Skip to main content
NCBI home page
American Journal of Physiology - Renal Physiology logoLink to American Journal of Physiology - Renal Physiology
. 2018 Feb 14;315(1):F1–F6. doi: 10.1152/ajprenal.00594.2017

Mechanisms of altered renal sodium handling in age-related hypertension

Alissa A Frame 1, Richard D Wainford 1,✉
PMCID: PMC6087788  PMID: 29442548

Abstract

The prevalence of hypertension rises with age to approximately two out of three adults over the age of 60 in the United States. Although the mechanisms underlying age-related hypertension are incompletely understood, sodium homeostasis is critical to the long-term regulation of blood pressure and there is strong evidence that aging is associated with alterations in renal sodium handling. This minireview focuses on recent advancements in our understanding of the vascular, neurohumoral, and renal mechanisms that influence sodium homeostasis and promote age-related hypertension.

Keywords: aging, hypertension, renal sodium handling

INTRODUCTION

Hypertension (HTN) is the leading risk factor for stroke, myocardial infarction, and chronic kidney disease and contributes to more than 10% of deaths worldwide (30, 39, 51a, 81). The prevalence of HTN, defined using the recently updated American Heart Association guidelines of greater than 130 mmHg systolic or 80 mmHg diastolic blood pressure (BP), increases from ~30% of United States adults aged 20–44 to more than 75% of adults above the age of 65, and the risk of HTN-related morbidity and mortality also increases with age (80). Despite a demonstrated clinical benefit of BP reduction on HTN-associated adverse outcomes (22, 61, 64), less than half of elderly patients with HTN currently achieve adequate BP control (15) based on the goal of less than 140 mmHg systolic and 90 mmHg diastolic recommended in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (11), and it is likely that control rates will be even lower under the more stringent AHA guidelines.

The mechanisms underlying age-related HTN have not been fully elucidated, but the importance of sodium homeostasis in the regulation of BP is well established and there is strong evidence that renal sodium handling is altered in aging animal models (3, 4) and elderly humans (19, 42). Furthermore, the salt sensitivity of BP, defined as an exaggerated pressor response to dietary sodium intake (78, 79), increases with age (41) and predicts the development of HTN and its associated adverse outcomes (1, 20, 44, 47, 78). This is especially relevant to the elderly global population given their lifelong exposure to an average daily sodium intake of ~4 g/day that far exceeds the recommendations of the American Heart Association (1.5 g/day) and World Health Organization (2 g/day) (1, 48, 54, 60).

Sodium homeostasis is regulated by several integrated physiological mechanisms, including the vascular, neurohumoral, and renal systems, which are altered in aging. These systems are modulated by other factors including oxidative stress (12, 13, 58), inflammation (2, 52), and genetics (35), which play important roles in age-related impairments in sodium homeostasis and BP regulation that are outside of the scope of this minireview. The focus of this minireview is to highlight recent developments in our understanding of the vascular, neurohumoral, and renal mechanisms influencing renal sodium handling and BP regulation that may ultimately contribute to the development of age-related HTN.

VASCULAR CHANGES IN AGE-RELATED HTN

Age-related alterations in the vascular system have been extensively reviewed elsewhere and include arterial stiffness and increased pulse pressure (66). One recent study suggested that aortic stiffness and increased central pulse pressure predict increased renal resistive index (assessed via Doppler ultrasonography of the renal arteries) and microalbuminuria (23), and another study indicated that renal resistive index correlates positively with age (32). Significantly, other studies have demonstrated that pressure natriuresis is blunted in aged mice (46) and rats (43), but the potential mechanistic link between vascular changes and altered renal sodium handling in age-related HTN is poorly defined. Importantly, in a study that confirmed the positive correlations among renal resistive index, age, and arterial stiffness, renal resistive index also correlated negatively with glomerular filtration rate (GFR) (8). Collectively, these studies raise the possibility that the transmission of central pulse pressure to the renal vasculature in aging results in functional kidney damage and reduced GFR and may thereby impair pressure natriuresis. Several studies have demonstrated that aged C57Bl/6 mice and Sprague-Dawley rats exhibit a loss of renal microvasculature, including peritubular and glomerular capillaries (29, 65, 69, 73), which is associated with increased renal resistive index (34) and increased BP (10) in humans and has been hypothesized to blunt pressure natriuresis (28). Furthermore, although the complex interactions among the vascular, neurohumoral, and renal mechanisms that may promote age-related HTN are outside of the scope of this review, the reduction in GFR associated with arterial stiffness and increased renal resistive index (8) could activate the renin-angiotensin-aldosterone system (RAAS) with potential subsequent effects on renal sodium handling described below.

NEUROHUMORAL ACTIVITY IN AGE-RELATED HTN

Renin-Angiotensin-Aldosterone System

The RAAS modulates fluid and sodium homeostasis, and the contribution of RAAS dysregulation to essential HTN is well established. RAAS activation increases BP via the effects of angiotensin II (ANG II), which promotes sympathetic nervous system (SNS) activity and systemic vasoconstriction and stimulates renal sodium reabsorption both directly and through the actions of aldosterone. While human aging is associated with a reduction in systemic RAAS activity (45, 53, 77), intrarenal RAAS sensitivity is enhanced in aging animal models (67, 70) and the recent studies summarized here indicate that this impairs renal sodium handling and contributes to age-related HTN. In C57Bl/6 mice, aging is associated with an enhanced pressor response to ANG II infusion mediated by exaggerated systemic vasoconstriction, decreased mesenteric artery ANG II type 2 receptor (AT2R) expression, and increased whole kidney ANG II type 1 receptor (AT1R) expression (14). Supporting the relevance of the age-related increase in renal AT1R expression in HTN, increased renal AT1R activity was associated with age-related HTN in F344/Brown Norway (FBN) rats (12, 13). Importantly, ANG II-evoked Na+-K+-ATPase activity, which generates the sodium gradient driving sodium reabsorption through apical transporters, is enhanced in renal proximal tubules isolated from aging FBN rats (13).

