Effect of Mycophenolate Mofetil on Kallikrein Expression in the Kidney of 5/6 Nephrectomized Rats

Ardiles, Leopoldo; Ehrenfeld, Pamela; Quiroz, Yasmir; Rodríguez‐Iturbe, Bernardo; Herrera-Acosta, Jaime; Mezzano, Sergio; Figueroa, Carlos D.

doi:10.1159/000066796

Cited by 9 publications

(6 citation statements)

References 45 publications

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“…It has been reported that male rats with 5/6 Nx have a significant reduction in urinary kallikrein activity and in renal kallikrein expression, 13 which is compatible with the renal structural abnormalities and the severe reduction in functional renal mass described in this model. The possible role of reduced kallikrein in some of these alterations is under discussion.…”

Section: Discussionsupporting

confidence: 76%

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Pregnant Rats With 5/6 Nephrectomy Have Normal Volume Expansion Despite Lower Renin and Kallikrein

2003

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Abstract-To test the hypothesis that normal volume expansion during pregnancy is impaired during chronic renal failure, we evaluated the effects of 5/6 nephrectomy (Nx) in Sprague-Dawley rats. Partial Nx was produced by ligation of 2/3 renal arteries and contralateral Nx. Control rats had a sham operation. Four weeks later, rats were assigned to nonpregnant (nϭ6/each) or pregnant groups (nϭ11 to 12/each). At day 21, blood pressure, plasma volume, renal function, hormonal levels, and reproductive outcome were determined. Statistical analysis was performed by ANOVA, and values were expressed as meanϮSEM. Rats with 5/6 Nx had proteinuria and lower creatinine clearance; pregnancy did not affect these parameters. Blood pressure increased in 5/6 Nx rats and was reduced by pregnancy. Key Words: pregnancy Ⅲ kidney failure Ⅲ plasma volume Ⅲ renin Ⅲ kallikrein Ⅲ aldosterone N ormal pregnancy is characterized by an initial reduction in peripheral vascular resistance that leads to several consequences such as decreased blood pressure, higher cardiac output, stimulation of the renin-angiotensin-aldosterone axis, and renal sodium and water retention, with expansion of plasma volume. 1-4 These changes allow an adequate supply of blood to the placenta and the developing fetus, and their absence is associated with pregnancy complications such as preeclampsia and fetal growth restriction. 5,6 To achieve positive sodium balance and cumulative plasma volume expansion, important changes in renal function also occur during pregnancy. There is a rise in glomerular filtration rate (GFR) and in renal plasma flow, the pressure natriuretic response is markedly blunted, 7,8 and vasoactive hormones from renal origin, such as kallikrein and renin, are increased during pregnancy. 9 On the basis of these observations, we have speculated that normal renal function and the ability of the kidney to increase the production of vasoactive hormones are important for adequate plasma volume expansion during pregnancy. To test this hypothesis, in the present study we evaluated the maternal and fetal effects of 5/6 nephrectomy (5/6 Nx) in SpragueDawley rats. In addition to the abnormalities characteristic of chronic renal failure, such as decreased GFR, moderate hypertension, and glomerular disease, 10 5/6 Nx is associated with alterations in the renin-angiotensin-aldosterone and kallikrein-kinin systems. 11-13 Methods Experimental DesignFemale Sprague-Dawley rats (160 to 190 g initial weight) were maintained at the Center for Medical Research animal care facilities in a controlled environment (22°to 24°C and a 12-hour light/dark cycle). The protocols met international guidelines for animal welfare and were reviewed and approved by the Institutional Review Board of the School of Medicine.Partial Nx was accomplished by means of a 2-stage operation, as previously described. 10 Two of three branches of the left renal artery were ligated to produce renal infarction, and contralateral nephrectomy was done 1 week later. Control animals had a sham operation. Fo...

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Section: Discussionsupporting

confidence: 76%

“…In addition to the abnormalities characteristic of chronic renal failure, such as decreased GFR, moderate hypertension, and glomerular disease, 10 5/6 Nx is associated with alterations in the renin-angiotensin-aldosterone and kallikrein-kinin systems. [11][12][13] …”

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confidence: 99%

Pregnant Rats With 5/6 Nephrectomy Have Normal Volume Expansion Despite Lower Renin and Kallikrein

2003

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“…The staining score was expressed as density per millimeters squared. This method of quantification has been validated in previous publications (4,5).…”

Section: Image Analysis Of Immunohistochemistry and In Situ Hybridizamentioning

confidence: 85%

Antihypertensive and renoprotective effect of the kinin pathway activated by potassium in a model of salt sensitivity following overload proteinuria

