Short- and long-term effect of angiotensin II receptor blockade in rats with experimental diabetes.

The short- and long-term effects of specific angiotensin II (AII) receptor blockade on the evaluation of glomerular injury in moderately hyperglycemic diabetic rats were studied. Three groups of animals were used, a control group, a group of diabetic rats treated with insulin, and a group of insulin-treated diabetic rats receiving the AII receptor antagonist losartan in drinking water. After 4 to 6 wk of observation, diabetic rats showed higher systolic blood pressure and GFR than normal controls. Losartan treatment prevented both systolic blood pressure and GFR rise. Three other groups of rats, similarly treated for a 1-yr period, were used for renal functional and morphologic evaluation. Diabetic animals had higher urinary protein excretion and glomerulosclerosis incidence than did normal controls. Losartan significantly prevented proteinuria and glomerulosclerosis. Evaluation of the sieving properties of the glomerular membrane by Ficoll fractional clearance showed an important increase in the filtration of this marker in diabetic animals, as compared with that in controls, and almost complete prevention of this change in losartan-treated animals. Theoretical analysis of fractional clearance data with a heteroporous model of glomerular size-selectivity showed that in diabetic animals the size of membrane pores was increased uniformly, as compared with that in controls. These changes were completely prevented by the AII receptor antagonist. The results presented here strongly indicate that reduction of AII activity plays a crucial role in the preservation of glomerular structure and function and suggest that the favorable effects previously observed with angiotensin-converting enzyme inhibition in this model depend directly on the reduction of AII activity.

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Impact of angiotensin II-mediated stimulation of sodium transporters in the nephron assessed by computational modeling

AJP Renal Physiology ◽

10.1152/ajprenal.00335.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. F1656-F1668 ◽

Cited By ~ 2

Author(s):

Aurélie Edwards ◽

Alicia A. McDonough

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Ang Ii ◽

Sodium Transporters ◽

Short And Long Term ◽

Physiological Impact ◽

Pressure Natriuresis ◽

Excretion Rates ◽

Volume Output

Angiotensin II (ANG II) raises blood pressure partly by stimulating tubular Na+ reabsorption. The effects of ANG II on tubular Na+ transporters (i.e., channels, pumps, cotransporters, and exchangers) vary between short-term and long-term exposure. To better understand the physiological impact, we used a computational model of transport along the rat nephron to predict the effects of short- and long-term ANG II-induced transporter activation on Na+ and K+ reabsorption/secretion, and to compare measured and calculated excretion rates. Three days of ANG II infusion at 200 ng·kg−1·min−1 is nonpressor, yet stimulates transporter accumulation. The increase in abundance of Na+/H+ exchanger 3 (NHE3) or activated Na+-K+-2Cl− cotransporter-2 (NKCC2-P) predicted significant reductions in urinary Na+ excretion, yet there was no observed change in urine Na+. The lack of antinatriuresis, despite Na+ transporter accumulation, was supported by Li+ and creatinine clearance measurements, leading to the conclusion that 3-day nonpressor ANG II increases transporter abundance without proportional activation. Fourteen days of ANG II infusion at 400 ng·kg−1·min−1 raises blood pressure and increases Na+ transporter abundance along the distal nephron; proximal tubule and medullary loop transporters are decreased and urine Na+ and volume output are increased, evidence for pressure natriuresis. Simulations indicate that decreases in NHE3 and NKCC2-P contribute significantly to reducing Na+ reabsorption along the nephron and to pressure natriuresis. Our results also suggest that differential regulation of medullary (decrease) and cortical (increase) NKCC2-P is important to preserve K+ while minimizing Na+ retention during ANG II infusion. Lastly, our model indicates that accumulation of active Na+-Cl− cotransporter counteracts epithelial Na+ channel-induced urinary K+ loss.

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Short- and long-term systolic blood pressure changes have different impacts on major adverse cardiovascular events: Results from a 12.5 years follow-up study

International Journal of Cardiology ◽

10.1016/j.ijcard.2019.11.122 ◽

2020 ◽

Vol 306 ◽

pp. 190-195 ◽

Cited By ~ 1

Author(s):

Jia Zheng ◽

Yanxia Xie ◽

Yali Wang ◽

Rongrong Guo ◽

Yue Dai ◽

...

