Vasoactive intestinal peptide infusion reverses existing renal interstitial fibrosis via a blood pressure independent mechanism in the rat

Qingxuan Jiangya Decoction (QXJYD) is a traditional Chinese medicine commonly used in the clinical treatment of hypertension. Earlier studies had shown that QXJYD could inhibit the elevation of blood pressure in spontaneously hypertensive rats (SHRs) and prevent remodeling of arterial vessels. This study examines the therapeutic efficacy of QXJYD against elevated blood pressure using the SHR model, as well as the mechanisms behind its antihypertensive activity and protection against renal fibrosis. The results showed that QXJYD significantly attenuated the increase in blood pressure in SHRs and mitigated the development of renal interstitial fibrosis. In addition, QXJYD also robustly decreased the excess accumulation of extracellular matrix and attenuated the elevated expression of MMPs. The antihypertensive effects and renal protection of QXJYD were determined to be strongly associated with inhibition of TGF-β1/Smad signaling pathway.

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Abstract 6: Heterozygous TGFβ1 Zinc-Finger Knockout Dahl S Rats Reveal Protection Against High-Salt Induced Renal Injury

Hypertension ◽

10.1161/hyp.60.suppl_1.a6 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Chun Cheng Andy Chen ◽

Aron Geurts ◽

Howard J Jacob ◽

Fan Fan ◽

Richard J Roman

Keyword(s):

Blood Pressure ◽

Zinc Finger ◽

Interstitial Fibrosis ◽

Stop Codon ◽

Premature Stop Codon ◽

Renal Medulla ◽

High Salt ◽

Glomerular Injury ◽

Renal Interstitial Fibrosis ◽

Protein Excretion

We used a zinc-finger nuclease strategy to create heterozygous TGFβ1 knockout rats (TGFβ1 +/- ) on a Dahl SS/Jr genetic background with a 22 base-pair frame shift mutation between nucleotides 191-212 which introduced a premature stop codon at amino acid 34. Intercrossing TGFβ1 +/- rats did not produce homozygous knockout rats, indicating that the mutation is embryonic lethal. Wildtype (WT) littermates and TGFβ1 +/- rats were fed either a 0.4% (normal salt, NS) or 8% NaCl (high salt, HS) diet for 5 weeks. When fed a NS diet, WT and TGFβ1 +/- exhibit similar renal cortical TGFβ1 expression (1.00±0.12 vs 1.05±0.05, arbitrary units), urinary TGFβ1 excretion (3.9±1.2 vs 5.3±0.4, μg/day), proteinuria (43±5 vs 36±4, mg/day), and minimal glomerular injury and tubulointerstitial fibrosis (TIF). 5 weeks of HS increased renal cortical TGFβ1 protein expression to a greater extent in WT versus TGFβ1 +/- (1.89±0.14 vs 1.52±0.09, arbitrary units) and TGFβ1 levels in urine increased to a greater extent in WT (41±10 μg/day) versus TGFβ1 +/- rats (18±4 μg/day) fed a HS diet for 1 week. Systolic blood pressure (SBP), measured by tail-cuff, was similar in WT (161±6 mmHg) and TGFβ1 +/- (162±7 mmHg) fed a NS diet and increased to the same extent in both WT (235±2 mmHg) and TGFβ1 +/- (239±4 mmHg) fed a HS diet for 5 weeks. Urinary protein excretion increased to a greater extent in WT versus TGFβ1 +/- (463±28 vs 313±36 mg/day) fed a HS diet for 5 weeks. Glomerular injury and renal cortical interstititial fibrosis were markedly reduced in TGFβ1 +/- versus WT after 5 weeks on a HS diet. Similarly, TIF in the renal medulla was less in TGFβ1 +/- compared with WT. These findings suggest that loss of one copy of the TGFβ1 gene blunts the increase in renal TGFβ1 protein in Dahl S rats fed a HS diet and slows the progression of proteinuria, glomerulosclerosis, and renal interstitial fibrosis independent of changes in blood pressure.

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Aliskiren attenuates proteinuria in mice with lupus nephritis by a blood pressure-independent mechanism

Lupus ◽

10.1177/0961203312471871 ◽

2012 ◽

Vol 22 (2) ◽

pp. 180-189 ◽

Cited By ~ 6

Author(s):

T-H Yen ◽

H-Y Yang ◽

Y-H Yeh ◽

P-H Chu ◽

C-J Wen ◽

...

