However, forskolin treatment significantly reduced their tissue levels by The effect of forskolin on the oxidative stress markers in a model of acute renal toxicity induced by cisplatin in experimental rats. Cisplatin induced a marked increase in TNF α, IL 1β, NF-kB, iNOS, MCP-1, and ICAM-1 levels in the renal tissues by 8.

The effect of forskolin on the inflammatory markers in a model of acute renal toxicity induced by cisplatin in experimental rats. The effect of forskolin on the levels of A ICAM-1 and B MCP-1 in the renal tissues in a model of acute renal toxicity induced by cisplatin in experimental rats.

a Statistically significant when examined in contrast to the negative control group. b Statistically significant when examined in contrast to the cisplatin group.

The level of caspase-3 expression in the renal tissues was 9. Cisplatin injection induced a 5. The effect of forskolin on A the expression of caspase-3 enzyme and B Bax to Bcl-2 ratio in the renal tissues in a model of acute renal toxicity induced by cisplatin in experimental rats.

Considering the Bax to Bcl-2 ratio, cisplatin showed to increase it by Notably, this ratio was significantly reduced in the forskolin-treated group, which showed no marked difference, when examined in contrast to the negative control group Figure 2B.

Markedly, cisplatin reduced EGF expression in the renal tissues by In contrast, forskolin attenuated this reduction by Additionally, there were no marked changes in the expression of the EGF in the forskolin-only-injected group, when examined in contrast to the negative control group.

The effect of forskolin on the expression of EGF in the renal tissues in a model of acute renal toxicity induced by cisplatin in experimental rats. Histopathological investigations results are shown in Figure 4 and also presented in Table 4.

Renal sections were obtained from all the assessed groups to evaluate the histopathological changes evoked by the different regimens of treatment. Indeed, the negative control section showed normal structures of both the renal glomeruli and tubules Figure 4A and B.

Also, cystic dilatation and patches of severe focal haemorrhage were particularly detected Figure 4C and D. No histological changes were detected in the renal sections obtained from the forskolin-only-injected group Figure 4F. The photomicrographs of the kidney sections that represent the different groups, stained by haematoxylin and eosin: A and B The control group showing normal histological structure of the kidney including both the glomeruli g and the tubules t.

C and D Renal sections obtained from the cisplatin-receiving group showing severe necrosis n , severe degeneration d as well as cystic dilatation of the renal tubules with some focal haemorrhage patches h in between see C. Additionally, homogenous eosinophilic casts were detected in the lumen of the tubules in the medullary part c see D.

E Renal section obtained from the forskolin-treated group showing moderate degeneration d and mild congestion g in the lining endothelium of the glomeruli. F Renal section obtained from the forskolin-only-treated rats showing no histological alterations.

The survival fraction of the different cancerous cells, when examined in contrast to the untreated control cell, is displayed in Figure 5. The treatment of all the types of human cancerous cells with cisplatin for 24 h induced a significant cytotoxicity, in a concentration-dependent way.

The inhibitory concentration 50 of the anti-cancer agent, cisplatin, was calculated to be 8. However, in the forskolin pre-treated wells, the inhibitory concentration 50 of cisplatin was 7. It was shown that the pre-treatment of cancer cells with forskolin, at a concentration of µM, for 24 h did not significantly alter the cytotoxic activity of cisplatin.

This was the first study to evaluate the possible protective effects conferred by the phytochemical, forskolin, against cisplatin-induced acute renal toxicity in rats. Besides, the plausible mechanisms contributing to this renoprotective impact were examined, including the oxidative stress, inflammation, apoptosis and the survival signals.

Moreover, to ensure that forskolin treatment would not negatively affect the activity of cisplatin as a cytotoxic agent, the modulatory effect of forskolin on the cytotoxic action of cisplatin was assessed in vitro.

Certainly, cisplatin-receiving rats showed a marked reduction in the total body weight besides a significant increase in the renal index. Also, other renal toxicity markers, including mortality, serum creatinine and BUN, were markedly increased, confirming the induction of the acute nephrotoxicity.