Extending these studies, the same group observed that age-related HTN in FBN rats is characterized by salt sensitivity of BP (58). Importantly, while aging was associated with an increase in renal cortical and medullary AT1R mRNA in FBN rats on a normal-salt diet, aged rats placed on a high-salt diet exhibited a further increase in medullary AT1R mRNA and Na+-K+-ATPase protein (58). These findings suggest that medullary AT1R may play a role in the salt-sensitive component of age-related HTN, perhaps in part via medullary sodium reabsorption driven by an enhanced sodium gradient generated by the Na+-K+-ATPase during high dietary salt intake. Although the role of oxidative stress in age-related HTN is beyond the scope of this review, it is important to note that oxidative stress had a causal role in AT1R activation in each of these studies (12, 13, 58). Furthermore, reduced activity of the dopamine D1 receptor, which mediates AT1R internalization (33), was also observed in aging FBN rats (12, 13, 58) and may promote age-related HTN via an increase in AT1R localized to the plasma membrane.

While these recent animal studies suggest that enhanced intrarenal ANG II signaling via AT1R promotes age-related HTN, previous human studies indicate that systemic RAAS components, including plasma renin activity and plasma aldosterone levels, decline with age (45, 50, 53, 77). Importantly, a recent study demonstrated that measures of aldosterone response to changes in dietary sodium intake are more relevant to cardiometabolic risk factors, including increased BP, than a single static aldosterone measurement (74). Confirming prior reports of an age-related impairment in aldosterone responses to sodium depletion and potassium infusion (50, 77), in a follow-up study human aging was associated with an inability to appropriately suppress or stimulate aldosterone in response to high or low dietary sodium intake, respectively (7).

Sympathetic Nervous System

Norepinephrine (NE) released by the SNS influences renal sodium handling indirectly through systemic vasoconstriction and promotes renal sodium reabsorption directly through renal vasoconstriction and subsequent reductions in GFR as well as activation of renal sodium transporters. Aging is associated with elevated SNS activity (16, 17), and a direct positive correlation between increased sympathetic tone and increased BP is present only in adults above the age of 40 (51). Despite this evidence, few studies to date have examined the role of renal sympathetic outflow in age-related HTN. While a study of organ-specific NE spillover suggested that renal sympathetic tone does not change with age (17), a recent publication indicated that an age-related increase in renal NE content is associated with elevated renal sodium reabsorption and HTN in both Wistar-Kyoto rats and spontaneously hypertensive rats (57). Furthermore, aging is characterized by inappropriate renal artery vasoconstriction in response to SNS stimuli, suggesting that renal sympathetic responsiveness may be enhanced in aging (37, 56). Although renal sodium excretion was not assessed, an exaggeration of renal sympathetic responsiveness could promote sodium retention and age-related HTN via renal artery vasoconstriction leading to a reduction in GFR or via direct activation of renal sodium transporters.

Importantly, studies in animal models of HTN and hypertensive patients suggest that removal of sympathetic outflow to the kidney via renal denervation has beneficial effects on BP (6, 18, 24, 25, 27, 31, 36, 38, 75). Although the Symplicity HTN-3 trial raised questions regarding the efficacy of renal denervation (5), clinical trials continue and a recent study demonstrated that the procedure is safe and reduces BP for at least 6 mo in elderly patients with resistant HTN (82). While the specific mechanisms by which renal denervation reduces BP in elderly patients have not been investigated, these may include reduced renal vascular resistance (55), reduced RAAS responsiveness (40), and enhanced renal sodium excretion (59), which have been observed following renal denervation in young animal models of HTN and hypertensive patients.

RENAL SODIUM TRANSPORT IN AGE-RELATED HTN

Proximal Tubule Sodium Transport

The sodium hydrogen exchanger and various organic ion cotransporters in the proximal tubule reabsorb ~65–70% of filtered sodium. A recent ex vivo study demonstrated that the activity of the basolateral Na+-K+-ATPase, which creates the gradient driving apical sodium reabsorption, is increased in proximal convoluted tubule and proximal straight tubule segments isolated from aged Sabra rats (63). Similarly, ANG II-evoked Na+-K+-ATPase activity is enhanced in renal proximal tubules isolated from aging FBN rats (13), which develop age-related HTN.

Loop of Henle

The sodium potassium chloride cotransporter (NKCC2) in the thick ascending limb of the loop of Henle reabsorbs ~25% of filtered sodium. A recent study demonstrated that aged FBN rats exhibit decreased basal NKCC2 protein expression and fail to increase NKCC2 expression in response to water restriction (71). These findings are consistent with the observation that basolateral Na+-K+-ATPase activity is reduced in the medullary thick ascending limb of aged Sabra rats (63). Although further studies investigating NKCC2 activity are required, these reports suggest that aging may be associated with a decline in NKCC2 activity and responsiveness that could have contributed to a delayed natriuretic response to furosemide observed previously in a small group of elderly patients (9).

