A Salt-Induced Reno-Cerebral Reflex Activates Renin-Angiotensin Systems and Promotes CKD Progression

Cao, Wei; Li, Aiqing; Wang, Liangliang; Zhou, Zicong; Su, Zhihua; Wei, Bin; Wilcox, Christopher S.; Hou, Fan Fan

doi:10.1681/asn.2014050518

Cited by 91 publications

(98 citation statements)

References 74 publications

(87 reference statements)

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“…RAS genes are regulated by several factors, including hyperglycemia, high-salt, albumin overload, reduced availability of nitric oxide and increased uremic toxin [4,8,45,46]. Recent studies show that loss of Klotho, an antiaging protein, also leads to RAS activation in diseased kidneys [47].…”

Section: Regulation Of Ras Expressionmentioning

confidence: 99%

“…It is well recognized that intrarenal RAS activation is associated with the development and progression of chronic kidney disease (CKD) by blood pressure-dependent and –independent mechanisms [4–8]. RAS consists of several components including angiotensinogen (AGT), renin, angiotensin-converting enzyme (ACE) and the angiotensin II (Ang II) type 1 and type 2 receptors (AT1 and AT2).…”

Section: Introductionmentioning

confidence: 99%

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Wnt/β-catenin signaling and renin–angiotensin system in chronic kidney disease

Zhou

Liu²

2016

Current Opinion in Nephrology and Hypertension

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Purpose of review Intrarenal activation of the renin–angiotensin system (RAS) plays an essential role in the pathogenesis of hypertension and chronic kidney diseases (CKD). However, how RAS genes are regulated in vivo was poorly understood until recently. This review focuses on recent findings of the transcriptional regulation of RAS components as well as their implication in developing novel strategies to treat the patients with CKD. Recent findings Bioinformatics analyses have uncovered the presence of putative binding sites for T cell factor (TCF)/β-catenin in the promoter region of all RAS genes. Both in vitro and in vivo studies confirm that Wnt/β-catenin is the master upstream regulator that controls the expression of all RAS components tested such as angiotensinogen, renin, angiotensin converting enzyme (ACE) and angiotensin II type I receptor (AT1) in the kidney. Targeted inhibition of Wnt/β-catenin, by either small molecule ICG-001 or endogenous Wnt antagonist Klotho, represses RAS activation and ameliorates proteinuria and kidney injury. Blockade of Wnt/β-catenin signaling also normalizes blood pressure in mouse model of CKD. Summary These recent studies identify Wnt/β-catenin as the master regulator that controls multiple RAS genes, and suggest that targeting this upstream signaling could be an effective strategy for the treatment of patients with hypertension and CKD.

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Section: Regulation Of Ras Expressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Wnt/β-catenin signaling and renin–angiotensin system in chronic kidney disease

Zhou

Liu²

2016

Current Opinion in Nephrology and Hypertension

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“…Sympathetic hyperactivity is considered an independent risk factor of cardiovascular death in patients with CKD (Kaur et al 2017). Patients with CKD have elevated noradrenaline concentrations in plasma (Rahman et al 1993), increased resting activity of sympathetic nerves (supplying the vessels in skeletal muscles or skin) (Converse et al 1992, Ligtenberg et al 1999, or altered sympathovagal balance (estimated from the ratio of low-frequency power to high-frequency power obtained by power spectral analysis of the heart rate variability) (Giordano et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Norepinephrine Turnover in the Left Ventricle of Subtotally Nephrectomized Rats