Several previous studies stated similar effects of the anti-cancer agent, cisplatin. Moreover, the histopathological examination confirmed severe degeneration, necrosis and haemorrhage in the renal sections observed from the cisplatin-treated group, whereas only moderate degeneration and mild congestion were observed in the lining endothelium in the group that received the forskolin treatment.

It is worth mentioning that no necrotic death was detected. After the nephroprotective effect of forskolin was reported, the next step was to evaluate the probable mechanisms contributing to this protective activity conferred by forskolin.

Definitely, cisplatin administration is correlated with a marked diminution of the intracellular anti-oxidant guarding mechanisms. Also, the production of the reactive oxygen and nitrogen species is certainly involved in the renal damage evoked by the anti-cancer agent, cisplatin.

Also, the MDA and NOX 1 levels were markedly enhanced, when examined in contrast to the control values. These results are comparable to those mentioned by preceding research studies.

Besides, the lipid peroxidation and NADPH oxidase-1 expression in renal tissues were particularly declined. Definitely, several anti-oxidant agents provided a marked protective effect against cisplatin-induced renal toxicity via reducing the oxidative stress.

Besides the contribution of the oxidative stress in the pathogenesis of cisplatin-evoked renal toxicity, inflammation is certainly involved. Consequently, the use of many anti-inflammatory agents notably lessened cisplatin-induced renal toxicity.

However, the levels of the assessed markers were markedly reduced in the renal tissues observed in the rats that received forskolin treatment, confirming its anti-inflammatory activity. As per previous studies, forskolin has considerable anti-inflammatory and anti-oxidant activities in vivo.

The link between the oxidative stress, inflammation and apoptosis is well documented. Besides, the engagement of the apoptotic pathways, both the intrinsic and the extrinsic, in the cisplatin-evoked renal toxicity is previously proved.

Notably, the forskolin treatment reduced the levels of caspase-3 enzyme and Bax to Bcl-2 ratio, when estimated in contrast to the cisplatin group. Besides apoptosis, the diminution of the growth factors together with their receptors has been shown to be remarkably engaged in the pathological process of the renal toxicity induced by cisplatin.

Ledeganck et al. Also, Gao et al. Moreover, the administration of exogenous EGF [ 49 ] and EGFR activation [ 50 ] enhance the regeneration and repair of renal tubular cells and accelerate renal function restoration following acute kidney injury induced by cisplatin.

Furthermore, using renoprotective agents such as platelet-rich plasma, in cisplatin nephrotoxicity model in rats, enhanced EGF expression as a part of its protective mechanisms.

CREB, in turn, plays an important role in the survival of renal tubules after injury. Eventually, it was important to evaluate the plausible modulatory sequel of forskolin on the cytotoxic action of cisplatin in vitro.

Four human cancerous cells lines were used for this objective, including HCT, PC3, Hela and HepG2 cancer cells. It is worth mentioning that the pre-treatment of the mentioned human cancerous cells with uM forskolin for 24 h did not remarkably alter cisplatin cytotoxicity in the four examined cancer cell lines.

Finally, it might be concluded that this study was the first one to show that forskolin treatment confers a significant renoprotection from the acute renal injury induced by the anti-cancer agent, cisplatin. This renoprotective impact might be partially ascribed to its marked anti-oxidant effect, where it significantly enhanced GSH and SOD renal levels.

This is in addition to the decreased lipid peroxides and NOX 1 levels. Additionally, forskolin markedly attenuated the cisplatin-provoked inflammatory response by reducing the renal levels of the determined pro-inflammatory markers.

Also, forskolin counteracted the cisplatin-enhanced renal cell death via reducing caspase-3 enzyme level and Bax to Bcl-2 ratio. That was in addition to increasing the renal expression of EGF. Moreover, forskolin pre-treatment manifested no effect on the cytotoxic activity of cisplatin in vitro.

Taken together, these findings provide a new providential path for applying forskolin to boost the therapeutic index of the anti-cancer agent, cisplatin.

The author would like to thank Dr. Adel Bakeer Professor in the Department of Pathology, Faculty of Veterinary Medicine at Cairo University, Egypt for the tremendous effort done in the part of the histopathological assessment.