Distal Convoluted Tubule

The sodium chloride cotransporter (NCC) in the distal convoluted tubule reabsorbs ~5% of filtered sodium. Recent studies have provided conflicting evidence regarding age-related changes in the NCC. In FBN rats, which develop age-related HTN (12, 13, 58), aging was associated with an increase in basal NCC expression and a failure to increase NCC expression in response to water restriction (71). In contrast, diminished Na+-K+-ATPase activity was observed in distal convoluted tubule segments isolated from aged Sabra rats (63), suggesting that the driving force for sodium reabsorption through the NCC is reduced. Furthermore, aging in C57Bl6/CBA/129 mice was associated with decreased basal activity of the NCC (72). However, aging was associated with larger ANG II-evoked increases in NCC activity and expression that correlated with larger increases in BP (72), indicating an age-related impairment in NCC responsiveness that could ultimately promote sodium retention and increase BP despite reduced basal activity.

Further studies are required to clarify these conflicting reports and to delineate the changes in NCC expression and activity that could potentially influence the development of age-related HTN. Given the increase in both salt sensitivity of BP (41) and sympathetic tone (16, 17) with age, a potential role for the NCC in age-related HTN is supported by recent evidence delineating a causal role of NE-evoked NCC activity in salt sensitive HTN, albeit in young mouse and rat models (49, 68, 76). Additionally, in a study of hypertensive patients aged 25–65 yr, increased age was correlated with improved therapeutic BP response to thiazide diuretics targeting the NCC (26). Although these findings must be interpreted cautiously, particularly given identical dosing regimens across ages despite known age-related differences in thiazide pharmacokinetics (62), it is possible that the enhanced response to thiazide diuretics reflects an age-related increase in NCC-mediated sodium reabsorption.

Collecting Duct

The epithelial sodium channel (ENaC) in the collecting duct reabsorbs ~2% of filtered sodium. Two recent studies reported decreases in basal ENaC activity in C57Bl6/CBA/129 mice (72) and basal ENaC expression in aged FBN rats (71). Furthermore, aged FBN rats fail to increase ENaC expression in response to water restriction (71). Interestingly, aging was associated with increased cortical collecting duct Na+-K+-ATPase activity in Sabra rats (63).

SUMMARY

Aging is associated with alterations in the vascular, neurohumoral, and renal sodium transport systems that influence renal sodium handling and BP. The studies highlighted in this minireview provide conflicting evidence regarding the specific impact of aging on these systems, but in all cases there is strong evidence of dysregulation and a role in altered renal sodium handling and age-related HTN (Table 1). Importantly, none of these changes occurs in isolation. The complex interactions between systemic and renal hemodynamics and the SNS and RAAS in aging are outside of the scope of this review but ultimately influence renal sodium reabsorption and BP in an integrated manner. Other factors, including oxidative stress (12, 13, 58), inflammation (2, 52), and genetics (35), also influence sodium homeostasis and play a part in age-related HTN. Each of these integrated mechanisms influencing renal sodium handling and BP in aging represents a potential therapeutic target for the treatment of age-related HTN.

Table 1.

Summary of the age-related alterations in the vascular, neurohumoral, and renal sodium transport systems that may contribute to impaired renal sodium handling and age-related hypertension

System Age-Related Change Species Reference(s)
Vascular
    Systemic Arterial stiffness Human 8, 66
↑Pulse pressure 66
    Renal ↑Renal resistive index 8, 32
Loss of peritubular and glomerular capillaries C57Bl/6 mice and SD rats 29, 65, 69, 73
Neurohumoral
    RAAS ↑Pressor response to ANG II C57Bl/6 mice 14
↓Vascular (mesenteric artery) AT2R mRNA expression
↑Whole kidney AT1R mRNA expression
↑Renal AT1R activity FBN rats 12, 13
↑Renal proximal tubule ANG II-evoked Na+-K+-ATPase activity 13
↑Renal cortical and medullary AT1R mRNA expression 58
↑Dietary sodium-evoked increase in medullary AT1R mRNA expression 58
↑Dietary sodium-evoked increase in medullary Na+-K+-ATPase protein expression 58
↓D1R activity 12, 13, 58
    SNS ↓Aldosterone responsiveness Human 7, 50, 77
↑Renal NE content WKY and SHR rats 57
↑Renal artery vasoconstrictor response to SNS stimuli Human 37, 56
Renal sodium transport
    Proximal tubule ↑ Na+-K+-ATPase activity Sabra rats 63
↑ANG II-evoked Na+-K+-ATPase activity FBN rats 13
    Loop of Henle ↓Basal NKCC2 protein expression FBN 71
↓Water restriction-evoked increase in NKCC2 protein
↓Medullary thick ascending limb Na+-K+-ATPase activity Sabra rats 63
Delayed response to furosemide Human 9
    Distal convoluted tubule ↑Basal NCC protein expression FBN rats 71
↓Water restriction-evoked increase in NCC protein
↓Distal convoluted tubule Na+-K+-ATPase activity Sabra rats 63
↓Basal NCC activity C57Bl6/CBA/129 mice 72
↑ANG II-evoked increase in NCC activity
↑Depressor response to hydrochlorothiazide Human 26
    Collecting duct ↓Basal ENaC activity C57Bl6/CBA/129 mice 72
↓Basal ENaC protein expression FBN rats 71
↓Water restriction-evoked increase in ENaC protein
↑Cortical collecting duct Na+-K+-ATPase activity Sabra rats 63
Open in a new tab

ANG II, angiotensin II; AT2R, angiotensin II type 2 receptor; AT1R, angiotensin II type 1 receptor; D1R, dopamine D1 receptor; NE, norepinephrine; NKCC2, sodium potassium chloride cotransporter; NCC, sodium chloride cotransporter; ENaC, epithelial sodium channel; SD, Sprague Dawley; FBN, F344/Brown Norway; WKY, Wister-Kyoto; SHR, spontaneously hypertensive rats; SNS, sympathetic nervous system; RAAS, renin-angiotensin-aldosterone system.

