scholarly journals Knockout of Macula Densa Neuronal Nitric Oxide Synthase Increases Blood Pressure in db/db Mice

Hypertension ◽  
2021 ◽  
Author(s):  
Jie Zhang ◽  
Ximing Wang ◽  
Yu Cui ◽  
Shan Jiang ◽  
Jin Wei ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Sodium Excretion ◽  
Filtration Rate ◽  
Leptin Receptor ◽  
Macula Densa ◽  
Glomerular Hyperfiltration ◽  
No Production

Hypertension is a common comorbid condition in patients with diabetes. The pathogenesis of hypertension in diabetes has not been fully clarified. Primary tubular hyperreabsorption may contribute, which may be counteracted by glomerular hyperfiltration in the early diabetic kidney. In this study, we hypothesize that in early diabetes, the macula densa neuronal nitric oxide synthase (NOS1)-derived nitric oxide (NO) production is enhanced, which blunts tubuloglomerular feedback (TGF) response, promotes glomerular hyperfiltration, and maintains normal blood pressure; conversely, insufficient NO generation by the macula densa induces hypertension by lowering glomerular filtration rate and thus inhibiting natriuresis. To test this hypothesis, we examined the changes of macula densa NOS1 expression and phosphorylation as well as NO production, TGF response, glomerular filtration rate, sodium excretion, and blood pressure in a murine model of leptin receptor-deficient (db/db) diabetes with or without macula densa-specific NOS1 deletion. We found that db/db mice presented reduced fractional renal sodium excretion and only a small increase in blood pressure, associated with upregulated expression and activity of macula densa NOS1, inhibited TGF response, and glomerular hyperfiltration. Genetic knockout of macula densa NOS1 restored the TGF response and attenuated glomerular hyperfiltration in db/db mice but also further reduced fractional renal sodium excretion and substantially increased blood pressure. In conclusion, the present study demonstrates that in the early stage of leptin receptor-deficient diabetes, the upregulation of macula densa NOS1 inhibits TGF and increases glomerular filtration rate, which counteracts renal sodium retention and limits the rise in blood pressure.

Short-term analysis of the relationship between blood pressure and urinary sodium excretion in normotensive subjects

2000 ◽  
Vol 98 (4) ◽  
pp. 495-500 ◽  
Author(s):  
Leonardo CENTONZA ◽  
Giovanna CASTOLDI ◽  
Roberto CHIANCA ◽  
Giuseppe BUSCA ◽  
Raffaello GOLIN ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Sodium Excretion ◽  
Filtration Rate ◽  
Urinary Sodium Excretion ◽  
Urinary Sodium ◽  
Short Term ◽  
Quiet Wakefulness ◽  
Normotensive Subjects

The aim of this study was to investigate whether, in the short term, physiological blood pressure changes are coupled with changes in urinary sodium excretion in normotensive subjects, maintained at fixed sodium intake and under controlled postural and behavioural conditions. Twelve normotensive subjects were recruited. For each subject, seven urine samples were collected at fixed time intervals during an overall 26 h period: late afternoon (16.00–20.00 hours), evening (20.00–24.00 hours), night (24.00–06.00 hours), quiet wakefulness (06.00–09.00 hours), morning (09.00–12.00 hours), post-prandial (12.00–15.00 hours) and afternoon (15.00–18.00 hours). Blood pressure was monitored by an ambulatory blood pressure device during the whole 26 h period. Each urine sample was used to measure urinary sodium excretion and glomerular filtration rate (creatinine clearance). Blood pressure, heart rate, urinary sodium excretion and glomerular filtration rate recorded in the daytime were higher than those measured during the night-time. A significant positive correlation between mean blood pressure and urinary sodium excretion was found during the night, over the whole 26 h period, and during two subperiods of the daytime: quiet wakefulness and the post-prandial period. The coefficient of the pressure–natriuresis curve was significantly decreased by postural changes. We conclude that, in normotensive subjects, blood pressure and urinary sodium excretion are coupled in the short term. The assumption of an upright posture can mask this relationship, presumably by activating neurohumoral factors.