Ardiles

Cárdenas

Burgos

et al. 2013

American Journal of Physiology-Renal Physiology

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The albumin overload model induces proteinuria and tubulointersitial damage, followed by hypertension when rats are exposed to a hypersodic diet. To understand the effect of kinin system stimulation on salt-sensitive hypertension and to explore its potential renoprotective effects, the model was induced in Sprague-Dawley rats that had previously received a high-potassium diet to enhance activity of the kinin pathway, followed with/without administration of icatibant to block the kinin B₂ receptor (B₂R). A disease control group received albumin but not potassium or icatibant, and all groups were exposed to a hypersodic diet to induce salt-sensitive hypertension. Potassium treatment increased the synthesis and excretion of tissue kallikrein (Klk1/rKLK1) accompanied by a significant reduction in blood pressure and renal fibrosis and with downregulation of renal transforming growth factor-β (TGF-β) mRNA and protein compared with rats that did not receive potassium. Participation of the B₂R was evidenced by the fact that all beneficial effects were lost in the presence of the B₂R antagonist. In vitro experiments using the HK-2 proximal tubule cell line showed that treatment of tubular cells with 10 nM bradykinin reduced the epithelial-mesenchymal transdifferentiation and albumin-induced production of TGF-β, and the effects produced by bradykinin were prevented by pretreatment with the B₂R antagonist. These experiments support not only the pathogenic role of the kinin pathway in salt sensitivity but also sustain its role as a renoprotective, antifibrotic paracrine system that modulates renal levels of TGF-β.

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“…Previous experiments have also indicated that adenovirus mediated HK gene delivery significantly attenuated gentamycin-induced nephrotoxicity and enhanced renal function [13]. The renal protective effects of the KKS have been demonstrated in several hypertensive rat models with progressive renal injury [10,[14][15][16][17]. Together, these findings suggest that a repressed renal KKS may play an important role in the pathogenesis of chronic renal failure and that delivery of the HK gene may represent a novel approach to treat chronic renal failure.…”

Section: Introductionmentioning

confidence: 88%

“…Dahl-salt sensitive rats, which have salt-induced hypertension, exhibit a dysfunctional kallikrein-kinin system (KKS) and are more susceptible to kidney injury than spontaneously hypertensive rats which have similar blood pressure [9]. Decreased kallikrein expression in the kidney of 5/6 nephrectomized rats was recently reported [10]. Dr. Yu and colleagues demonstrated that polymorphisms in the human tissue kallikrein gene promoter are etiologic effectors of hypertension and hypertension-associated end-stage renal failure [11].…”

Section: Introductionmentioning

confidence: 99%

Delivery of Recombinant Adeno-Associated Virus-Mediated Human Tissue Kallikrein for Therapy of Chronic Renal Failure in Rats

Wan

et al. 2008

Human Gene Therapy

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The tissue kallikrein-kinin system is important in regulating cardiovascular and renal function, and dysregulation of the system has been implicated in heart and kidney pathologies. These findings suggest that if balance can be restored to the kallikrein-kinin axis, then associated disease progression may be attenuated. To test this hypothesis, recombinant adeno-associated virus (rAAV)-mediated human tissue kallikrein (HK) expression was induced in a rodent model of chronic renal failure involving 5/6 nephrectomy. rAAV-HK treatment attenuated the rise in blood pressure, glomerular sclerosis, and tubulointerstitial injury observed in this model. rAAV-HK treatment also attenuated renal function decline as measured by urinary microalbumin, osmolarity and cGMP levels. RT-PCR analysis showed that rAAV-HK treated rats had higher levels of bradykinin-B 2 receptor (B 2 R) and dopamine D 1 -like receptor mRNAs. In contrast, angiotensin II receptor 1, endothelin ET A receptor, and vasopressin V 2 receptor mRNAs were markedly downregulated in kidneys from HK-treated rats. Bradykinin induced similar changes in receptor levels and prevented TGF-β1-induced tubulointerstitial fibrosis. The effects of bradykinin could be reversed by the B 2 R antagonist HOE-140. Together, these findings suggest that restoration of the kallikrein-kinin system reduces kidney injury and protects renal function in 5/6 nephrectomized rats via changes in the expression and activation of G-protein coupled receptors including B 2 R.

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Effect of Mycophenolate Mofetil on Kallikrein Expression in the Kidney of 5/6 Nephrectomized Rats

Cited by 9 publications

References 45 publications

Pregnant Rats With 5/6 Nephrectomy Have Normal Volume Expansion Despite Lower Renin and Kallikrein

Pregnant Rats With 5/6 Nephrectomy Have Normal Volume Expansion Despite Lower Renin and Kallikrein

Antihypertensive and renoprotective effect of the kinin pathway activated by potassium in a model of salt sensitivity following overload proteinuria

Delivery of Recombinant Adeno-Associated Virus-Mediated Human Tissue Kallikrein for Therapy of Chronic Renal Failure in Rats

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