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Immunolocalization of renin, Kidney tissue section from CsA treated rat showing a glomerulus with its afferent arteriole. Renin immunoreactivity is observed in the JGA and along the afferent arteriole. Magnification x 500.
Source publication
To determine whether Cyclosporine A (CsA) alters the intrarenal expression of the renin and type 1 angiotensin II receptor genes, male adult Sprague-Dawley rats were given 25 mg/kg/day CsA s.c. for three weeks (CsA, N = 20) and were compared to pair-fed vehicle treated rats (Con, N = 20). The intrarenal distribution of renin and its mRNA was assess...
Contexts in source publication
Context 1
... analysis Comparison between blood pressure, plasma renin activity, histochemical ratios and grain counts of CsA and Con groups D The distribution of renin within the kidney of Con and CsA treated rats is shown in Figures 1 and 2. Renin immunoreactiv- ity was markedly enhanced in CsA (Fig. 1) when compared to Con (Fig. 2). ...
Context 2
... analysis Comparison between blood pressure, plasma renin activity, histochemical ratios and grain counts of CsA and Con groups D The distribution of renin within the kidney of Con and CsA treated rats is shown in Figures 1 and 2. Renin immunoreactiv- ity was markedly enhanced in CsA (Fig. 1) when compared to Con (Fig. 2). The intrarenal distribution of renin was altered in the CsA group (Fig. 1). Immunoreactive renin was observed along afferent arterioles upstream from the glomerulus in the CsA group whereas it was limited to the classical juxtaglomer- ular location in the Con group. The mean length of AA immunostaining ...
Context 3
... plasma renin activity, histochemical ratios and grain counts of CsA and Con groups D The distribution of renin within the kidney of Con and CsA treated rats is shown in Figures 1 and 2. Renin immunoreactiv- ity was markedly enhanced in CsA (Fig. 1) when compared to Con (Fig. 2). The intrarenal distribution of renin was altered in the CsA group (Fig. 1). Immunoreactive renin was observed along afferent arterioles upstream from the glomerulus in the CsA group whereas it was limited to the classical juxtaglomer- ular location in the Con group. The mean length of AA immunostaining was higher in CsA (74.1 4.47 m) than in the Con group (37 5.12 pm; P < 0.05). Also, the %LAA was higher in ...
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Introduction:
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Materials and methods:
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Citations
... In addition, we also confirmed that CsA-treated rats developed both systolic and diastolic hypertension as previously demonstrated [14]. Although some data suggest that oxidative stress plays a role [14,33], a primary role of sodium retention in CsA-induced hypertension has been prompted by several evidences [7,8,29]. On this line, by in vivo micropuncture studies we identified that the site for primary sodium reabsorption was the TAL. ...
Background:
The use of Cyclosporin A (CsA) is hampered by the development of nephrotoxicity including hypertension, which is partially dependent on renal sodium retention. To address this issue, we have investigated in vivo sodium reabsorption in different nephron segments of CsA-treated rats through micropuncture study coupled to expression analyses of sodium transporters. To translate the findings in rats to human, kidney transplanted patients with CsA treatment were enrolled in the study.
Methods:
Adult male Sprague-Dawley rats were treated with CsA (15 mg/kg/day) for 21 days, followed by micropuncture study and expression analyses of sodium transporters. CsA-treated kidney transplanted patients with resistant hypertension have been challenged with 50 mg furosemide.
Results:
CsA-treated rats developed hypertension associated with reduced glomerular filtration rate (GFR). In vivo microperfusion study demonstrated a significant decrease in rate of absolute fluid reabsorption (Jv) in the proximal tubule (PT) but enhanced sodium reabsorption (JNa) in thick ascending limb of Henle's loop (TAL). Expression analyses of sodium transporters at the same nephron segments further revealed a reduction in Na+-H+ exchanger isoform 3 (NHE3) in the renal cortex, while TAL-specific, furosemide-sensitive Na+-K+-2Cl- cotransporter (NKCC2) and NHE3 were significantly upregulated in ISOM. CsA-treated patients had a larger excretion of urinary NKCC2 protein at basal condition, and higher diuretic response to furosemide, showing increased FeNa+, FeCl- and FeCa2+ compared to both healthy controls and FK506-treated transplanted patients.
Conclusion:
All together, these findings suggest that up-regulation of NKCC2 along the TAL facilitates sodium retention and contributes to the development of CsA-induced hypertension.
