplementation decreased blood pressure in hydronephrotic animals, but not in the controls. Under control conditions, reactivity and sensitivity of the TGF response were greater in the hydronephrotic group. 7-NI administration increased TGF reactivity and sensitivity in control animals, whereas, in hydronephrotic animals, neuronal NOS (nNOS) inhibition had no effect. L-Arginine attenuated TGF response more in hydronephrotic kidneys than in controls. The hydronephrotic animals displayed various degrees of histopathological changes. ADMA and SDMA levels were higher and the renal expressions of nNOS and endothelial NOS proteins were lower in animals with hydronephrosis. Reduced NO availability in the diseased kidney in hydronephrosis, and subsequent resetting of the TGF mechanism, plays an important role in the development of hypertension.ADMA; tubuloglomerular feedback; L-arginine; L-NAME; telemetry; blood pressure HYPERTENSION IS THE MOST COMMON chronic disorders worldwide and secondary forms of hypertension are found in 5-10% of the hypertensive population, of which most can be linked to renal disease (24). In humans, as well as in experimental models of salt-sensitive hypertension, there is a growing body of evidence pointing at a close relationship between nitric oxide (NO) deficiency and development of hypertension (37).Hydronephrosis due to obstruction at the level of the pelvicureteric junction is a common condition in children, with an incidence in newborns of ϳ1%. The obstruction is mostly partial and congenital of origin. Unilateral hydronephrosis causes salt-sensitive hypertension in both rats (5) and mice (7).The renal function in hydronephrotic animals, measured as renal blood flow and glomerular filtration rate (GFR), is rather...

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“…It must explain how the kidney is the essential initiating organ as proposed by Guyton [4]. It must identify the unknown " Subtle renal injury" [5] as the fundamental fault which has genetic basis but can also be influenced by several environmental factors, and can be reproduced in several forms of secondary hypertension -including Goldblatt models and mineralocorticoid excess syndromes.…”

Section: Preamblementioning

confidence: 99%

A Single Initiating Cause of Hypertension; Potential for Primary Prevention

Sambhi¹

2014

J Hypertens

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Subtle Renal Injury Is Likely a Common Mechanism for Salt-Sensitive Essential Hypertension

Cited by 87 publications

References 64 publications

How does salt retention raise blood pressure?

How does salt retention raise blood pressure?

Role of nitric oxide deficiency in the development of hypertension in hydronephrotic animals

A Single Initiating Cause of Hypertension; Potential for Primary Prevention

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