Magnesium lithospermate B attenuates renal injury in 5/6 renal ablation/infarction rats by mitochondrial pathway of apoptosis

Background. Chronic kidney disease (CKD) is a global health burden with high mortality and morbidity. Clinical efficacy has been demonstrated for Shen Shuai II Recipe (SSR), an approved and widely used Chinese herbal medicine for over 20 years in China, to attenuate CKD progression. In this study, we explored the underlying molecular mechanisms of SSR benefits and studied its effects on apoptosis, a critical process in CKD development and progression. CKD was induced in rats with 5/6 renal ablation and infarction (A/I). Eight weeks after SSR treatment, we mainly assessed the severity of renal injury and fibrosis, the translocation of apoptotic factors in the mitochondrial apoptosis pathway, the degree of mitochondrial dysfunction, and the nuclear and mitochondrial translocation of p53. Furthermore, we detected the interaction of p53 with antiapoptotic Bcl-xL and Bcl-2 proteins. Our results showed that SSR significantly attenuated renal injury and fibrosis and inhibited the mitochondrial accumulation of proapoptotic proteins Bax and Puma and release of cytochrome c from mitochondria to the cytosol in a rat CKD model. In addition, SSR also improved the mitochondrial function and inhibited the nuclear and mitochondrial translocation of p53. In addition, SSR suppressed the p53 transactivation and the interaction of p53 with Bcl-xL and Bcl-2. These results suggested that SSR could block apoptosis in CKD by inhibiting p53 transcriptional-dependent and transcriptional-independent proapoptotic function and the mitochondrial pathway of apoptosis.

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Abstract 153: Born with a Single Kidney versus Nephrectomy: Similar End Point, Different Mechanism of Injury

Hypertension ◽

10.1161/hyp.60.suppl_1.a153 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Xuexiang Wang ◽

Ashley Johnson ◽

Jonathan Lee ◽

Leah Solberg-Woods ◽

Michael R Garrett

Keyword(s):

Renal Function ◽

Renal Injury ◽

Time Course ◽

Course Evaluation ◽

Pathophysiological Mechanism ◽

Mechanism Of Injury ◽

Nephron Number ◽

Unilateral Renal Agenesis ◽

Renal Ablation ◽

Single Kidney

A relatively common abnormality of the urogenital tract in humans is the development of only a single kidney (1:500 to 1:1000). Clinical studies suggest that patients born with a single kidney can develop proteinuria, hypertension, and even renal failure later in life. In contrast, studies in children who undergo nephrectomy or adults who serve as kidney donors appear to exhibit little difference in renal function compared to two-kidney subjects. Invasive techniques such as nephrectomy or renal ablation have been used to generate animal models to recapitulate this human congenital disorder. The progression of injury in these models is attributed to hyperfiltration which refers to changes in hemodynamics that cause glomerular damage leading to hypertension. Recently, our lab developed a new genetic animal model [heterogeneous stock derived model of unilateral renal agenesis, (HSRA)] that develops with a single kidney in 50-75% of offspring. The model is characterized by reduced nephron number, kidney hypertrophy, and renal injury that leads to a decline in renal function. Time course evaluation of blood pressure, renal hemodynamics, and renal injury was performed in 4 groups; (1) HSRA-S (1-kidney), (2) HSRA-C (2-kidney littermates), (3) HSRA-UNX3 (uninephrectomy-week 3) and (4) HSRA-UNX8 (uninephrectomy-week 8). Nephrectomized animals demonstrated hyperfiltration, whereas single kidney animals (HSRA-S) did not. This suggests a different pathophysiological mechanism of injury between congenital and nephrectomized rats. At later time points, proteinuria for HSRA-UNX3 (82±22.9 mg/24h) and HSRA-UNX8 (46±18.1) were significantly higher than HSRA-C (11±6.4), while HSRA-S (109±15.7) demonstrated the highest proteinuria. GFR was lowest in HSRA-S (656±123.9 ul/min/gKW), followed by HSRA-UNX3 (1151±112.4), HSRA-UNX8 (1309±98.3) and HSRA-C (1544±111.7). Microarray studies have identified several developmental genes ( Hox5b , Smoc2 and c- Kit ) that may be linked to reduced nephron number and other structural changes that could predispose the HSRA-S to kidney injury later in life. These results demonstrate that rats born with a single kidney are more prone to renal injury than nephrectomized rats and the mechanism is likely different.

