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Effects of CXB on secretion of VEGF and PGE2 from ADPKD cells. Levels of VEGF (a) and PGE2 (b) in media were determined by ELISA. *P < 0.05, **P < 0.01 vs. control; n = 8
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Autosomal dominant polycystic kidney disease (ADPKD) is a progressive chronic kidney disease. To date there are no effective medicines to halt development and growth of cysts. In the present study, we explored novel effects of celecoxib (CXB), a COX-2 specific inhibitor, on primary cultures of human ADPKD cyst-lining epithelial cells. Primary cultu...
Citations
... Meanwhile, the stimulation of the ERK/MAPK pathway results in a subsequent increase in COX-2 synthesis which in turn causes an increase in cell inflammation (Souza et al., 2004). In line with that, MAPK/ERK signaling pathway was previously reported to be inhibited by decreasing levels of COX-2, which reduce cell proliferation, depress cell cycle progression, and trigger apoptosis in renal epithelial cells (Xu et al., 2012). Additionally, LPS itself has been shown to induce the production of COX-2 (Grishin et al., 2006). ...
Acute kidney injury (AKI) is a very critical cause of death in the whole world. Lipopolysaccharide (LPS) induces kidney damage by activating various deleterious inflammatory and oxidative pathways. Protocatechuic acid, a natural phenolic compound, has shown to exert beneficial effects against oxidative and inflammatory responses. The study aimed to clarify the nephron-protective activity of protocatechuic acid in LPS-induced acute kidney damage in mice. Forty male Swiss mice were allocated in four groups as follows: normal control group; LPS (250 μg/kg; i.p) -induced kidney injury group; LPS-injected mice treated with protocatechuic acid (15 mg/kg, p.o), and LPS-injected mice treated with protocatechuic acid (30 mg/kg, p.o.). Significant toll like receptor 4 (TLR4)-mediated activation of IKBKB/NF-κB and MAPK/Erk/COX-2 inflammatory pathways has been observed in kidneys of mice treated with LPS. Oxidative stress was revealed by inhibition of total anti-oxidant capacity, catalase, nuclear factor erythroid 2-related factor 2 (Nrf2) and NAD(P)H quinone oxidoreductase (NQO1) enzyme along with increased nitric oxide level. In parallel, focal inflammatory effects were shown in between the tubules and glomeruli as well as in the perivascular dilated blood vessels at the cortex affecting the normal morphology of the kidney tissues of LPS-treated mice. However, treatment with protocatechuic acid reduced LPS-induced changes in the aforementioned parameters and restored normal histological features of the affected tissues. In conclusion, our study uncovered that protocatechuic acid has nephron-protective effects in mice with AKI through opposing different inflammatory and oxidative cascades.
... Bindarit is an inhibitor of MCP-1/CCL2 synthesis, and in PCK rats, it ameliorated PKD evolution [101]. Other therapeutic approaches targeting inflammatory cytokines are etanercept, a tumor necrosis factor-alpha (TNF-α) inhibitor [102], and celecoxib, a highly selective cyclooxygenase 2 (COX-2) inhibitor, which prevented human cyst-lining epithelial cell growth [103] (Tables 2, 3). ...
Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous genetic disorder included in ciliopathies, representing the fourth cause of end stage renal disease (ESRD), with an estimated prevalence between 1:1000 and 1:2500. It is mainly caused by mutations in the PKD1 and PKD2 genes encoding for polycystin 1 (PC1) and polycystin 2 (PC2), which regulate differentiation, proliferation, survival, apoptosis, and autophagy. The advances in the knowledge of multiple molecular pathways involved in the pathophysiology of ADPKD led to the development of several treatments which are currently under investigation. Recently, the widespread approval of tolvaptan and, in Italy, of long-acting release octreotide (octreotide-LAR), represents but the beginning of the new therapeutic management of ADPKD patients. Encouraging results are expected from ongoing randomized controlled trials (RCTs), which are investigating not only drugs acting on the calcium/cyclic adenosin monoposphate (cAMP) pathway, the most studied target so far, but also molecules targeting specific pathophysiological pathways (e.g. epidermal growth factor (EGF) receptor, AMP-activated protein kinase (AMPK) and KEAP1-Nrf2) and sphingolipids. Moreover, studies on animal models and cultured cells have also provided further promising therapeutic strategies based on the role of intracellular calcium, cell cycle regulation, MAPK pathway, epigenetic DNA, interstitial inflammation, and cell therapy. Thus, in a near future, tailored therapy could be the key to changing the natural history of ADPKD thanks to the vigorous efforts that are being made to implement clinical and preclinical studies in this field. Our review aimed to summarize the spectrum of drugs that are available in the clinical practice and the most promising molecules undergoing clinical, animal, and cultured cell studies.Graphical abstract
... In addition, dabrafenib is a well-known inhibitor of B-Raf, which suppresses the downstream Ras/Raf/ERK/MAPK pathway (Spagnolo et al., 2014), which has been approved for clinical use for the treatment of non-small cell lung cancer expressing B-Raf V600E mutations and in melanoma (Odogwu et al., 2018). Inhibition of Raf kinase has found to attenuate renal fibrosis (Xu et al., 2012b;Chen et al., 2019). ...