GRANTS

This work was supported by National Heart, Lung, and Blood Institute Grants R01-HL-107330 and K02-HL-112718 and American Heart Association Grants 16MM32090001 and 17GRNT3367002 (to R. D. Wainford) and National Institute of Diabetes and Digestive and Kidney Diseases Grant F31-DK-116501 (to A. A. Frame).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

A.A.F. drafted manuscript; A.A.F. and R.D.W. edited and revised manuscript; R.D.W. approved final version of manuscript.

REFERENCES

  • 1.Appel LJ, Frohlich ED, Hall JE, Pearson TA, Sacco RL, Seals DR, Sacks FM, Smith SC Jr, Vafiadis DK, Van Horn LV. The importance of population-wide sodium reduction as a means to prevent cardiovascular disease and stroke: a call to action from the American Heart Association. Circulation 123: 1138–1143, 2011. doi: 10.1161/CIR.0b013e31820d0793. [DOI] [PubMed] [Google Scholar]
  • 2.Barbieri M, Ferrucci L, Corsi AM, Macchi C, Lauretani F, Bonafè M, Olivieri F, Giovagnetti S, Franceschi C, Paolisso G. Is chronic inflammation a determinant of blood pressure in the elderly? Am J Hypertens 16: 537–543, 2003. doi: 10.1016/S0895-7061(03)00861-6. [DOI] [PubMed] [Google Scholar]
  • 3.Bengele HH, Mathias RS, Alexander EA. Impaired natriuresis after volume expansion in the aged rat. Ren Physiol 4: 22–29, 1981. [DOI] [PubMed] [Google Scholar]
  • 4.Bengele HH, Mathias RS, Perkins JH, Alexander EA. Urinary concentrating defect in the aged rat. Am J Physiol Renal Fluid Electrolyte Physiol 240: F147–F150, 1981. [DOI] [PubMed] [Google Scholar]
  • 5.Bhatt DL, Kandzari DE, O’Neill WW, D’Agostino R, Flack JM, Katzen BT, Leon MB, Liu M, Mauri L, Negoita M, Cohen SA, Oparil S, Rocha-Singh K, Townsend RR, Bakris GL; SYMPLICITY HTN-3 Investigators . A controlled trial of renal denervation for resistant hypertension. N Engl J Med 370: 1393–1401, 2014. doi: 10.1056/NEJMoa1402670. [DOI] [PubMed] [Google Scholar]
  • 6.Böhm M, Mahfoud F, Ukena C, Hoppe UC, Narkiewicz K, Negoita M, Ruilope L, Schlaich MP, Schmieder RE, Whitbourn R, Williams B, Zeymer U, Zirlik A, Mancia G; GSR Investigators . First report of the Global SYMPLICITY Registry on the effect of renal artery denervation in patients with uncontrolled hypertension. Hypertension 65: 766–774, 2015. doi: 10.1161/HYPERTENSIONAHA.114.05010. [DOI] [PubMed] [Google Scholar]
  • 7.Brown JM, Underwood PC, Ferri C, Hopkins PN, Williams GH, Adler GK, Vaidya A. Aldosterone dysregulation with aging predicts renal vascular function and cardiovascular risk. Hypertension 63: 1205–1211, 2014. doi: 10.1161/HYPERTENSIONAHA.114.03231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Calabia J, Torguet P, Garcia I, Martin N, Mate G, Marin A, Molina C, Valles M. The relationship between renal resistive index, arterial stiffness, and atherosclerotic burden: the link between macrocirculation and microcirculation. J Clin Hypertens (Greenwich) 16: 186–191, 2014. doi: 10.1111/jch.12248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Chaudhry AY, Bing RF, Castleden CM, Swales JD, Napier CJ. The effect of ageing on the response to frusemide in normal subjects. Eur J Clin Pharmacol 27: 303–306, 1984. doi: 10.1007/BF00542164. [DOI] [PubMed] [Google Scholar]
  • 10.Cheng C, Diamond JJ, Falkner B. Functional capillary rarefaction in mild blood pressure elevation. Clin Transl Sci 1: 75–79, 2008. doi: 10.1111/j.1752-8062.2008.00016.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee . The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 Report. JAMA 289: 2560–2572, 2003. doi: 10.1001/jama.289.19.2560. [DOI] [PubMed] [Google Scholar]
  • 12.Chugh G, Lokhandwala MF, Asghar M. Altered functioning of both renal dopamine D1 and angiotensin II type 1 receptors causes hypertension in old rats. Hypertension 59: 1029–1036, 2012. doi: 10.1161/HYPERTENSIONAHA.112.192302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Chugh G, Lokhandwala MF, Asghar M. Oxidative stress alters renal D1 and AT1 receptor functions and increases blood pressure in old rats. Am J Physiol Renal Physiol 300: F133–F138, 2011. doi: 10.1152/ajprenal.00465.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Dinh QN, Drummond GR, Kemp-Harper BK, Diep H, De Silva TM, Kim HA, Vinh A, Robertson AAB, Cooper MA, Mansell A, Chrissobolis S, Sobey CG. Pressor response to angiotensin II is enhanced in aged mice and associated with inflammation, vasoconstriction and oxidative stress. Aging (Albany NY) 9: 1595–1606, 2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 1988-2008. JAMA 303: 2043–2050, 2010. doi: 10.1001/jama.2010.650. [DOI] [PubMed] [Google Scholar]
  • 16.Esler M, Hastings J, Lambert G, Kaye D, Jennings G, Seals DR. The influence of aging on the human sympathetic nervous system and brain norepinephrine turnover. Am J Physiol Regul Integr Comp Physiol 282: R909–R916, 2002. doi: 10.1152/ajpregu.00335.2001. [DOI] [PubMed] [Google Scholar]