Endothelin Excretion in Hypertensive Pregnancy: Relationship to Glomerular Filtration Rate, Blood Pressure, and Sodium Excretion

1994 ◽  
Vol 7 (4 Pt 1) ◽  
pp. 308-313 ◽  
Author(s):  
M.-X. Wang ◽  
M. A. Brown ◽  
M. L. Buddie ◽  
M. A. Carlton ◽  
G. M. Cario ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Sodium Excretion ◽  
Filtration Rate ◽  
Hypertensive Pregnancy

scholarly journals Increase in Bioavailability of Nitric Oxide After Renal Denervation Improves Kidney Function in Sheep With Hypertensive Kidney Disease

Hypertension ◽  
2021 ◽  
Vol 77 (4) ◽  
pp. 1299-1310
Author(s):  
Reetu R. Singh ◽  
Zoe M. McArdle ◽  
Lindsea C. Booth ◽  
Clive N. May ◽  
Geoff A. Head ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Glomerular Filtration Rate ◽  
Kidney Disease ◽  
Glomerular Filtration ◽  
Kidney Function ◽  
Filtration Rate ◽  
Renal Denervation ◽  
Healthy Sheep ◽  
No Bioavailability

Overactivity of renal sympathetic nerves and nitric oxide (NO) deficiency occur in hypertensive chronic kidney disease (CKD). In sheep with hypertensive CKD and NO deficiency, renal denervation (RDN) reduces blood pressure and improves kidney function (glomerular filtration rate). We hypothesized that this improvement in glomerular filtration rate after RDN is associated with increased NO bioavailability. In this study, glomerular filtration rate response to systemic inhibition of NOS (NO synthase) was examined in healthy and CKD sheep at 2 and 30 months after a sham (intact nerves) or RDN procedure. Basal urinary total nitrate (nitrate+nitrite) excretion was examined at 2 and 30 months, and kidney protein expression of endothelial and neuronal NOS was assessed at 30 months. Urinary nitrate+nitrite in CKD-RDN and healthy sheep was ≈50% to 70% greater than in CKD-intact. During NOS inhibition, the fall in glomerular filtration rate in CKD-RDN sheep was ≈20% greater than in CKD-intact. These effects in CKD-RDN sheep were similar to those in healthy sheep. Endothelial NOS protein expression was lower in CKD-intact sheep compared with healthy sheep and compared with CKD-RDN. In summary, RDN normalizes NO bioavailability and restores contribution of NO to renal hemodynamics in CKD. These changes may promote improvements in kidney function and sustained blood pressure lowering after RDN in hypertensive CKD.

Natriuresis Following Fourth Ventricle Perfusion with High-sodium Artificial CSF

1975 ◽  
Vol 53 (3) ◽  
pp. 363-367 ◽  
Author(s):  
S. S. Passo ◽  
J. R. Thornborough ◽  
A. B. Rothballer
Keyword(s):  
Blood Pressure ◽  
Cerebrospinal Fluid ◽  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Sodium Excretion ◽  
Fourth Ventricle ◽  
Filtration Rate ◽  
Urinary Sodium Excretion ◽  
Urinary Sodium ◽  
High Sodium

Perfusion of the fourth cerebral ventricle with high-sodium artificial cerebrospinal fluid was found to result in an increase in urinary sodium excretion in anesthetized cats. The natriuresis was accompanied by an increase in blood pressure and glomerular filtration rate. However, in animals with the changes in blood pressure and glomerular filtration rate prevented by alpha-adrenergic blockade (phenoxybenzamine), the increase in urinary sodium excretion persisted. The data suggest the presence of a neural mechanism in the vicinity of the fourth ventricle sensitive to cerebrospinal fluid sodium levels and capable of affecting urinary sodium excretion independent of changes in blood pressure or glomerular filtration rate. The possible role of the area postrema and adjacent medulla is considered.

Hyperfiltration in ubiquitin C-terminal hydrolase L1-deleted mice

2018 ◽  
Vol 132 (13) ◽  
pp. 1453-1470 ◽  
Author(s):  
Naomi C. Boisvert ◽  
Chet E. Holterman ◽  
Jean-François Thibodeau ◽  
Rania Nasrallah ◽  
Eldjonai Kamto ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Vascular Reactivity ◽  
Renal Hemodynamics ◽  
Cyclooxygenase 2 ◽  
Glomerular Hyperfiltration ◽  
Angiotensin Converting Enzyme Inhibition ◽  
Renal Nerve