Reem N. El-Naga: Funding, Conceptualization, Conduction of the experimental work, Carrying out the statistical, Formal analysis, and writing the manuscript. This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

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Continuous intravenous administration of CDH at 0. Continuous intravenous administration of CDH at high doses 0.

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Pflügers Arch. Download references. was supported by the Deutsche Forschungsgemeinschaft DFG, German Research Foundation , project number , SFB project A2 and A3. and R. were supported by the Deutsche Forschungsgemeinschaft DFG, German Research Foundation , project number , SFB project A3.

was supported by the Interdisciplinary Center for Clinical Research Erlangen project J This work was performed by J. and K. in fulfillment of the requirements for obtaining the degree Dr. and Dr. We are grateful to Prof.

Peters Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands for providing us with animals with a floxed PKD1 allele. Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D, Regensburg, Germany.

Department of Nephrology and Hypertension, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany. You can also search for this author in PubMed Google Scholar. performed experiments, I. analyzed data and wrote the paper. Correspondence to Karl Kunzelmann. Peer review information Nature Communications thanks the anonymous reviewer s for their contribution to the peer review of this work.

Open Access This article is licensed under a Creative Commons Attribution 4. Reprints and permissions. Cyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo.

Nat Commun 11 , Download citation. Received : 06 February Accepted : 29 July Published : 28 August Anyone you share the following link with will be able to read this content:.

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nature nature communications articles article. Download PDF. Subjects Ion channel signalling Nephrons Polycystic kidney disease. Abstract In autosomal dominant polycystic kidney disease ADPKD multiple bilateral renal cysts gradually enlarge, leading to a decline in renal function.

Introduction Polycystic kidney diseases PKDs comprise a number of inherited disorders that lead to bilateral renal cyst development. Results TMEM16A supports cyst growth in Pkd1-deficient plMDCK cells In ADPKD, cysts mainly originate from principal cells of the collecting duct 9 , Full size image.

Discussion The present data demonstrate the crucial role of TMEM16A for the growth of renal cysts in a mouse model for ADPKD and in Pkd1 -deficient plMDCK cells in vitro.

Table 1 Primers used for genotyping. Full size table. Data availability All relevant data are available from the authors.

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Share Feedback. The accepted level of significance in this work was stated at 0. Concerning kidney functions: There was no significant difference in serum urea and creatinine levels between the control and FSK groups. Glycerol injection significantly increased serum urea, and creatinine level in glycerol AKI group compared to the control group.

Forskolin treatment resulted in a significant reduction in urea, creatinine levels compared to the glycerol AKI group. About oxidative stress markers: There was no significant difference in MDA level and GST activity between the control and FSK groups. Glycerol injection significantly increased MDA level and GST activity in glycerol AKI group compared to the control group.

Forskolin treatment resulted in a significant reduction in MDA level and GST activity compared to the glycerol AKI group. About TNF-α and caspase-3, there was no significant difference in TNF-α level and caspase-3 activity between the control and FSK groups.

Glycerol injection significantly increased TNF-α, and caspase-3in glycerol AKI group compared to the control group. Forskolin treatment resulted in a significant reduction in TNF-α and caspase-3 compared to the glycerol AKI group. This table showed that there is significant downregulation in SIRT1 mRNA expression in glycerol group.

On the other hand there is significant upregulation in SIRT1 mRNA expression with forskolin treatment that indicates renal protective effect of forskolin. Glycerol exposure in AKI group caused severe hemorrhage, inflammatory cell infiltration and edema compared to normal renal histology and architecture of the control and forskolin groups.

Exposure to glycerol in AKI group caused in a significant increase in caspase-3 expression compared to the control and forskolin groups. Renal dysfunction is a very serious medical problem; change of the normal physiological oxidant-anti oxidant balance was reported as a main cause for kidney injuries [ 24 ].