  • 17.Esler MD, Turner AG, Kaye DM, Thompson JM, Kingwell BA, Morris M, Lambert GW, Jennings GL, Cox HS, Seals DR. Aging effects on human sympathetic neuronal function. Am J Physiol Regul Integr Comp Physiol 268: R278–R285, 1995. doi: 10.1152/ajpregu.1995.268.1.R278. [DOI] [PubMed] [Google Scholar]
  • 18.Esler MD, Krum H, Schlaich M, Schmieder RE, Böhm M, Sobotka PA; Symplicity HTN-2 Investigators . Renal sympathetic denervation for treatment of drug-resistant hypertension: one-year results from the Symplicity HTN-2 randomized, controlled trial. Circulation 126: 2976–2982, 2012. doi: 10.1161/CIRCULATIONAHA.112.130880. [DOI] [PubMed] [Google Scholar]
  • 19.Fish LC, Murphy DJ, Elahi D, Minaker KL. Renal sodium excretion in normal aging: decreased excretion rates lead to delayed handling of sodium loads. Geriatr Nephrol Urol 4: 145–151, 1994. doi: 10.1007/BF01523974. [DOI] [Google Scholar]
  • 20.Franco V, Oparil S. Salt sensitivity, a determinant of blood pressure, cardiovascular disease and survival. J Am Coll Nutr 25, Suppl: 247S–255S, 2006. doi: 10.1080/07315724.2006.10719574. [DOI] [PubMed] [Google Scholar]
  • 22.Hardy ST, Loehr LR, Butler KR, Chakladar S, Chang PP, Folsom AR, Heiss G, MacLehose RF, Matsushita K, Avery CL. Reducing the blood pressure-related burden of cardiovascular disease: impact of achievable improvements in blood pressure prevention and control. J Am Heart Assoc 4: e002276, 2015. doi: 10.1161/JAHA.115.002276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Hashimoto J, Ito S. Central pulse pressure and aortic stiffness determine renal hemodynamics: pathophysiological implication for microalbuminuria in hypertension. Hypertension 58: 839–846, 2011. doi: 10.1161/HYPERTENSIONAHA.111.177469. [DOI] [PubMed] [Google Scholar]
  • 24.Henegar JR, Zhang Y, De Rama R, Hata C, Hall ME, Hall JE. Catheter-based radiorefrequency renal denervation lowers blood pressure in obese hypertensive dogs. Am J Hypertens 27: 1285–1292, 2014. doi: 10.1093/ajh/hpu048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Hering D, Marusic P, Walton AS, Lambert EA, Krum H, Narkiewicz K, Lambert GW, Esler MD, Schlaich MP. Sustained sympathetic and blood pressure reduction 1 year after renal denervation in patients with resistant hypertension. Hypertension 64: 118–124, 2014. doi: 10.1161/HYPERTENSIONAHA.113.03098. [DOI] [PubMed] [Google Scholar]
  • 26.Huang CC, Leu HB, Wu TC, Lin SJ, Chen JW. Clinical predictors of the response to short-term thiazide treatment in nondiabetic essential hypertensives. J Hum Hypertens 22: 329–337, 2008. doi: 10.1038/sj.jhh.1002330. [DOI] [PubMed] [Google Scholar]
  • 27.Intapad S, Tull FL, Brown AD, Dasinger JH, Ojeda NB, Fahling JM, Alexander BT. Renal denervation abolishes the age-dependent increase in blood pressure in female intrauterine growth-restricted rats at 12 months of age. Hypertension 61: 828–834, 2013. doi: 10.1161/HYPERTENSIONAHA.111.00645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Johnson RJ, Schreiner GF. Hypothesis: the role of acquired tubulointerstitial disease in the pathogenesis of salt-dependent hypertension. Kidney Int 52: 1169–1179, 1997. doi: 10.1038/ki.1997.442. [DOI] [PubMed] [Google Scholar]
  • 29.Kang DH, Anderson S, Kim YG, Mazzalli M, Suga S, Jefferson JA, Gordon KL, Oyama TT, Hughes J, Hugo C, Kerjaschki D, Schreiner GF, Johnson RJ. Impaired angiogenesis in the aging kidney: vascular endothelial growth factor and thrombospondin-1 in renal disease. Am J Kidney Dis 37: 601–611, 2001. doi: 10.1053/ajkd.2001.22087. [DOI] [PubMed] [Google Scholar]
  • 30.Kannel WB. Elevated systolic blood pressure as a cardiovascular risk factor. Am J Cardiol 85: 251–255, 2000. doi: 10.1016/S0002-9149(99)00635-9. [DOI] [PubMed] [Google Scholar]
  • 31.Kapusta DR, Pascale CL, Kuwabara JT, Wainford RD. Central nervous system Gαi2-subunit proteins maintain salt resistance via a renal nerve-dependent sympathoinhibitory pathway. Hypertension 61: 368–375, 2013. doi: 10.1161/HYPERTENSIONAHA.111.00014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Kawai T, Kamide K, Onishi M, Hongyo K, Yamamoto-Hanasaki H, Oguro R, Maekawa Y, Yamamoto K, Takeya Y, Sugimoto K, Ohishi M, Rakugi H. Relationship between renal hemodynamic status and aging in patients without diabetes evaluated by renal Doppler ultrasonography. Clin Exp Nephrol 16: 786–791, 2012. doi: 10.1007/s10157-012-0627-1. [DOI] [PubMed] [Google Scholar]
  • 33.Khan F, Spicarová Z, Zelenin S, Holtbäck U, Scott L, Aperia A. Negative reciprocity between angiotensin II type 1 and dopamine D1 receptors in rat renal proximal tubule cells. Am J Physiol Renal Physiol 295: F1110–F1116, 2008. doi: 10.1152/ajprenal.90336.2008. [DOI] [PubMed] [Google Scholar]