Neuronal ubiquitin C-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme that maintains intracellular ubiquitin pools and promotes axonal transport. Uchl1 deletion in mice leads to progressive axonal degeneration, affecting the dorsal root ganglion that harbors axons emanating to the kidney. Innervation is a crucial regulator of renal hemodynamics, though the contribution of neuronal UCHL1 to this is unclear. Immunofluorescence revealed significant neuronal UCHL1 expression in mouse kidney, including periglomerular axons. Glomerular filtration rate trended higher in 6-week-old Uchl1-/- mice, and by 12 weeks of age, these displayed significant glomerular hyperfiltration, coincident with the onset of neurodegeneration. Angiotensin converting enzyme inhibition had no effect on glomerular filtration rate of Uchl1-/- mice indicating that the renin–angiotensin system does not contribute to the observed hyperfiltration. DCE-MRI revealed increased cortical renal blood flow in Uchl1-/- mice, suggesting that hyperfiltration results from afferent arteriole dilation. Nonetheless, hyperglycemia, cyclooxygenase-2, and nitric oxide synthases were ruled out as sources of hyperfiltration in Uchl1-/- mice as glomerular filtration rate remained unchanged following insulin treatment, and cyclooxygenase-2 and nitric oxide synthase inhibition. Finally, renal nerve dysfunction in Uchl1-/- mice is suggested given increased renal nerve arborization, decreased urinary norepinephrine, and impaired vascular reactivity. Uchl1-deleted mice demonstrate glomerular hyperfiltration associated with renal neuronal dysfunction, suggesting that neuronal UCHL1 plays a crucial role in regulating renal hemodynamics.

Effect of a kinin antagonist on renal function and haemodynamics during alterations in sodium balance in conscious normotensive rats

1990 ◽  
Vol 78 (2) ◽  
pp. 165-168 ◽  
Author(s):  
Paolo Madeddu ◽  
Nicola Glorioso ◽  
Aldo Soro ◽  
Paolo Manunta ◽  
Chiara Troffa ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Renal Function ◽  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Renal Blood Flow ◽  
Sodium Excretion ◽  
Filtration Rate ◽  
Sodium Intake ◽  
Urinary Sodium Excretion

1. To evaluate whether sodium intake can modulate the action of endogenous kinins on renal function and haemodynamics, a receptor antagonist of bradykinin was infused in conscious normotensive rats maintained on either a normal or a low sodium diet. 2. The antagonist inhibited the hypotensive effect of exogenously administered bradykinin. It did not change the vasodepressor effect of acetylcholine, dopamine or prostaglandin E2. 3. The antagonist did not affect mean blood pressure, glomerular filtration rate, renal blood flow or urinary sodium excretion, in rats on sodium restriction. It did not change mean blood pressure, glomerular filtration rate or urinary sodium excretion, but decreased renal blood flow, in rats on a normal sodium intake. 4. The kallikrein–kinin system has a role in the regulation of renal blood flow in rats on a normal sodium diet.

CNS-induced natriuresis and renal hemodynamics in conscious rats

1983 ◽  
Vol 245 (6) ◽  
pp. F763-F771 ◽  
Author(s):  
D. Beasley ◽  
R. L. Malvin ◽  
D. R. Mouw
Keyword(s):  
Blood Pressure ◽  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Antidiuretic Hormone ◽  
Sodium Excretion ◽  
Filtration Rate ◽  
Plasma Renin ◽  
Renal Nerve ◽  
Natriuretic Hormone ◽  
Renal Nerve Activity

Sodium excretion was studied following experimental elevation of cerebrospinal fluid (CSF) sodium in heterozygous and homozygous (DI) Brattleboro rats given exogeneous antidiuretic hormone. Sodium excretion increased 4.5-fold in heterozygous and 3.5-fold in DI rats. The natriuresis in both groups was rapid in onset and occurred with a simultaneous kaliuresis. Blood pressure increased approximately 10 mmHg in the heterozygous but not in the DI rats. Accordingly, increased blood pressure may contribute to the natriuresis but is not the sole mechanism. Plasma renin concentration did not change in the DI rats during high Na CSF infusion, and chronic bilateral renal denervation did not abolish the natriuresis. Glomerular filtration rate increased during the high Na period in both the intact and renally denervated rats. These data provide evidence that a natriuretic mechanism exists that is not mediated by changes in antidiuretic hormone, renal nerve activity, mean arterial pressure, aldosterone, or angiotensin II, and thus may be due to another circulating substance or natriuretic hormone. This hormone may act totally or in part by increasing glomerular filtration rate.

Effects of small C-ANF receptor ligands on plasma levels of atrial natriuretic factor, blood pressure, and renal function in the rat

1991 ◽  
Vol 69 (10) ◽  
pp. 1561-1566 ◽  
Author(s):  
Juraj Okolicany ◽  
Glenn A. McEnroe ◽  
Lisa C. Gregory ◽  
John A. Lewicki ◽  
Thomas Maack
Keyword(s):  
Blood Pressure ◽  
Amino Acids ◽  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Plasma Levels ◽  
Sodium Excretion ◽  
Filtration Rate ◽  
Recovery Period ◽  
Receptor Ligands ◽  
Arterial Blood