Keyword(s):

Blood Pressure ◽

Systolic Blood Pressure ◽

Cardiovascular Events ◽

Major Adverse Cardiovascular Events ◽

Follow Up Study ◽

Short And Long Term ◽

Pressure Changes

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Abstract 76: Effects of Long-term Angiotensin-II Infusion on Cardiac and Renal Fibrosis are Blunted in TNFR1-deficient Mice

Circulation Research ◽

10.1161/res.117.suppl_1.76 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Magdalena Mayr ◽

Clemens Duerrschmid ◽

Dorellyn B Lee ◽

Guillermo Medrano ◽

George E Taffet ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Systolic Blood Pressure ◽

Renal Fibrosis ◽

Cardiac Fibrosis ◽

Ang Ii ◽

Fibrotic Response ◽

2D Echocardiography ◽

Collagen Iii

Background: Brief systemic infusion of Angiotensin-II (Ang-II) to wild-type (WT) mice initiates the development of cardiac interstitial fibrosis. Genetic deletion of tumor necrosis factor receptor 1 (TNFR1) obviates this development and concurrently inhibits Ang-II-induced cardiac remodeling and dysfunction. We now investigated long-term effects of Ang-II on the heart, kidney, and cardiorenal function. Methods: WT and TNFR1-KO mice were infused with 1.5 ug/kg/min Ang-II for 1 and 6 weeks (no uninephrectomy or high-salt diet). Heart, kidney, and serum were isolated and evaluated by histology, cytometry, qPCR, and ELISA techniques. Cardiac function was determined by 2D-echocardiography, systolic blood pressure by tail-cuff plethysmography. Results: Brief infusion of Ang-II to WT mice did not evoke a fibrotic response in the kidney. However, after 6 weeks, WT kidneys developed minimal, but significant interstitial collagen deposition which was supported by upregulation of collagen-I, collagen-III, and alpha-smooth muscle actin gene activation. This fibrotic development was associated with the appearance of myeloid fibroblast precursors, pro-inflammatory M1 and pro-fibrotic M2 cells, and myofibroblasts. Transcriptional expression of pro-inflammatory and pro-fibrotic genes was also increased. These changes were not seen in Ang-II-infused TNFR1-KO kidneys. In WT hearts, despite the disappearance of myeloid cells, cardiac fibrosis persisted throughout the 6-week infusion. WT hearts developed clear evidence of accelerated cardiac hypertrophy and remodeling associated with impaired systolic function. Again, these changes were not seen in Ang-II-infused TNFR1-KO hearts. By contrast, both WT and TNFR1-KO mice responded identically with similar elevations of systolic blood pressure, and serum blood urea nitrogen and creatinine levels. Conclusions: Ang-II-infusion induced an immediate fibrotic response in the heart while fibrosis in the kidney developed slowly. The cardiac fibrosis was accompanied by progressive adverse remodeling and worsening of function over time. TNFR1-KO mice were protected from the Ang-II-induced cardiac and renal fibrosis, despite similar increases in blood pressure and renal dysfunction.

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Angiotensin responsiveness in hyperfiltering and nonhyperfiltering diabetic rats.

Journal of the American Society of Nephrology ◽

10.1681/asn.v461346 ◽

1993 ◽

Vol 4 (6) ◽

pp. 1346-1353

Author(s):

B M Wilkes ◽

P F Mento ◽

M A Vernace

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Mean Arterial Pressure ◽

Arterial Pressure ◽

Urine Volume ◽

Diabetic Rats ◽

Filtration Fraction ◽

Blood Pressure Responses ◽

Systemic Responses ◽

Normal Controls

Renal and systemic responses to angiotensin II were studied in hyperglycemic diabetic rats (streptozotocin, 60 mg/kg, i.v.) and vehicle-injected controls at 24 h, 1 wk, 2 mo, or at 6 to 12 mo. In normal rats, the GFR was less than 0.80 mL/min per 100 g body wt (0.57 +/- 0.02 mL/min per 100 g body wt; range: 0.40 to 0.79 mL/min per 100 g body wt; N = 45). Hyperfiltration (GFR > or = 0.80 mL/min per 100 g body wt) was observed in all diabetic rats studied at 1 wk (GFR, 1.03 +/- 0.07 mL/min per 100 g body wt; N = 5; P < 0.001 versus control). However, at earlier and later times, GFR was elevated in only 8 of 18 of the diabetic rats (44%), with an overall prevalence of 56% (13 of 23). Mean arterial pressure, plasma glucose, urine volume, and filtration fraction were not different in hyperfiltering diabetic rats compared with nonhyperfiltering diabetic rats or normal controls. Angiotensin II (12.5 ng/kg per minute i.v.) had no effect on GFR in normal rats or nonhyperfiltering diabetic rats, but it normalized GFR in hyperfiltering diabetic rats (0.74 +/- 0.05 mL/min per 100 g body wt). In contrast with the renal effects of angiotensin II, blood pressure responses were similar in hyperfiltering and nonhyperfiltering diabetic rats. The findings that angiotensin II infusion caused a greater fall in GFR in hyperfiltering diabetic rats than in nonhyperfiltering diabetic rats, but that blood pressure responses were similar, suggests a localized abnormality in angiotensin responsiveness in the kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)

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Abstract 13025: Deficiency of Interleukin-1 Receptor Antagonist Promotes Angiotensin II-induced Aortic Inflammation and Aneurysm

Circulation ◽

10.1161/circ.130.suppl_2.13025 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Koji Akita ◽