Chronic kidney disease (CKD) is the end result of a plethora of renal insults, including repeated episodes of acute or toxic kidney injury, glomerular, or diabetic kidney disease. It affects a large number of the population worldwide, resulting in significant personal morbidity and mortality and economic cost to the community. Hence it is appropriate to focus on treatment strategies that interrupt the development of kidney fibrosis, the end result of all forms of CKD, in addition to upstream factors that may be specific to certain diseases. However, the current clinical approach to prevent or manage renal fibrosis remains unsatisfactory. The rising importance of receptor-interacting serine/threonine-protein kinase (RIPK) 3 in the inflammatory response and TGF-β1 signaling is increasingly recognized. We discuss here the biological functions of RIPK3 and its role in the development of renal fibrosis.
... The expression and activity of COX2 and mPGES1 are increased in polycystic kidneys and PGE2 is found at high concentrations in cyst fluid [212][213][214][215]. COX derived eicosanoids such as PGE2, and PGI2 stimulate cell proliferation, fluid secretion, and three-dimensional collagen gel cystogenesis of cultured PKD and in inner medullary collecting duct cells [216,217]. Non-selective COX inhibition, selective COX2 inhibition, and dietary interventions that reduce COX activities and prostanoid levels in cystic kidneys ameliorated PKD in Han:SPRD cy/+ rats, a non-orthologous model with cysts derived mainly from proximal tubules, and possibly in Pkd2 WS25/− mice [215,[218][219][220][221][222][223]. In our experience, celecoxib, a specific COX2 inhibitor was ineffective in PCK rats and Pkd1 RC/RC mice at 250-1000 ppm administered in the food from 3 to 10 weeks of age (PCK) or 4 to 24 weeks (Pkd1 RC/RC ) (Fig. 7). ...
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic disorder associated with polycystic liver disease (PLD) and other extrarenal manifestations, the most common monogenic cause of end-stage kidney disease, and a major burden for public health. Many studies have shown that alterations in G-protein and cAMP signaling play a central role in its pathogenesis. As for many other diseases (35% of all approved drugs target G-protein coupled receptors (GPCRs) or proteins functioning upstream or downstream from GPCRs), treatments targeting GPCR have shown effectiveness in slowing the rate of progression of ADPKD. Tolvaptan, a vasopressin V2 receptor antagonist is the first drug approved by regulatory agencies to treat rapidly progressive ADPKD. Long-acting somatostatin analogs have also been effective in slowing the rates of growth of polycystic kidneys and liver. Although no treatment has so far been able to prevent the development or stop the progression of the disease, these encouraging advances point to G-protein and cAMP signaling as a promising avenue of investigation that may lead to more effective and safe treatments. This will require a better understanding of the relevant GPCRs, G-proteins, cAMP effectors, and of the enzymes and A-kinase anchoring proteins controlling the compartmentalization of cAMP signaling. The purpose of this review is to provide an overview of general GPCR signaling; the function of polycystin-1 (PC1) as a putative atypical adhesion GPCR (aGPCR); the roles of PC1, polycystin-2 (PC2) and the PC1-PC2 complex in the regulation of calcium and cAMP signaling; the cross-talk of calcium and cAMP signaling in PKD; and GPCRs, adenylyl cyclases, cyclic nucleotide phosphodiesterases, and protein kinase A as therapeutic targets in ADPKD.