  • 34.Kimura N, Kimura H, Takahashi N, Hamada T, Maegawa H, Mori M, Imamura Y, Kusaka Y, Yoshida H, Iwano M. Renal resistive index correlates with peritubular capillary loss and arteriosclerosis in biopsy tissues from patients with chronic kidney disease. Clin Exp Nephrol 19: 1114–1119, 2015. doi: 10.1007/s10157-015-1116-0. [DOI] [PubMed] [Google Scholar]
  • 35.Krug AW, Tille E, Sun B, Pojoga L, Williams J, Chamarthi B, Lichtman AH, Hopkins PN, Adler GK, Williams GH. Lysine-specific demethylase-1 modifies the age effect on blood pressure sensitivity to dietary salt intake. Age (Dordr) 35: 1809–1820, 2013. doi: 10.1007/s11357-012-9480-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Krum H, Schlaich MP, Sobotka PA, Böhm M, Mahfoud F, Rocha-Singh K, Katholi R, Esler MD. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet 383: 622–629, 2014. [Erratum in Lancet 383: 602, 2014.] doi: 10.1016/S0140-6736(13)62192-3. [DOI] [PubMed] [Google Scholar]
  • 37.Kuipers NT, Sauder CL, Kearney ML, Ray CA. Interactive effect of aging and local muscle heating on renal vasoconstriction during isometric handgrip. Am J Physiol Renal Physiol 297: F327–F332, 2009. doi: 10.1152/ajprenal.00165.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Li D, Wang Q, Zhang Y, Li D, Yang D, Wei S, Su L, Ye T, Zheng X, Peng K, Zhang L, Zhang Y, Yang Y, Ma S. A novel swine model of spontaneous hypertension with sympathetic hyperactivity responds well to renal denervation. Am J Hypertens 29: 63–72, 2016. doi: 10.1093/ajh/hpv066. [DOI] [PubMed] [Google Scholar]
  • 39.Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell 104: 545–556, 2001. doi: 10.1016/S0092-8674(01)00241-0. [DOI] [PubMed] [Google Scholar]
  • 40.Lu J, Ling Z, Chen W, Du H, Xu Y, Fan J, Long Y, Chen S, Xiao P, Liu Z, Zrenner B, Yin Y. Effects of renal sympathetic denervation using saline-irrigated radiofrequency ablation catheter on the activity of the renin-angiotensin system and endothelin-1. J Renin Angiotensin Aldosterone Syst 15: 532–539, 2014. doi: 10.1177/1470320313506480. [DOI] [PubMed] [Google Scholar]
  • 41.Luft FC, Miller JZ, Grim CE, Fineberg NS, Christian JC, Daugherty SA, Weinberger MH. Salt sensitivity and resistance of blood pressure. Age and race as factors in physiological responses. Hypertension 17, Suppl: I102–I108, 1991. doi: 10.1161/01.HYP.17.1_Suppl.I102. [DOI] [PubMed] [Google Scholar]
  • 42.Luft FC, Weinberger MH, Fineberg NS, Miller JZ, Grim CE. Effects of age on renal sodium homeostasis and its relevance to sodium sensitivity. Am J Med 82, Suppl 1B: 9–15, 1987. doi: 10.1016/0002-9343(87)90266-X. [DOI] [PubMed] [Google Scholar]
  • 43.Masilamani S, Hobbs GR, Baylis C. The acute pressure natriuresis response blunted and the blood pressure response reset in the normal pregnant rat. Am J Obstet Gynecol 179: 486–491, 1998. doi: 10.1016/S0002-9378(98)70384-9. [DOI] [PubMed] [Google Scholar]
  • 44.Meneton P, Jeunemaitre X, de Wardener HE, MacGregor GA. Links between dietary salt intake, renal salt handling, blood pressure, and cardiovascular diseases. Physiol Rev 85: 679–715, 2005. doi: 10.1152/physrev.00056.2003. [DOI] [PubMed] [Google Scholar]
  • 45.Messerli FH, Sundgaard-Riise K, Ventura HO, Dunn FG, Glade LB, Frohlich ED. Essential hypertension in the elderly: haemodynamics, intravascular volume, plasma renin activity, and circulating catecholamine levels. Lancet 2: 983–986, 1983. doi: 10.1016/S0140-6736(83)90977-7. [DOI] [PubMed] [Google Scholar]
  • 46.Mirabito KM, Hilliard LM, Kett MM, Brown RD, Booth SC, Widdop RE, Moritz KM, Evans RG, Denton KM. Sex- and age-related differences in the chronic pressure-natriuresis relationship: role of the angiotensin type 2 receptor. Am J Physiol Renal Physiol 307: F901–F907, 2014. doi: 10.1152/ajprenal.00288.2014. [DOI] [PubMed] [Google Scholar]
  • 47.Morimoto A, Uzu T, Fujii T, Nishimura M, Kuroda S, Nakamura S, Inenaga T, Kimura G. Sodium sensitivity and cardiovascular events in patients with essential hypertension. Lancet 350: 1734–1737, 1997. doi: 10.1016/S0140-6736(97)05189-1. [DOI] [PubMed] [Google Scholar]
  • 48.Mozaffarian D, Fahimi S, Singh GM, Micha R, Khatibzadeh S, Engell RE, Lim S, Danaei G, Ezzati M, Powles J; Global Burden of Diseases Nutrition and Chronic Diseases Expert Group . Global sodium consumption and death from cardiovascular causes. N Engl J Med 371: 624–634, 2014. doi: 10.1056/NEJMoa1304127. [DOI] [PubMed] [Google Scholar]
  • 49.Mu S, Shimosawa T, Ogura S, Wang H, Uetake Y, Kawakami-Mori F, Marumo T, Yatomi Y, Geller DS, Tanaka H, Fujita T. Epigenetic modulation of the renal β-adrenergic-WNK4 pathway in salt-sensitive hypertension. Nat Med 17: 573–580, 2011. [Erratum in Nat Med 17: 1020, 2011; Nat Med 18: 630, 2012.] doi: 10.1038/nm.2337. [DOI] [PubMed] [Google Scholar]