In the current study glycerol injection led to marked down regulation of SIRT1gene expression as well as aggressive increase in urea, creatinine, GST, MDA, TNF-α, Caspase-3 levels and histopathological abnormalities. This was explained by [ 27 ] who stated that glycerol-induced nephrotoxicity is mediated by renal ischemia that induces oxidative stress and lipid peroxidation of the proximal tubular cells, triggering the release of a group of mediators, including caspases and cytokines, leading to activation of the leukocytes leading to tubular necrosis in the renal cortix [ 28 ] and histological changes as tubular injury which are in line with the problems observed clinically [ 29 ].

In the present work administration of forskolin improves the abnormalities of the tested parameters as well as increase SIRT1 expression. Also, decrease the levels of urea, creatinine, MDA, TNF-α and decrease the activities of GST, Caspase-3, improve the histopathological changes.

Forskoline was found to protect against various oxidative stress injuries by its antioxidant, anti-apoptotic and anti-inflammatory effects [ 15 ]. These results suggest that FSK decreases oxidative stress and improves the acute kidney injury of glycerol, this is in agree with [ 30 ] that reported the protective effect of chronic administration of forskolin on glycemia and oxidative stress in rats with and without induced diabetes.

Forskolin increased the indirect anti-oxidant capacity by activating the endogenous anti-oxidant enzymatic defense system [ 33 ], and by increasing the expression of SIRT1 gene, which increases its antioxidant target genes so reduces the ROS in the kidney.

By decreasing the oxidative stress and cellular damage, forskolin improved the GFR and consequently improved plasma urea and creatinine concentrations [ 31 ]. This is in agreement with previous studies which reported that forskolin decreased the lipid peroxidation in pre-treated erythrocytes and concluded that the antioxidant effect of forskolin could be compared with the effects of probucol and vitamin E [ 34 ].

It has been observed that in vitro forskolin increased the level of the antioxidants [ 19 ] Also there is anti-inflammatory effect of forskolin which is related to its antagonistic effect on TNF-α and also by decreasing the level of inflammatory mediators as histamine, interleukins IL-1β,IL-4, IL-6, IL-8 , leukotriene LT-4 , antigens [ 30 ].

It has a regulatory effect on gene silencing; apoptosis and cell proliferation. SIRT1 is involved in the pathogenesis of many kidney problems, SIRT1 can inhibit the apoptosis produced by injury of kidney cell, reduce kidney inflammation, improve function of the mitochondria, and decrease oxidative stress, so, SIRT1 can protect the kidney from acute injury [ 35 ].

SIRT1 activators, FSK exerts a protective effect by inhibiting the effects of cellular stresses, reducing glomerular and tubular cell inflammation and apoptosis. SIRT1 reduces mesangial cell apoptosis that is triggered by oxidative stress by decreasing the activity of p53 activity [ 36 ] and promoting TGF-β-induced apoptotic signaling of glomerular mesangial cells so it protect from oxidative stress, and TGF-β dependent apoptosis.

TGF-β and oxidative stress are responsible for many renal diseases, so chemical activators of SIRT1 improve the cell inflammation was by NF-κB deacetylation [ 37 ]. Production of oxygen free radicals by glycerol enhances oxidative damage in the mitochondria.

That leads to mitochondrial vacuolation and increases production of oxygen free radical and the apoptosis of renal tubular cells, resulting in AKI [ 38 ] through up-regulation of SIRT1 expression by FSK it protects against the acute renal injury induced by glycerol by two mechanisms.

First mechanism, SIRT1 up-regulation can degrade excessive free radicals, so increase purine degradation, and lead to ATP generation thus can ameliorate AKI by inhibition of oxidative stress and the another mechanism, SIRT1 by up-regulating the number and function of mitochondria that have a direct effect on cell apoptosis, ATP synthesis, and maintains the normal cell and organ functions.

Disturbance in Mitochondrial is an important factor for acute kidney disease that is caused by toxic substances or ischemia [ 39 ]. FSK significantly increased the SIRT1 mRNA in kidneys of rats.

The relative amounts of SIRT1 mRNA were higher in rats treated with FSK compared to untreated rats. This is in agreement with [ 40 ] who reported that the oxidative stress is a major cause and aggravating factor for kidney diseases.