In this article, after a very brief review on ANF receptors, we report our study on the effects of small C-ANF receptor ligands in the rat. Two small ligands were synthesized: 2-napthoxyacetyl-isonipecotyl-rANF 11–15-NH2 (5 aa), containing 5 amino acids; and Ala7-rANF 8–17-NH2 (10 aa), containing 10 amino acids from the ring structure of ANF 1–28. After control periods, 5 aa or 10 aa were infused i.v. at a dose of 10 μg∙min−1∙kg−1 body weight for 70 min in anesthetized rats, followed by a 60-min recovery period. The 5 aa and 10 aa peptides significantly and reversibly increased plasma levels of endogenous immunoreactive ANF by 106 ± 29 and 52 ± 24 pg/mL, respectively. Infusion of the 5 aa peptide significantly decreased mean arterial blood pressure from 113 ± 1 to 100 ± 3 mmHg (1 mmHg = 133.32 Pa) and increased glomerular filtration rate from 1.6 ± 0.2 to 2.3 ± 0.2 mL/min, sodium excretion from 0.6 ± 0.3 to 3.4 ± 0.4 μmol/min, and potassium excretion from 0.5 ± 0.2 to 1.2 ± 0.2 μmol/min. Similar results were obtained with the 10 aa peptide. The effects of both peptides on blood pressure and sodium excretion persisted throughout the recovery period. The results confirm and extend previous observations showing that C-ANF receptors mediate the removal of ANF from the circulation. The shortening of the minimal peptide length necessary to bind to C-ANF receptors markedly enhances the possibility of developing orally active C-ANF receptor ligands for the treatment of cardiovascular and renal diseases.Key words: C-ANF receptors, linear atrial peptides, glomerular filtration rate, natriuresis, kaliuresis.

scholarly journals FP005THE EFFECT OF SODIUM NITRITE ON BLOOD PRESSURE, GLOMERULAR FILTRATION RATE AND SODIUM EXCRETION IN HEALTHY SUBJECTS

2015 ◽  
Vol 30 (suppl_3) ◽  
pp. iii67-iii67
Author(s):  
Jeppe B Rosenbaek ◽  
Safa Therwani ◽  
Janni M Jensen ◽  
Frank H Mose ◽  
Erling B Pedersen ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Sodium Nitrite ◽  
Sodium Excretion ◽  
Healthy Subjects ◽  
Filtration Rate

Studies on the Mechanism of Sodium Excretion in Uraemia

1972 ◽  
Vol 42 (6) ◽  
pp. 711-723 ◽  
Author(s):  
R. Wilkinson ◽  
J. A. Luetscher ◽  
A. J. Dowdy ◽  
C. Gonzales ◽  
G. W. Nokes
Keyword(s):  
Blood Pressure ◽  
Glomerular Filtration Rate ◽  
Creatinine Clearance ◽  
Glomerular Filtration ◽  
Sodium Excretion ◽  
Filtration Rate ◽  
Plasma Renin ◽  
Sodium Depletion ◽  
Sodium Loading ◽  
Arteriolar Tone

1. A group of eight patients with advanced renal failure, and a creatinine clearance of 3·8–24 ml/min, were subjected to sodium loading and sodium depletion. 2. With sodium loading there was a consistent increase in blood pressure (0·01 < P <0·02), an increase in creatinine clearance that was significantly related to changes in mean arterial pressure (r = +0·3, 001 < P < 0·02); an increase in urinary sodium excretion that was closely correlated with changes in creatinine clearance (r = +0·82, P < 0·001); a decrease in fractional reabsorption of filtered sodium that was inversely proportional to creatinine clearance (r = −0·63, 0·05< P < 0·1). 3. Fractional reabsorption of filtered sodium was proportional to creatinine clearance both in the sodium-loaded (r = +0·86, 0·001 < P < 0·01) and sodium-depleted states (r = +0·92, 0·001 < P < 0·01). 4. Urinary aldosterone excretion and plasma renin activity consistently increased with sodium depletion, the percentage increases of the two being significantly related (r = +0·95, P < 0·001). 5. The results suggest that excretion of a sodium load in uraemia may be effected in part as the result of a raised blood pressure that elevates the glomerular filtration rate; by increasing the peritubular capillary pressure this may be responsible for the observed decrease in reabsorption of filtered sodium. The responsiveness of glomerular filtration rate to blood pressure changes suggests a decrease in afferent arteriolar tone that may account for the increased sodium excretion per nephron which occurs even in uraemic patients without hypertension. 6. It is suggested that aldosterone may continue to play an important regulatory role in sodium homeostasis in uraemia and that renin concentrations are the major determinants of aldosterone production in uraemia.

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