Renoprotective activity of aliskiren, a renin inhibitor in cyclosporine A induced hypertensive nephropathy in dTG mice

Saraswat, Megha; Addepalli, Veeranjaneyulu; Jain, Mukul; Pawar, Vishwanath D.; Patel, Rakesh B.

doi:10.1016/j.pharep.2013.08.005

Cited by 9 publications

(6 citation statements)

References 32 publications

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“…Following 28 days of BID 10 mg/kg ALS oral dosing in C57BL/6-(hREN)/(hAGT) double transgenic mice with concurrent coadministered subcutaneous cyclosporine A (20 mg/kg), urinary KIM-1 (approximately 3.25 ng/mL) was not significantly changed ( p > 0.05) compared to the control group. 33 In our study, we may have only observed a transient increase in KIM-1 through NP usage.…”

Section: Discussionmentioning

confidence: 57%

“…This change may also be timedependent as the Saraswat et al study showed that BUN (22.33 + 0.56 mg/dL) was not significantly changed (p > 0.05) compared to the control group. 33 In another study, Sprague-Dawley rats treated with daily intramusculuar gentamicin (100 mg/kg) and ALS (25 mg/ kg) via osmotic pump for 14 days, plasma creatinine concentration was reduced compared to gentamicin alone. 34 Further, in five out of six nephrectomized rats treated with oral 10 mg/kg ALS over 4 weeks, plasma creatinine was significantly reduced (p < 0.05) compared to nephrectomized controls.…”

Section: Discussionmentioning

confidence: 97%

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Formulation and in vivo evaluation of aliskiren-loaded poly(lactic-co-glycolic) acid nanoparticles

Murrell

Coleman

Brown

et al. 2018

Toxicology Research and Application

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Aliskiren (ALS) is a direct renin inhibitor with low bioavailability and high drug cost. The goal of this study was to increase the bioavailability of ALS through nanoformulation. The optimized formulation was then evaluated in spontaneously hypertensive rats (SHRs). We developed an ALS poly(lactic-co-glycolic) acid nanoparticle (ALS-NP) through the emulsion-diffusion-evaporation method with various solvents, stabilizer concentrations, and centrifugation speeds. SHRs were orally dosed with 30 mg/kg ALS or dose equivalent ALS-NP. Several parameters were assayed in plasma and/or urine at baseline and 24 h post-dose, while pharmacokinetic analysis included serial sampling. The optimum formulation was found with ethyl acetate, a 1.00% w/v didodecyldimethylammonium bromide concentration, and a 10,000 r/min (15,554 g) centrifugation speed. A 168% relative bioavailability was observed as a result of ALS-NP administration along with significant, as determined by Student's t-test, increases in the maximum ALS plasma concentration (p ¼ 0.0189) and the area under the plasma concentration-time curve from 0 to infinity (p ¼ 0.0095). Conversely, a reduction was found in oral volume of distribution (p ¼ 0.0009) and oral clearance (p ¼ 0.0298). Blood urea nitrogen increased significantly after dosing in both groups (p < 0.0001 and p < 0.0001); however, no statistical difference was found between endpoint levels (p > 0.05) following one-way analysis of variance (ANOVA). Kidney injury molecule-1 increased following ALS dosing (p ¼ 0.0486), while ALS-NP showed a decrease (p ¼ 0.027) which was also significantly decreased compared to ALS-Final (p ¼ 0.0008) when examined using two-way ANOVA. Urinary potassium excretion decreased significantly, as shown by two-way ANOVA, only in the ALS group (p ¼ 0.0274) which was also significantly reduced compared to ALS-NP-Final (p ¼ 0.016). Using the current formulation and at the dosage tested, ALS-NP showed a more favorable pharmacokinetic profile and positive kidney changes compared to ALS in regard to select outcomes. Thus, NP formulation may further improve ALS renoprotection in addition to increasing bioavailabilty.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 97%

Formulation and in vivo evaluation of aliskiren-loaded poly(lactic-co-glycolic) acid nanoparticles

Murrell

Coleman

Brown

et al. 2018

Toxicology Research and Application

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“…14 In the literature, data are scarce addressing the beneficial effect of Alisk in CNI nephrotoxicity. One of the two related studies has investigated only blood and urine samples in CyA-treated hypertensive mice, 48 the other report focusing on Tac-induced nephropathy has examined whole kidney samples to prove attenuation of oxidative stress. 49 However, none of them focused on the source of renin or explained the subsequent vascular changes.…”