Kikuo Isoda ◽

Sarasa Isobe ◽

Tomiharu Niida ◽

Hiroyuki Daida

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Systolic Blood Pressure ◽

Receptor Antagonist ◽

Abdominal Aorta ◽

Interleukin 1 ◽

Mrna Levels ◽

Interleukin 1 Receptor Antagonist ◽

Abdominal Aortic ◽

Tnf Α

Introduction: Angiotensin II (AngII) increases arterial pressure and induces inflammation. Although interleukin-1 receptor antagonist (IL-1Ra) is one of the most important anti-inflammatory cytokines, the role of IL-1Ra in AngII-induced aortic inflammation and aneurysm remains unknown. Methods and Results: To determine the contrition of IL-1Ra to AngII-induced aortic inflammation, male wild-type (WT) (n=18) and IL-1Ra-deficient (IL-1Ra-/-) (n=18) mice were infused with AngII (3000ng/kg per minute) using subcutaneous osmotic pumps for 28 days. 7 days after infusion, real-time PCR of abdominal aorta in IL-1Ra-/- mice revealed significantly increased mRNA levels of IL-6 (2.1-fold, p<0.01), TNF-α (4.1-fold, p<0.01), and MMP-9 (20.3-fold, p<0.05) compared with WT mice. 14 days after infusion, both systolic blood pressure (178±21 vs 135±21 mmHg, p<0.01)and abdominal aortic width (1.02±0.12 vs 0.82±0.05 mm, p<0.01) in IL-1Ra-/- mice significantly increased compared with WT mice. Moreover, AngII infusion into IL-1Ra-/- mice also led to a significant increased occurrence of fatal aortic rupture (IL-1Ra-/-: 89% vs WT: 6%, p<0.01). Next, WT (n=6) and IL-1Ra-/- (n=6) mice were infuse with AngII for only 14 days, and histological analyses were performed at 28 days after operation. Interestingly, the abdominal aortic width in IL-1Ra-/- mice more significantly increased than those in WT mice (1.57±0.34 vs 0.80±0.04 mm, p<0.01), although IL-1Ra-/- and WT mice did not differ with regard to systolic blood pressure (105±15 vs 109±13 mmHg, p=0.61) at 28 days after operation. Histological analyses revealed there were numerous inflammatory cells around the abdominal aorta in IL-1Ra-/- mice, but not in WT mice. Furthermore, elastin staining showed destruction of the elastic lamina of abdominal aorta in IL-1Ra-/- mice. TNF-α protein expression also increased significantly in IL-1Ra-/- mice compared to WT mice at 28days. Conclusions: The present study shows that IL-1Ra deficiency in mice led to increase inflammation and the development of aortic aneurysm after AngII infusion. Furthermore, our results also showed IL-1Ra deficiency continued the AngII-induced inflammation even though blood pressure was improved after cessation of AngII infusion.

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Blood pressure-independent renoprotection in diabetic rats treated with AT1 receptor–neprilysin inhibition compared with AT1 receptor blockade alone

Clinical Science ◽

10.1042/cs20160197 ◽

2016 ◽

Vol 130 (14) ◽

pp. 1209-1220 ◽

Cited By ~ 21

Author(s):

Lodi C.W. Roksnoer ◽

Richard van Veghel ◽

Marian C. Clahsen- van Groningen ◽

René de Vries ◽

Ingrid M. Garrelds ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Vascular Reactivity ◽

Diabetic Rats ◽

At1 Receptor ◽

Heart Weight ◽

Receptor Blockade ◽

Beneficial Effects ◽

Neprilysin Inhibition ◽

Pressure Independent

ARNI [dual AT1 (angiotensin II type 1) receptor–neprilysin inhibition] exerts beneficial effects on blood pressure and kidney function in heart failure, compared with ARB (AT1 receptor blockade) alone. We hypothesized that ARNI improves cardiac and kidney parameters in diabetic TGR(mREN2)27 rats, an angiotensin II-dependent hypertension model. Rats were made diabetic with streptozotocin for 5 or 12 weeks. In the final 3 weeks, rats were treated with vehicle, irbesartan (ARB) or irbesartan+thiorphan (ARNI). Blood pressure, measured by telemetry in the 5-week group, was lowered identically by ARB and ARNI. The heart weight/tibia length ratio in 12-week diabetic animals was lower after ARNI compared with after ARB. Proteinuria and albuminuria were observed from 8 weeks of diabetes onwards. ARNI reduced proteinuria more strongly than ARB, and a similar trend was seen for albuminuria. Kidneys of ARNI-treated animals showed less severe segmental glomerulosclerosis than those of ARB-treated animals. After 12 weeks, no differences between ARNI- and ARB-treated animals were found regarding diuresis, natriuresis, plasma endothelin-1, vascular reactivity (acetylcholine response) or kidney sodium transporters. Only ARNI-treated rats displayed endothelin type B receptor-mediated vasodilation. In conclusion, ARNI reduces proteinuria, glomerulosclerosis and heart weight in diabetic TGR(mREN2)27 rats more strongly than does ARB, and this occurs independently of blood pressure.

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