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Magnesium lithospermate B ameliorates cephaloridine-induced renal injury

Experimental and Toxicologic Pathology ◽

10.1016/s0940-2993(97)80100-5 ◽

1997 ◽

Vol 49 (5) ◽

pp. 337-341 ◽

Cited By ~ 14

Author(s):

Takako Yokozawa ◽

Erbo Dong ◽

Zhong Wu Liu ◽

Toru Shibata ◽

Masatsune Hasegawa ◽

...

Keyword(s):

Renal Injury ◽

Magnesium Lithospermate B

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Renal expression of COX-2, ANG II, and AT1 receptor in remnant kidney: strong renoprotection by therapy with losartan and a nonsteroidal anti-inflammatory

AJP Renal Physiology ◽

10.1152/ajprenal.00238.2003 ◽

2004 ◽

Vol 286 (5) ◽

pp. F945-F954 ◽

Cited By ~ 57

Author(s):

Anderson Ricardo Roman Gonçalves ◽

Clarice Kazue Fujihara ◽

Ana Lúcia Mattar ◽

Denise Maria Avancini Costa Malheiros ◽

I. L. Noronha ◽

...

Keyword(s):

Renal Injury ◽

Sham Operation ◽

Ang Ii ◽

Treatment Groups ◽

Renal Structure ◽

Renal Ablation ◽

Cox 2 ◽

Anti Inflammatory ◽

Antiinflammatory Effects ◽

Structural Injury

Chronic renal injury can be mediated by angiotensin II (ANG II) and prostanoids through hemodynamic and inflammatory mechanisms and attenuated by individual suppression of these mediators. In rats with ⅚ renal ablation (Nx), we investigated 1) the intrarenal distribution of COX-2, ANG II, and the AT1 receptor (AT1R); 2) the renoprotective and antiinflammatory effects of an association between the AT1R blocker, losartan (Los), and the gastric sparing anti-inflammatory nitroflurbiprofen (NOF). Adult male Munich-Wistar rats underwent Nx or sham operation (S), remaining untreated for 30 days, after which renal structure was examined in 12 Nx rats (Nxpre). The remaining rats were followed during an additional 90 days, distributed among 4 treatment groups: NxV (vehicle), NxLos (Los), NxNOF (NOF), and NxLos/NOF (Los/NOF). Nxpre rats exhibited marked albuminuria, hypertension, glomerulosclerosis, interstitial expansion, and macrophage infiltration, accompanied by abnormal glomerular, vascular, and interstitial COX-2 expression. ANG II appeared in interstitial cells, in contrast to S, in which ANG II was virtually confined to afferent arterioles. Intrarenal AT1R distribution shifted from mostly tubular in S to predominantly interstitial in Nxpre. All these changes were aggravated at 120 days and attenuated by Los and NOF monotherapies. Los/NOF treatment arrested renal structural injury and ANG II expression and reversed hypertension, albuminuria, and renal inflammation. In conclusion, abnormal expression of COX-2, ANG II, and AT1R may be key to development of renal injury in Nx. Concomitant COX-2 inhibition and AT1R blockade arrested renal injury and may represent a useful strategy in the treatment of chronic nephropathies.

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Ac‐SDKP Prevents Renal Injury and Dysfunction in Rats with Subtotal Renal Ablation

The FASEB Journal ◽

10.1096/fasebj.23.1_supplement.605.15 ◽

2009 ◽

Vol 23 (S1) ◽

Author(s):

Tang‐Dong Liao ◽

Xiao‐Ping Yang ◽

Martin A. D'Ambrosio ◽

Yanlu Zhang ◽

Nour‐Eddine Rhaleb ◽

...