et al. 2019

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Increased activity of the sympathetic nervous system (SNS) has been proposed as a risk factor for increased cardiovascular mortality in patients with chronic kidney disease (CKD). Information on the activity of cardiac sympathetic innervation is non-homogeneous and incomplete. The aim of our study was to evaluate the tonic effect of SNS on heart rate, norepinephrine turnover and direct and indirect effects of norepinephrine in left ventricles of subtotally nephrectomized rats (SNX) in comparison with sham-operated animals (SHAM). Renal failure was verified by measuring serum creatinine and urea levels. SNX rats developed increased heart rates and blood pressure (BP). The increase in heart rate was not caused by sympathetic overactivity as the negative chronotropic effect of metipranolol did not differ between the SNX and SHAM animals. The positive inotropic effects of norepinephrine and tyramine on papillary muscle were not significantly different. Norepinephrine turnover was measured after the administration of tyrosine hydroxylase inhibitor, pargyline, tyramine, desipramine, and KCl induced depolarization. The absolute amount of released norepinephrine was comparable in both groups despite a significantly decreased norepinephrine concentration in the cardiac tissue of the SNX rats. We conclude that CKD associated with renal denervation in rats led to adaptive changes characterized by an increased reuptake and intracellular norepinephrine turnover which maintained normal reactivity of the heart to sympathetic stimulation.

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“…Dietary salt determines glomerulosclerosis and renal injury in rats with RRM (Cao et al . ), and to some extent, also in patients with CKD (Lipkowitz & Wilcox ). A high‐salt diet induces oxidative stress and impairs myogenic responses of afferent arterioles in mice with RRM (Lai et al .…”

mentioning

confidence: 99%

“…Afferent arterioles exposed to oxidative stress or prolonged hypertension show inward remodelling with a decrease in luminal diameter and an increase in the cross-sectional area of the media (Gattone et al 1983). Dietary salt determines glomerulosclerosis and renal injury in rats with RRM (Cao et al 2015), and to some extent, also in patients with CKD (Lipkowitz & Wilcox 2014). A high-salt diet induces oxidative stress and impairs myogenic responses of afferent arterioles in mice with RRM .…”

mentioning

confidence: 99%

High‐salt diet induces outward remodelling of efferent arterioles in mice with reduced renal mass

et al. 2016

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Aim The glomerular filtration rate (GFR) falls progressively in chronic kidney disease (CKD) which is caused by a reduction in the number of functional nephrons. The dysfunctional nephron exhibits a lower glomerular capillary pressure that is induced by an unbalance between afferent and efferent arteriole. Therefore, we tested the hypothesis that oxidative stress induced by CKD differentially impairs the structure or function of efferent versus afferent arterioles. Methods C57BL/6 mice received sham operations (sham) or 5/6 nephrectomy (RRM) and 3 months of normal or high salt diet or tempol. GFR was assessed from the plasma inulin clearance, arteriolar remodeling from media/lumen area ratio, myogenic responses from changes in luminal diameter with increases in perfusion pressure and passive wall compliance from the wall stress/strain relationships. Results Mice with RRM fed a high salt (versus sham) had a lower GFR (553±25 versus 758±36μl/min/g kidney, p<0.01) and a larger efferent arteriolar diameter (9.6±0.8 versus 7.4±0.7μm, p<0.05) resulting in a lower media/lumen area ratio (1.4±0.1 versus 2.4±0.2, p<0.01). These alterations were corrected by tempol. The myogenic responses of efferent arterioles were about one-half that of afferent arterioles and were unaffected by RRM or salt. Passive wall compliance was reduced by high salt in both afferent and efferent arterioles. Conclusion A reduction in renal mass with a high salt diet induces oxidative stress that leads to an outward eutrophic remodeling in efferent arterioles and reduced wall compliance in both afferent and efferent arterioles. This may contribute to the lower GFR in this model of CKD.

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A Salt-Induced Reno-Cerebral Reflex Activates Renin-Angiotensin Systems and Promotes CKD Progression

Cited by 91 publications

References 74 publications

Wnt/β-catenin signaling and renin–angiotensin system in chronic kidney disease

Wnt/β-catenin signaling and renin–angiotensin system in chronic kidney disease

Norepinephrine Turnover in the Left Ventricle of Subtotally Nephrectomized Rats

High‐salt diet induces outward remodelling of efferent arterioles in mice with reduced renal mass

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