... Several investigations have shown that CsA-treated rats have enhanced plasma renin activity [88], Ang II levels [89], and tissue renin synthesis [90]. Furthermore, CsA therapy increases angiotensin-converting enzyme activity (ACE) [91], upregulates AT1-R in vascular and renal tissue [92], and accelerates the vasoconstrictive effects of Ang II [93]. Treatment with UGT1A1 antisense in combination with CsA significantly decreased mRNA expression of renal AT1-R compared with the CsA-treated group. ...
Cyclosporine A (CSA) is an immunosuppressive drug that has improved transplant survival rates. However, its use is often limited because it is thought to be linked to the development of chronic kidney disease after kidney transplants. This study aimed to investigate the protective effects and underlying mechanisms of physiological unconjugated (UC) hyperbilirubinemia mediated by UGT1A1 antisense oligonucleotide in a mouse model of CsA-induced chronic kidney disease, and match these with that of chitosan (CH) as a natural chelator against kidney injury. In the current study, CsA-treated mice were given an intravenous injection of UGT1A1 antisense morpholino oligonucleotide (16 µg/kg) every third day for 14 days. In serum samples, bilirubin, creatinine, and urea were determined. Markers of oxidative stress, antioxidant activities, and mRNA expression of target genes PPAR-α, cFn, eNOS, NF-B, AT1-R, ETA-R, Kim-1, and NGAL were measured in the kidney tissues. Moreover, histopathological examinations were carried out on the kidney tissue. Physiological UC hyperbilirubinemia could be a promising protective strategy against CsA-induced kidney disease in transplant recipients. UGT1A1 antisense oligonucleotide-induced physiological UC hyperbilirubinemia serum significantly protected against CsA-induced kidney dysfunction. UCB acts as a signaling molecule that protects against kidney disease through different mechanisms, including antioxidant, anti-inflammatory, and hormonal action, by activating nuclear hormone receptors (PPAR-α). Moreover, it significantly downregulated mRNA expression of NF-kB, ETA-R, iNOS, AT1-R, cFn, Kim-1, and NGAL in the kidney tissue and alleviated CsA-induced kidney histological changes in CsA-treated mice.
... CNI are known to suppress the expression of angiotensin II receptor type 1 (AT1R). 34 In our experiments, AT1R mRNA was reduced in CsA-treated MD cells as well (−45%, P < .001; Figure S2D). Despite this fact, Ang II still exerted significant effects suggesting that the residual AT1R expression was sufficient to mediate Ang II signalling. ...
Aim
The use of calcineurin inhibitors such as cyclosporine A (CsA) for immunosuppression after solid organ transplantation is commonly limited by renal side effects. CsA‐induced deterioration of glomerular filtration rate and sodium retention may be related with juxtaglomerular dysregulation due to suppressed cyclooxygenase 2 (COX‐2) and stimulated renin biosynthesis. We tested, whether CsA‐induced COX‐2 suppression is caused by hyperactive renin‐angiotensin system (RAS) and whether RAS inhibition may alleviate the related side effects.
Methods
Rats received CsA, the RAS inhibitor candesartan, or the COX‐2 inhibitor celecoxib acutely (3 days) or chronically (3 weeks). Molecular pathways mediating effects of CsA and RAS on COX‐2 were studied in cultured macula densa cells.
Results
Pharmacological or siRNA‐mediated calcineurin inhibition in cultured cells enhanced COX‐2 expression via p38 mitogen‐activated protein kinase and NF‐kB signaling, whereas angiotensin II abolished these effects. Acute and chronic CsA administration to rats led to RAS activation along with reduced cortical COX‐2 expression, creatinine clearance, and fractional sodium excretion. Evaluation of major distal salt transporters, NKCC2 and NCC, showed increased levels of their activating phosphorylation upon CsA. Concomitant candesartan treatment blunted these effects acutely and completely normalized the COX‐2 expression and renal functional parameters at long‐term. Celecoxib prevented the candesartan‐induced improvements of creatinine clearance and sodium excretion.
Conclusion
Suppression of juxtaglomerular COX‐2 upon CsA results from RAS activation, which overrides the cell‐autonomous, COX‐2‐stimulatory effects of calcineurin inhibition. Angiotensin II antagonism alleviates CsA nephrotoxicity via the COX‐2‐dependent normalization of creatinine clearance and sodium excretion.
... Thus, renin null cells not only persisted but also their distribution and number along the renal arterial tree were expanded in a pattern that replicated the distribution of renin cells during fetal development and in response to physiological stress in adult animals. 17,29,[44][45][46][47][48] The underlying mechanisms responsible for the renin null cells' attempt to maintain the endocrine phenotype of the native renin cell are intriguing. Renin cells are sensors designed to receive and respond to signals that convey the composition and volume of the extracellular fluid and the level of blood pressure. ...