Keyword(s):

Renal Injury ◽

Renal Ablation

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Magnesium lithospermate B improves renal hemodynamics and reduces renal oxygen consumption in 5/6th renal ablation/infarction rats

BMC Nephrology ◽

10.1186/s12882-019-1221-5 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 3

Author(s):

Pinglan Lin ◽

Ming Wu ◽

Junyan Qin ◽

Jing Yang ◽

Chaoyang Ye ◽

...

Keyword(s):

Oxygen Consumption ◽

Renal Hemodynamics ◽

Magnesium Lithospermate B ◽

Renal Ablation ◽

Renal Oxygen Consumption ◽

Renal Oxygen

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Curcumin Induces Nrf2 Nuclear Translocation and Prevents Glomerular Hypertension, Hyperfiltration, Oxidant Stress, and the Decrease in Antioxidant Enzymes in 5/6 Nephrectomized Rats

Oxidative Medicine and Cellular Longevity ◽

10.1155/2012/269039 ◽

2012 ◽

Vol 2012 ◽

pp. 1-14 ◽

Cited By ~ 75

Author(s):

Edilia Tapia ◽

Virgilia Soto ◽

Karla Mariana Ortiz-Vega ◽

Guillermo Zarco-Márquez ◽

Eduardo Molina-Jijón ◽

...

Keyword(s):

Antioxidant Enzymes ◽

Protective Effect ◽

Renal Injury ◽

Nuclear Translocation ◽

Interstitial Fibrosis ◽

Oxidant Stress ◽

Systemic Hypertension ◽

Glomerular Sclerosis ◽

Renal Ablation ◽

Glomerular Hypertension

Renal injury resulting from renal ablation induced by 5/6 nephrectomy (5/6NX) is associated with oxidant stress, glomerular hypertension, hyperfiltration, and impaired Nrf2-Keap1 pathway. The purpose of this work was to know if the bifunctional antioxidant curcumin may induce nuclear translocation of Nrf2 and prevents 5/6NX-induced oxidant stress, renal injury, decrease in antioxidant enzymes, and glomerular hypertension and hyperfiltration. Four groups of rats were studied: (1) control, (2) 5/6NX, (3) 5/6NX+CUR,and (4) CUR (n=8–10). Curcumin was given by gavage to NX5/6+CURand CUR groups (60 mg/kg/day) starting seven days before surgery. Rats were studied 30 days after NX5/6 or sham surgery. Curcumin attenuated 5/6NX-induced proteinuria, systemic and glomerular hypertension, hyperfiltration, glomerular sclerosis, interstitial fibrosis, interstitial inflammation, and increase in plasma creatinine and blood urea nitrogen. This protective effect was associated with enhanced nuclear translocation of Nrf2 and with prevention of 5/6NX-induced oxidant stress and decrease in the activity of antioxidant enzymes. It is concluded that the protective effect of curcumin against 5/6NX-induced glomerular and systemic hypertension, hyperfiltration, renal dysfunction, and renal injury was associated with the nuclear translocation of Nrf2 and the prevention of both oxidant stress and the decrease of antioxidant enzymes.

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Resistance to Remnant Nephropathy in the Wistar-Furth Rat

Journal of the American Society of Nephrology ◽

10.1681/asn.v104814 ◽

1999 ◽

Vol 10 (4) ◽

pp. 814-821

Author(s):

WAYNE R. FITZGIBBON ◽

EDDIE L. GREENE ◽

JASJIT S. GREWAL ◽

FLORENCE N. HUTCHISON ◽

SALLY E. SELF ◽

...