Section: Discussionmentioning

confidence: 99%

Calcineurin-inhibition Results in Upregulation of Local Renin and Subsequent Vascular Endothelial Growth Factor Production in Renal Collecting Ducts

et al. 2016

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Background Tacrolimus (Tac) and Cyclosporine A (CyA) calcineurin inhibitors (CNIs) are 2 effective immunosuppressants which are essential to prevent allograft rejection. Calcineurin inhibitors are known to be nephrotoxic. However, the precise mechanism of nephrotoxicity is not fully understood. In this study, we investigated the in vivo effects of CNIs on the local renal renin-angiotensin system in the collecting duct (CD). Methods Three-week-old mice were treated with either vehicle, CyA (2 mg/kg per day), Tac (0.075 mg/kg per day), CyA + Aliskiren (25 mg/kg per day), or Tac + Aliskiren for 3 weeks. Serum creatinine was measured. Renin and vascular endothelial growth factor (VEGF) contents in CD were evaluated with flow cytometry and multiphoton microscopy. The diameter of vessels was assessed with multiphoton microscopy, and the amount of renal collagen was determined by real-time polymerase chain reaction and Masson staining. Results The elevated level of serum creatinine in CNI groups was abolished by Aliskiren. Flow cytometric analysis found elevated renin content in principal cells, which was prevented by Aliskiren. This result was further confirmed with multiphoton microscopy. The VEGF content in CD correlated with reduced capillary diameter and with the formation of fibrotic islands. Conclusions Calcineurin inhibitors induce production of renin in the CD that may contribute to decreased renal blood flow. In turn, CD responds with increased VEGF production, resulting in disproportional vessel growth, further worsening the local hypoxia and striped fibrosis surrounding the CDs. Aliskiren, a direct renin inhibitor blocks these effects and improves CNI-induced nephropathy by decreasing renin production in the CDs. Our data suggest that Aliskiren may be used for the prevention of CNI nephrotoxicity.

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“…In addition, many research studies have been conducted to suggest supplemental agents to confer additional protection for the kidney against CYCinduced toxicity. These supplemental agents may include herbal drugs [3][4][5] , endothelin-1 receptor antagonists 6 , antihypertensive drugs or β-blockers [7][8][9] , NADPH oxidase activity inhibitor 10 , antioxidants 11 , omega-3 fatty acids 12 , apelin peptide 13 , and/or renin inhibitor 14 . Gender and sex hormones are also important factors that influence the effects of CYC [15][16][17][18][19] .…”

Section: Introductionmentioning

confidence: 99%

Cyclosporine-A induced nephrotoxicity in male and female rats: Is zinc a suitable protective supplement?

et al. 2018

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Background: Cyclosporine (CYC) is an immunosuppressant drug used widely in kidney transplant patient. The major side effect of CYC is nephrotoxicity. In this study, three different doses of CYC alone or accompanied with zinc (Zn) supplement were administrated in male and female rats to determine the kidney tissue damages and functions. Methods: Male and female rats were treated with 10, 50 or 100 mg/kg/day of CYC alone or accompanied with 10 mg /kg/day of Zn sulfate for 10 days. The parameters related to renal function were determined and the kidney tissues were subjected to histological evaluation. Results: All male and female animals were treated with high dose CYC (100 mg/kg/day) alone or accompanied with Zn supplement during the experiment. The data obtained for the serum levels of creatinine (Cr) and blood urea nitrogen/Cr ratio, clearance of Cr, kidney weight (KW), sodium (Na) filtration rate, Na excretion rate and Na excretion fraction (%) in surviving animals suggest a role of gender in the variation of these factors. The kidney tissue damage score (KTDS) was increased as the dosage of CYC was elevated, and the Zn supplement attenuated the KTDS in animals treated with low dose CYC (10 mg/kg/day). Conclusion: The CYC-induced nephrotoxicity may be gender-related, and the 10 mg/kg dose of Zn sulphate as a supplement may possibly prevent the induced nephrotoxicity in males due to its antioxidant effects.

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Renoprotective activity of aliskiren, a renin inhibitor in cyclosporine A induced hypertensive nephropathy in dTG mice

Cited by 9 publications

References 32 publications

Formulation and in vivo evaluation of aliskiren-loaded poly(lactic-co-glycolic) acid nanoparticles

Formulation and in vivo evaluation of aliskiren-loaded poly(lactic-co-glycolic) acid nanoparticles

Calcineurin-inhibition Results in Upregulation of Local Renin and Subsequent Vascular Endothelial Growth Factor Production in Renal Collecting Ducts

Cyclosporine-A induced nephrotoxicity in male and female rats: Is zinc a suitable protective supplement?

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