  • 50.Mulkerrin E, Epstein FH, Clark BA. Aldosterone responses to hyperkalemia in healthy elderly humans. J Am Soc Nephrol 6: 1459–1462, 1995. [DOI] [PubMed] [Google Scholar]
  • 51.Narkiewicz K, Phillips BG, Kato M, Hering D, Bieniaszewski L, Somers VK. Gender-selective interaction between aging, blood pressure, and sympathetic nerve activity. Hypertension 45: 522–525, 2005. doi: 10.1161/01.HYP.0000160318.46725.46. [DOI] [PubMed] [Google Scholar]
  • 51a.National Center for Health Statistics Mortality Multiple Cause Micro-Datafiles; 2011; Public-Use Data File and Documentation: NHLBI Tabulation (Online). https://www.cdc.gov/nchs/nvss/mortality_public_use_data.htm [6 May 2016].
  • 52.Norlander AE, Madhur MS. Inflammatory cytokines regulate renal sodium transporters: how, where, and why? Am J Physiol Renal Physiol 313: F141–F144, 2017. doi: 10.1152/ajprenal.00465.2016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Noth RH, Lassman MN, Tan SY, Fernandez-Cruz A Jr, Mulrow PJ. Age and the renin-aldosterone system. Arch Intern Med 137: 1414–1417, 1977. doi: 10.1001/archinte.1977.03630220056014. [DOI] [PubMed] [Google Scholar]
  • 54.O’Donnell M, Mente A, Yusuf S. Sodium intake and cardiovascular health. Circ Res 116: 1046–1057, 2015. doi: 10.1161/CIRCRESAHA.116.303771. [DOI] [PubMed] [Google Scholar]
  • 55.Ott C, Janka R, Schmid A, Titze S, Ditting T, Sobotka PA, Veelken R, Uder M, Schmieder RE. Vascular and renal hemodynamic changes after renal denervation. Clin J Am Soc Nephrol 8: 1195–1201, 2013. doi: 10.2215/CJN.08500812. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Patel HM, Mast JL, Sinoway LI, Muller MD. Effect of healthy aging on renal vascular responses to local cooling and apnea. J Appl Physiol (1985) 115: 90–96, 2013. doi: 10.1152/japplphysiol.00089.2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Pinto V, Amaral J, Silva E, Simão S, Cabral JM, Afonso J, Serrão MP, Gomes P, Pinho MJ, Soares-da-Silva P. Age-related changes in the renal dopaminergic system and expression of renal amino acid transporters in WKY and SHR rats. Mech Ageing Dev 132: 298–304, 2011. doi: 10.1016/j.mad.2011.06.003. [DOI] [PubMed] [Google Scholar]
  • 58.Pokkunuri I, Chugh G, Rizvi I, Asghar M. Age-related hypertension and salt sensitivity are associated with unique cortico-medullary distribution of D1R, AT1R, and NADPH-oxidase in FBN rats. Clin Exp Hypertens 37: 1–7, 2015. doi: 10.3109/10641963.2014.977489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Pöss J, Ewen S, Schmieder RE, Muhler S, Vonend O, Ott C, Linz D, Geisel J, Rump LC, Schlaich M, Böhm M, Mahfoud F. Effects of renal sympathetic denervation on urinary sodium excretion in patients with resistant hypertension. Clin Res Cardiol 104: 672–678, 2015. doi: 10.1007/s00392-015-0832-5. [DOI] [PubMed] [Google Scholar]
  • 60.Powles J, Fahimi S, Micha R, Khatibzadeh S, Shi P, Ezzati M, Engell RE, Lim SS, Danaei G, Mozaffarian D; Global Burden of Diseases Nutrition and Chronic Diseases Expert Group (NutriCoDE) . Global, regional and national sodium intakes in 1990 and 2010: a systematic analysis of 24 h urinary sodium excretion and dietary surveys worldwide. BMJ Open 3: e003733, 2013. doi: 10.1136/bmjopen-2013-003733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Rashid P, Leonardi-Bee J, Bath P. Blood pressure reduction and secondary prevention of stroke and other vascular events: a systematic review. Stroke 34: 2741–2748, 2003. doi: 10.1161/01.STR.0000092488.40085.15. [DOI] [PubMed] [Google Scholar]
  • 62.Sabanathan K, Castleden CM, Adam HK, Ryan J, Fitzsimons TJ. A comparative study of the pharmacokinetics and pharmacodynamics of atenolol, hydrochlorothiazide and amiloride in normal young and elderly subjects and elderly hypertensive patients. Eur J Clin Pharmacol 32: 53–60, 1987. doi: 10.1007/BF00609957. [DOI] [PubMed] [Google Scholar]
  • 63.Scherzer P, Gal-Moscovici A, Sheikh-Hamad D, Popovtzer MM. Sodium-pump gene-expression, protein abundance and enzyme activity in isolated nephron segments of the aging rat kidney. Physiol Rep 3: e12369, 2015. doi: 10.14814/phy2.12369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.SPRINT Research Group; Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, Reboussin DM, Rahman M, Oparil S, Lewis CE, Kimmel PL, Johnson KC, Goff DC Jr, Fine LJ, Cutler JA, Cushman WC, Cheung AK, Ambrosius WT. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 373: 2103–2116, 2015. doi: 10.1056/NEJMoa1511939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Stefanska A, Eng D, Kaverina N, Duffield JS, Pippin JW, Rabinovitch P, Shankland SJ. Interstitial pericytes decrease in aged mouse kidneys. Aging (Albany NY) 7: 370–382, 2015. doi: 10.18632/aging.100756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Sun Z. Aging, arterial stiffness, and hypertension. Hypertension 65: 252–256, 2015. doi: 10.1161/HYPERTENSIONAHA.114.03617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Tank JE, Vora JP, Houghton DC, Anderson S. Altered renal vascular responses in the aging rat kidney. Am J Physiol Renal Physiol 266: F942–F948, 1994. doi: 10.1152/ajprenal.1994.266.6.F942. [DOI] [PubMed] [Google Scholar]