Keyword(s):

Renal Injury ◽

Renal Mass ◽

Wistar Rats ◽

Renal Damage ◽

Mass Reduction ◽

Mesangial Proliferation ◽

Antihypertensive Regimen ◽

Renal Ablation ◽

Study Support ◽

And Control

Abstract. The Wistar-Furth rat, an inbred strain resistant to actions of mineralocorticoids, was used to study the concept that mineralocorticoids contribute to progressive renal injury. It was postulated that if chronic nephropathy depends on aldosterone and if Wistar-Furth rats are resistant to aldosterone, remnant nephropathy would be attenuated in Wistar-Furth rats. Wistar-Furth rats and control Wistar rats were subjected to 5/6 nephrectomy or a sham procedure and then followed for 4 wk. Renal ablation resulted in hypertension at 4 wk in both strains (164 ± 5 [Wistar-Furth] versus 184 ± 7 [Wistar] mmHg mean arterial pressure), with sham animals remaining normotensive (134 ± 6 mmHg). Renal damage in response to 5/6 nephrectomy was greatly decreased in Wistar-Furth rats compared with Wistar rats. Albuminuria was markedly less in Wistar-Furth rats (12.7 ± 4.2 [Wistar-Furth] versus 97.4 ± 22.6 [Wistar] mg/d per 100 g body wt, P < 0.01). Glomerular damage, consisting of mesangial proliferation, mesangial lysis, and segmental necrosis, was observed in 42% of glomeruli from Wistar rats but in 0% of glomeruli from Wistar-Furth rats (P < 0.01). To address the possibility that higher BP in partially nephrectomized Wistar rats mediated the greater renal damage, the study was repeated, with Wistar rats (not Wistar-Furth rats) being treated with a hydralazine-reserpine-hydrochlorothiazide regimen. Although this antihypertensive regimen equalized BP (conscious systolic) (144 ± 8 mmHg [Wistar] versus 157 ± 7 mmHg [Wistar-Furth] at 4 wk), albuminuria remained more than 10-fold greater in Wistar rats. In summary, renal damage upon 5/6 nephrectomy was markedly reduced in Wistar-Furth rats, a finding not attributable to reduced systemic BP. Since Wistar-Furth rats have been shown previously to be resistant to the actions of mineralocorticoids, the data from the present study support the hypothesis that aldosterone mediates, at least in part, the renal injury attendant to renal mass reduction.

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Chronic inhibition of nuclear factor-κB attenuates renal injury in the 5/6 renal ablation model

AJP Renal Physiology ◽

10.1152/ajprenal.00184.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. F92-F99 ◽

Cited By ~ 84

Author(s):

Clarice K. Fujihara ◽

Gláucia R. Antunes ◽

Ana L. Mattar ◽

Denise M. A. C. Malheiros ◽

José M. Vieira ◽

...

Keyword(s):

Renal Injury ◽

Immunohistochemical Analysis ◽

Nuclear Factor Κb ◽

Pyrrolidine Dithiocarbamate ◽

Sham Operation ◽

Ang Ii ◽

Renal Ablation ◽

Glomerular Hypertension ◽

New Strategy ◽

Ablation Model

Recent studies indicated that the nuclear transcription factor, NF-κB, activates a number of proinflammatory genes in subjects with progressive nephropathies. We investigated whether NF-κB inhibition limits progressive renal injury in the 5/6 renal ablation model (Nx). Adult male Munich-Wistar rats were subdivided in four groups: S ( n = 16), subjected to sham operation; S+PDTC ( n = 18), sham-operated rats receiving the NF-κB inhibitor pyrrolidine-dithiocarbamate (PDTC; 60 mg·kg−1·day−1) in drinking water; Nx ( n = 16), Nx rats receiving vehicle only; and Nx+PDTC ( n = 19), Nx rats given PDTC as above. Thirty days after renal ablation, Nx rats exhibited systemic and glomerular hypertension. Only the former was attenuated by PDTC treatment. Sixty days after renal ablation, Nx rats exhibited marked hypertension, albuminuria and creatinine retention, as well as glomerulosclerosis and cortical interstitial expansion/inflammation. Immunohistochemical analysis of Nx rats showed renal interstitial infiltration by macrophages and by cells staining positively for ANG II and its receptor, AT1. Glomerular and interstitial cells expressing the p65 subunit of the NF-κB system were also found. PDTC treatment attenuated renal injury and inflammation, as well as the density of cells staining positively for the p65 subunit. Activation of the NF-κB system plays an important role in the pathogenesis of renal injury in the Nx model. Inhibition of this system may represent a new strategy to prevent the progression of chronic kidney disease.

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