Experimental or spontaneous genomic mutations of the renin-angiotensin system or its pharmacological inhibition in early life leads to renal abnormalities, including poorly developed renal medulla, papillary atrophy, hydronephrosis, inability to concentrate the urine, polyuria, polydipsia, renal failure, and anemia. At the core of such complex phenotype is the presence of unique vascular abnormalities: the renal arterioles do not branch or elongate properly and they have disorganized, concentric hypertrophy. This lesion has been puzzling because it is often found in hypertensive individuals whereas mutant or pharmacologically inhibited animals are hypotensive. Remarkably, when renin cells are ablated with diphtheria toxin, the vascular hypertrophy does not occur, suggesting that renin cells per se may contribute to the vascular disease. To test this hypothesis, on a Ren1c-/- background, we generated mutant mice with reporter expression (Ren1c-/-;Ren1
c
-Cre;R26R.mTmG and Ren1c-/-;Ren1
c
-Cre;R26R.LacZ) to trace the fate of renin
null
cells. To assess whether renin
null
cells maintain their renin promoter active, we used Ren1c-/-;Ren1
c
-YFP mice that transcribe YFP (yellow fluorescent protein) directed by the renin promoter. We also followed the expression of Akr1b7 and miR-330-5p, markers of cells programmed for the renin phenotype. Contrary to what we expected, renin
null
cells did not die or disappear. Instead, they survived, increased in number along the renal arterial tree, and maintained an active molecular memory of the myoepitheliod renin phenotype. Furthermore, null cells of the renin lineage occupied the walls of the arteries and arterioles in a chaotic, directionless pattern directly contributing to the concentric arterial hypertrophy.
... La ciclosporine entraîne non seulement une augmentation de la sécrétion de rénine mais aussi une augmentation de sa synthèse par l'appareil juxtaglomérulaire (174) ce qui entraînerait une hyperplasie de cet ensemble fonctionnel lors d'un traitement chronique par ciclosporine (175). Il y a un recrutement de cellules avec accumulation de rénine au niveau de l'artériole glomérulaire afférente lors d'un traitement par ciclosporine (176). Par ailleurs, l'hyperplasie de l'appareil juxta-glomérulaire et le recrutement précoce de macrophages avec la prolifération d'autres cellules inflammatoires au niveau tubulo-interstitiel sont associés à la hyalinose artériolaire afférente ainsi qu'à la fibrose interstitielle avec atrophie tubulaire (177). ...
Cyclosporine A (cyclo) is a widely used drug in kidney transplantation: its anticalcineurin actioninhibits T lymphocytes activation and prevents allograft rejection. Despite a huge benefit on graftsurvival, cyclo exerts a side effect that limits its use: nephrotoxicity. Vasculotoxicity appears to becentral: cyclo enhances renal vasoconstriction by altering vasoactive factors and vascular smoothmuscle cells (VSMC) response to vasoactive factors. Beyond its effects on sodium reabsorption,Mineralocorticoid Receptor (MR) acts on vascular tone by modulating both endothelial and VSMCresponses to vasoactive factors. Our working hypothesis was that MR could participate to cycloinducedvasoconstriction and that MR inactivating (pharmacologically or genetically) could alleviatecyclo-induced nephrotoxicity. Two genetically MR-knock out (MR-KO) were generated: inendothelial or VSMC. Only VSMC MR-KO mice were protected from cyclo-induced nephrotoxicity.We also show that such an effect was mediated by vascular tone modulation. This prevention was alsoconferred by the systemic pharmacological antagonism of MR (by canrenoate) in mice but not duringnephrotoxicity induced by tacrolimus (another anticalcineurine drug used in kidney transplantation).Then, we proposed to use MR pharmacological antagonism in humans (by eplerenone) during kidneytransplantation. We first had to prove its safety in such a population. Among 31 cyclo-treated patients,only 9 developed hyperkalemia (>5mmol/L) and none presented serious side effect. We propose akalemia higher than 4.35mmol/L at baseline to be the marker of a higher risk of developinghyperkalemia under treatment. The efficiency of eplerenone to prevent/alleviate cyclo-inducednephrotoxicity during kidney transplantation should be tested during a randomized controlled trial.
... In the present study, in agreement with our previous investigation [Damiano et al., 2013], we have demonstrated that chronic treatment with CsA significantly increase the BP after 21 days of treatment at the dose of 15 mg/kg/ i.p./die/2 ml (Fig. 1). Several researchers suggest an important role of oxidative stress in CsA induced hypertension and renal failure [Tufro-McReddie et al., 1993;Damiano et al., 2013], but the mechanism by which CsA causes these effects is still unclear. ...