Keyword(s):

Blood Pressure ◽

Lupus Nephritis ◽

Independent Mechanism ◽

Pressure Independent

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Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism

AJP Renal Physiology ◽

10.1152/ajprenal.00283.2001 ◽

2002 ◽

Vol 282 (6) ◽

pp. F991-F997 ◽

Cited By ~ 463

Author(s):

Marilda Mazzali ◽

John Kanellis ◽

Lin Han ◽

Lili Feng ◽

Yi-Yang Xia ◽

...

Keyword(s):

Blood Pressure ◽

Renin Angiotensin System ◽

Renal Vasculature ◽

Angiotensin System ◽

Salt Diet ◽

Low Salt ◽

Independent Mechanism ◽

Pressure Independent ◽

Proliferation In Vitro

Hyperuricemia is associated with hypertension and vascular disease, but whether this represents a causal relationship or an epiphenomenon remains unknown. We recently reported a model of mild hyperuricemia in rats that results in increased blood pressure and mild renal fibrosis. In this study, we examined the effect of hyperuricemia on the renal vasculature. Rats fed 2% oxonic acid and a low-salt diet for 7 wk developed mild hyperuricemia (1.8 vs. 1.4 mg/dl, P < 0.05), hypertension [147 vs. 127 mmHg systolic blood pressure (SBP), P < 0.05], and afferent arteriolar thickening, with a 35% increase in medial area ( P < 0.05). Allopurinol or benziodarone prevented the hyperuricemia, hypertension, and arteriolopathy. Hydrochlorothiazide treatment did not prevent the hyperuricemia or arteriolopathy despite controlling blood pressure. In contrast, the arteriolopathy and hypertension were prevented by both enalapril and losartan. Uric acid also directly stimulated vascular smooth muscle cell proliferation in vitro, and this was partially inhibited by losartan. Thus hyperuricemia induces a renal arteriolopathy in rats that is blood pressure independent and involves the renin-angiotensin system.

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High salt intake induces left ventricular interstitial fibrosis by a blood pressure and angiotensin II type 1 receptor‐independent mechanism

The FASEB Journal ◽

10.1096/fasebj.23.1_supplement.626.9 ◽

2009 ◽

Vol 23 (S1) ◽

Author(s):

Daniele Nunes Ferreira ◽

Isis A. Katayama ◽

Ivone B. Oliveira ◽

Kaleizu T. Rosa ◽

Michella S. Coelho ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Salt Intake ◽

Interstitial Fibrosis ◽

Left Ventricular ◽

High Salt ◽

High Salt Intake ◽

Independent Mechanism

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Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01103.2007 ◽

2008 ◽

Vol 294 (2) ◽

pp. H1058-H1066 ◽

Cited By ~ 37

Author(s):

Johannes Jacobi ◽

Renke Maas ◽

Nada Cordasic ◽

Kilian Koch ◽

Roland E. Schmieder ◽

...

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Asymmetric Dimethylarginine ◽

Interstitial Fibrosis ◽

Target Organ Damage ◽

Organ Damage ◽

Target Organ ◽

Ang Ii ◽

Renal Interstitial Fibrosis

The aim of the present study was to investigate the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) in angiotensin II (ANG II)-induced hypertension and target organ damage in mice. Mice transgenic for the human DDAH1 gene (TG) and wild-type (WT) mice (each, n = 28) were treated with 1.0 μg·kg−1·min−1 ANG II, 3.0 μg·kg−1·min−1 ANG II, or phosphate-buffered saline over 4 wk via osmotic minipumps. Blood pressure, as measured by tail cuff, was elevated to the same degree in TG and WT mice. Plasma levels of ADMA were lower in TG than WT mice and were not affected after 4 wk by either dose of ANG II in both TG and WT animals. Oxidative stress within the wall of the aorta, measured by fluorescence microscopy using the dye dihydroethidium, was significantly reduced in TG mice. ANG II-induced glomerulosclerosis was similar between WT and TG mice, whereas renal interstitial fibrosis was significantly reduced in TG compared with WT animals. Renal mRNA expression of protein arginine methyltransferase (PRMT)1 and DDAH2 increased during the infusion of ANG II, whereas PRMT3 and endogenous mouse DDAH1 expression remained unaltered. Chronic infusion of ANG II in mice has no effect on the plasma levels of ADMA after 4 wk. However, an overexpression of DDAH1 alleviates ANG II-induced renal interstitial fibrosis and vascular oxidative stress, suggesting a blood pressure-independent effect of ADMA on ANG II-induced target organ damage.

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