  • 68.Terker AS, Yang CL, McCormick JA, Meermeier NP, Rogers SL, Grossmann S, Trompf K, Delpire E, Loffing J, Ellison DH. Sympathetic stimulation of thiazide-sensitive sodium chloride cotransport in the generation of salt-sensitive hypertension. Hypertension 64: 178–184, 2014. doi: 10.1161/HYPERTENSIONAHA.114.03335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Thomas SE, Anderson S, Gordon KL, Oyama TT, Shankland SJ, Johnson RJ. Tubulointerstitial disease in aging: evidence for underlying peritubular capillary damage, a potential role for renal ischemia. J Am Soc Nephrol 9: 231–242, 1998. [DOI] [PubMed] [Google Scholar]
  • 70.Thompson MM, Oyama TT, Kelly FJ, Kennefick TM, Anderson S. Activity and responsiveness of the renin-angiotensin system in the aging rat. Am J Physiol Regul Integr Comp Physiol 279: R1787–R1794, 2000. doi: 10.1152/ajpregu.2000.279.5.R1787. [DOI] [PubMed] [Google Scholar]
  • 71.Tian Y, Riazi S, Khan O, Klein JD, Sugimura Y, Verbalis JG, Ecelbarger CA. Renal ENaC subunit, Na-K-2Cl and Na-Cl cotransporter abundances in aged, water-restricted F344 x Brown Norway rats. Kidney Int 69: 304–312, 2006. doi: 10.1038/sj.ki.5000076. [DOI] [PubMed] [Google Scholar]
  • 72.Tiwari S, Li L, Riazi S, Halagappa VK, Ecelbarger CM. Sex and age result in differential regulation of the renal thiazide-sensitive NaCl cotransporter and the epithelial sodium channel in angiotensin II-infused mice. Am J Nephrol 30: 554–562, 2009. doi: 10.1159/000252776. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Urbieta-Caceres VH, Syed FA, Lin J, Zhu XY, Jordan KL, Bell CC, Bentley MD, Lerman A, Khosla S, Lerman LO. Age-dependent renal cortical microvascular loss in female mice. Am J Physiol Endocrinol Metab 302: E979–E986, 2012. doi: 10.1152/ajpendo.00411.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Vaidya A, Underwood PC, Hopkins PN, Jeunemaitre X, Ferri C, Williams GH, Adler GK. Abnormal aldosterone physiology and cardiometabolic risk factors. Hypertension 61: 886–893, 2013. doi: 10.1161/HYPERTENSIONAHA.111.00662. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Wainford RD, Carmichael CY, Pascale CL, Kuwabara JT. Gαi2-protein-mediated signal transduction: central nervous system molecular mechanism countering the development of sodium-dependent hypertension. Hypertension 65: 178–186, 2015. doi: 10.1161/HYPERTENSIONAHA.114.04463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Walsh KR, Kuwabara JT, Shim JW, Wainford RD. Norepinephrine-evoked salt-sensitive hypertension requires impaired renal sodium chloride cotransporter activity in Sprague-Dawley rats. Am J Physiol Regul Integr Comp Physiol 310: R115–R124, 2016. doi: 10.1152/ajpregu.00514.2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Weidmann P, De Myttenaere-Bursztein S, Maxwell MH, de Lima J. Effect on aging on plasma renin and aldosterone in normal man. Kidney Int 8: 325–333, 1975. doi: 10.1038/ki.1975.120. [DOI] [PubMed] [Google Scholar]
  • 78.Weinberger MH. Salt sensitivity of blood pressure in humans. Hypertension 27: 481–490, 1996. doi: 10.1161/01.HYP.27.3.481. [DOI] [PubMed] [Google Scholar]
  • 79.Weinberger MH, Miller JZ, Luft FC, Grim CE, Fineberg NS. Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertension 8: II127–II134, 1986. doi: 10.1161/01.HYP.8.6_Pt_2.II127. [DOI] [PubMed] [Google Scholar]
  • 80.Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC Jr, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA Sr, Williamson JD, Wright JT Jr. ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 71: e13–e115, 2018. doi: 10.1161/HYP.0000000000000065. [DOI] [PubMed] [Google Scholar]
  • 81.World Health Organization A Global Brief on Hypertension (Online). http://www.who.int/cardiovascular_diseases/publications/global_brief_hypertension/en/. [6 May 2016].
  • 82.Ziegler AK, Bertog S, Kaltenbach B, Id D, Franke J, Hofmann I, Vaskelyte L, Sievert H. Efficacy and safety of renal denervation in elderly patients with resistant hypertension. Catheter Cardiovasc Interv 86: 299–303, 2015. doi: 10.1002/ccd.25166. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Physiology - Renal Physiology are provided here courtesy of American Physiological Society

RESOURCES