... Apocynin restored this effect (*P < 0.05 vs. control group, # P < 0.05 vs. the CsA group). fibronectin abundance, during CsA chronic renal injury is in agreement with the previous hypothesis that a pivotal role in the pathophysiologic process induced by CsA is made by the fibrosis and vasoconstriction [Tufro-McReddie et al., 1993]. ...
Cyclosporine A (CsA) is the prototype of immunosuppressant drugs that has provided new perspectives in human and veterinary medicine to prevent organ transplant rejection and to treat certain autoimmune diseases and dermatologic diseases. Unfortunately, the treatment with CSA is often limited by severe adverse effects such as hypertension and nephrotoxicity. Some data suggest that reactive oxygen species and the oxidative stress play an important role in its pathogenesis, in particular the superoxide (O2 -) that is the most powerful free radical generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase present mainly in the kidney. The present study has been designed to investigate the role of Apocynin a selective inhibitor of NADPH oxidase activity on cyclosporine-induced adverse effect. In this study we have evaluated the effect of CsA, used alone or in association with Apocynin on blood pressure (BP), on glomerular filtration rate(GFR), on absoluted fluid reabsorption (Jv) in proximal tubule (PT), on O2 - concentration and on nitric oxide (NO) production. We have demonstrated that CsA administration increase superoxide concentration in the aorta, decrease the NO concentration, reduce GFR and the Jv in PT and induce a significant increase BP. Moreover, we have shown that Apocynin treatment restore these haemodynamic alterations, as well as NO and superoxide productions. In conclusion, the reported data indicate that CsA induced nephrotoxicity and hypertension are related to NADPH oxidase activity, in fact Apocynin protects the kidney function and blood pressure from toxic effects induced by CsA through the inhibition of NADPH oxidase activity. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
... Nevertheless, inhibition of AT 1 Rs by valsartan diminished the deleterious effects of I/R on glomerular function and renal microcirculation in a rat model of ischemic acute renal failure (16). There is evidence that calcineurin inhibitors do upregulate AT 1 Rs (17). The use of angiotensin-converting enzyme inhibitors or AT 1 R blockers in patients experiencing delayed allograft function was associated with longer transplant survival (18) and graft survival in general (19). ...
We previously described angiotensin II type 1 receptor-activating antibodies (AT1R-Abs) in renal transplant recipients with vascular rejection and malignant hypertension. In this study, we tested the hypothesis that AT1R-Abs can cause renal artery contraction by AT1R activation with renal ischemia representing a key permissive factor and therefore contribute to renal pathologic condition.
Isolated renal and mesenteric arteries from Lewis rats were incubated with purified AT1R-Abs from patients with human leukocyte antigen antibody-negative vascular rejection. Vascular contraction was measured using small vessel myography. The measurements were repeated with renal arteries derived from native kidneys subjected to ischemia-reperfusion or after transplantation in a low-responder Fischer 344-to-Lewis rat kidney-transplantation model.
AT1R-Abs acted in a vascular bed-specific manner and caused small contractions only in native rat renal arteries but not in mesenteric arteries. AT1R-Abs did not alter the vascular reactivity to phenylephrine, angiotensin II, or acetylcholine in native renal arteries. In contrast, AT1R-Abs caused a pronounced (>10-fold) contraction of renal arteries after ischemia and after allogeneic transplantation. Pretreatment with pharmacologic AT1R blocker only partially inhibited the AT1R-Abs-induced contraction, which was almost completely abolished by neutralizing peptides targeting epitopes of AT1R-Abs on the second loop of AT1R.
These data demonstrate that AT1R-Abs can induce renal vascular contraction under predisposing conditions such as in ischemic or transplanted kidneys. Neutralizing antibodies against specific epitopes in the AT1R can ameliorate this contraction.
... This experiment determined whether the hypotensive effect of ethanol in glycerol-treated rats could be replicated in other models of acute (cisplatin, single dose of 10 mg/kg i.p.; Santos et al., 2007) or chronic renal failure (cyclosporine, 25 mg/kg/day for 3 weeks s.c.; Tufro-McReddie et al., 1993). Four groups of rats (two cisplatin and two cyclosporine, n = 6 each) were used and allocated to receive i.v. ...