Oxidative-stress molecules, as reactive oxygen species, increase in the kidneys of rat models for acute kidney injury, pharmacological up-regulation of sirt1 activity in the renal tubules significantly decreases acute kidney injury and prevents its progression to a chronic kidney disease CKD by ameliorating oxidative stress [ 22 ].

In conclusion the produced beneficial effect of forskolin in protection against nephrotoxicity is due to its ability to modulate the disrupted expression of SIRT1, the pharmacological enhancement of SIRT1, exerts cyto-protective effects through its anti-apoptotic, anti-oxidative, and anti-inflammatory effects, simultaneously with up-regulation of mitochondrial biogenes so forskolin may become a new therapeutic target of kidney disease.

We gratefully thank the technical and administrative staff at the departments of pharmacology, biochemistry and pathology, Faculty of Medicine, Benha University for their assistance and support.

Department of Pharmacology, Faculty of Medicine, Benha University, Egypt. Safwa M. Elnoury, "Forskolin Modulate Silent Information Regulator 1 SIRT1 gene Expression and Halts Experimentally-Induced Acute Kidney Injury," Egyptian Journal of Basic and Clinical Pharmacology , Vol.

About the Journal Abstracting and Indexing Aims and Scope Article Processing Charges Articles in Press Author Guidelines Contact Information Editorial Board Editorial Workflow Publication Ethics Reviewer Guidelines Table of Contents Egyptian Society of Pharmacology and Experimental Therapeutics ESPET.

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Elnoury Department of Pharmacology, Faculty of Medicine, Benha University, Egypt Received 30 October ; Accepted 18 January Editor: Mahmoud El-Mas Copyright © Safwa M. Introduction Nephrotoxicity is one of the most common kidney problems. Materials and Methods 2. Animals Thirty two adult male albino rats at 11—13 weeks old weighing — g were used in this study after acclimatization for one week.

Drugs Forskolin and glycerol were obtained from Sigma-Aldrich Chemical Co. Experimental design Rats were randomly divided into four groups. Sample preparation and biochemical assays Blood was collected via cardiac puncture; the serum was quickly separated through centrifuge.

Immuno-histochemical staining Kidneys were fixed in formalin and then put in paraffin according to the usual histological technique.

RT-qPCR Total RNA was extracted from blood by using RNA Mini Kit Qiagen, USA by using manufacturer's instruction where the quantity and quality of RNA were determined by Nano drops Thermo Fisher Scientific — NanoDrop products Wilmington, Delaware USA.

Statistical Analysis The collected data were tabulated and analyzed using SPSS version 16 software Spss Inc, Chicago, ILL Company data were expressed as mean ± standard deviation and range.

Results Concerning kidney functions: There was no significant difference in serum urea and creatinine levels between the control and FSK groups. Effects of forskolin on renal histopathology Glycerol exposure in AKI group caused severe hemorrhage, inflammatory cell infiltration and edema compared to normal renal histology and architecture of the control and forskolin groups.

Figure 1: A photomicrograph of a cut section in the kidney of a control rat showing normal kidney architecture. Figure 2: A photomicrograph of a cut section in the kidney of a forskolingroup showing normal kidney architecture. Figure 3: A photomicrograph of a cut section in the kidney of AKI group showing severe hemorrhage straight arrow , edemaand inflammatory cell infiltration curved arrow.

Figure 5: A photomicrograph of a cut section in the kidney of a control group with minimal expression of caspase Figure 6: A photomicrograph of a cut section in the kidney of a control group with minimal expression of caspase Effects of forskolin on the apoptosis marker caspase-3 Exposure to glycerol in AKI group caused in a significant increase in caspase-3 expression compared to the control and forskolin groups.

Figure 7: A photomicrograph of a cut section in the kidney of AKI group showing marked expression of caspase Discussion Renal dysfunction is a very serious medical problem; change of the normal physiological oxidant-anti oxidant balance was reported as a main cause for kidney injuries [ 24 ].

Acknowledgements We gratefully thank the technical and administrative staff at the departments of pharmacology, biochemistry and pathology, Faculty of Medicine, Benha University for their assistance and support.

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