... for renin on kidney samples from animals treated by CI for 7 or 28 days showed an increase in numbers of staining foci in the kidney cortex and elongated expression of renin along the afferent arterioles, suggesting that CI treatment resulted in the recruitment of renin-containing cells (Figs. 6C–E, 7-day data not shown; Iijima et al., 2000; Tufromcreddie et al., 1993). Renin staining in the kidney juxtaglomerular cells of CI-treated animals is less intense than in the control or Rapatreated animals, probably due to increased renin release from these cells, which supports the activation of RAS following CI treatment. ...
Calcineurin inhibitor (CI) therapy has been associated with chronic nephrotoxicity, which limits its long-term utility for suppression of allograft rejection. In order to understand the mechanisms of the toxicity, we analyzed gene expression changes that underlie the development of CI immunosuppressant-mediated nephrotoxicity in male Sprague-Dawley rats dosed daily with cyclosporine (CsA; 2.5 or 25 mg/kg/day), FK506 (0.6 or 6 mg/kg/day), or rapamycin (1 or 10 mg/kg/day) for 1, 7, 14, or 28 days. A significant increase in blood urea nitrogen was observed in animals treated with CsA (high) or FK506 (high) for 14 and 28 days. Histopathological examination revealed tubular basophilia and mineralization in animals given CsA (high) or FK506 (low and high). We identified a group of genes whose expression in rat kidney is correlated with CI-induced kidney injury. Among these genes are two genes, Slc12a3 and kidney-specific Wnk1 (KS-Wnk1), that are known to be involved in sodium transport in the distal nephrons and could potentially be involved in the mechanism of CI-induced nephrotoxicity. The downregulation of NCC (the Na-Cl cotransporter coded by Slc12a3) in rat kidney following CI treatment was confirmed by immunohistochemical staining, and the downregulation of KS-Wnk1 was confirmed by quantitative real-time-polymerase chain reaction (qRT-PCR). We hypothesize that decreased expression of Slc12a3 and KS-Wnk1 could alter the sodium chloride reabsorption in the distal tubules and contribute to the prolonged activation of the renin-angiotensin system, a demonstrated contributor to the development of CI-induced nephrotoxicity in both animal models and clinical settings. Therefore, if validated as biomarkers in humans, SLC12A3 and KS-WNK1 could potentially be useful in the early detection and reduction of CI-related nephrotoxicity in immunosuppressed transplant patients when monitoring the health of kidney xenographs in clinical practice.
... Several evidences suggest the involvement of renin angiotensin system (RAS) in CsA induced nephrotoxicity (Mason et al., 1991). Increased renin content in kidney tissues and hyperplasia of granular cells in the juxtaglomerular apparatus have been observed in CsA-treated rats (Nitta et al., 1987;Tufro-McReddie et al., 1993). Avdonin et al. (1999) reported that chronic CsA administration upregulates angiotensin type-1 (AT 1 ) receptors in vascular and renal tissue. ...
... Cyclosporine increases renin release and synthesis directly from JG cells (Kurtz et al., 1988). CsA treatment downregulated AT 1 -receptor gene expression in vivo (Tufro-McReddie et al., 1993) but upregulated AT 1 receptors in human vascular smooth muscle cells (Avdonin et al., 1999). In the present study, administration of AT 1 -receptor antagonist could decrease plasma creatinine and PUN levels, improved GFR and normalized blood pressure suggesting that these effects were mediated by AII. ...
The experiment was conducted to investigate the effects of renin-angiotensin blockade on renal function, renal norepinephrine (NE) contents and renal oxidative stress in Cyclosporine A (CsA) induced renal impairment in rats. Rats were assigned into three groups; group 1 (control group), receiving vehicle (propylene glycol) 1 ml/kg./day, subcutaneously (s/c). for 28 days; group 2 (CsA group), receiving CsA 15 mg/kg/day, s/c for 28 days; group 3 (CsA and losartan (LST) group), receiving CsA 15 mg/kg./day, s/c with the administration of LST 10 mg/k.g./day orally for 28 days. The results showed that CsA administration alone elevated mean arterial pressure (MAP), reduced renal function, as assessed by increased plasma urea nitrogen and decreased glomerular filtration rate. CsA stimulated renal sympathetic activity as assessed by increased renal NE content and induced oxidative stress, as indicated by increased renal malondialdehyde (MDA) and decreased concentrations of renal reduced glutathione (GSH). Losartan, the angiotensin type 1 (AT1) receptor antagonist markedly decreased MAP, improved renal function, reduced renal NE content and reduced renal MDA. It is concluded that enhanced renal sympathetic activity and oxidative stress by CsA were mediated by angiotensin II. Blocking the renin-angiotensin system can ameliorate the renal impairment caused by CsA.