... Studies have shown that exogenous VEGF-A may improve kidney function. For instance, as shown in Table 6, VEGF-A-targeted therapy using SU-5416 and celecoxib are somewhat effective in improving cystic disease (Xu et al., 2012). Delivery of exogenous mesenchymal stem cells (MSCs) improved vascular density and kidney function in PCK rats by releasing VEGF-A (Franchi et al., 2016). ...
... Mechanism Effect on PKD model Reference Celecoxib COX-2 inhibitor 1. In cyst-lining epithelial cells from patients with ADPKD: Inhibited expression of VEGFR-2 and Raf-1, thereby, reduced inflammation and fibrosis Xu et al. (2012) NS-398 COX-2 inhibitor In Han:SPRD-cy rats with inherited kidney disease: Slows disease progression and attenuates altered prostanoid production Sankaran, Bankovic-Calic, Ogborn, Crow, and Aukema (2007) Acetylsalicylic acid COX-2 inhibitor In Han:SPRD-cy rats: Reduced COX products, cyst growth, and kidney water content Ibrahim et al. (2015) Etanercept TNF-α inhibitor In Pkd2 +/− mice: Inhibit cyst formation Li et al. (2008) WTACE2 ...
... Inhibition of COX-2 with CXB prevented growth of human ADPKD cyst-lining epithelial cells (Xu et al., 2012). Also, NS-398, a selective COX-2 inhibitor, markedly slowed disease progression and attenuated altered prostanoid production in a rat model (Sankaran, Bankovic-Calic, Ogborn, Crow, & Aukema, 2007). ...
Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic inherited renal cystic disease that occurs in different races worldwide. It is characterized by the development of a multitude of renal cysts, which leads to massive enlargement of the kidney and often to renal failure in adulthood. ADPKD is caused by a mutation in PKD1 or PKD2 genes encoding the proteins polycystin‐1 and polycystin‐2, respectively. Recent studies showed that cyst formation and growth result from deregulation of multiple cellular pathways like proliferation, apoptosis, metabolic processes, cell polarity, and immune defense. In ADPKD, intracellular cyclic adenosine monophosphate (cAMP) promotes cyst enlargement by stimulating cell proliferation and transepithelial fluid secretion. Several interventions affecting many of these defective signaling pathways have been effective in animal models and some are currently being tested in clinical trials. Moreover, the stem cell therapy can improve nephropathies and according to studies were done in this field, can be considered as a hopeful therapeutic approach in future for PKD. This study provides an in‐depth review of the relevant molecular pathways associated with the pathogenesis of ADPKD and their implications in development of potential therapeutic strategies.
... Table S11) of which several are known to be implicated in ADPKD (i.e. PI3K-AKT, MAPK, Hippo, JAK-STAT and TGF-β signaling) [39,45,55,[61][62][63][64][65][66][67][68][69][70][71][72][73][74], suggesting that these pathways are already modified at pre-cystic stage. ...
Mutations in the PKD1 or PKD2 genes are the cause of autosomal dominant polycystic kidney disease (ADPKD). The encoded proteins localize within the cell membrane and primary cilia and are proposed to be involved in mechanotransduction. Therefore, we evaluate shear stress dependent signaling in renal epithelial cells and the relevance for ADPKD. Using RNA sequencing and pathway analysis, we compared gene expression of in vitro shear stress treated Pkd1−/− renal epithelial cells and in vivo pre-cystic Pkd1del models. We show that shear stress alters the same signaling pathways in Pkd1−/− renal epithelial cells and Pkd1wt controls. However, expression of a number of genes was slightly more induced by shear stress in Pkd1−/− cells, suggesting that Pkd1 has the function to restrain shear regulated signaling instead of being a mechano-sensing activator. We also compared altered gene expression in Pkd1−/− cells during shear with in vivo transcriptome data of kidneys from Pkd1del mice at three early pre-cystic time-points. This revealed overlap of a limited number of differentially expressed genes. However, the overlap between cells and mice is much higher when looking at pathways and molecular processes, largely due to altered expression of paralogous genes. Several of the altered pathways in the in vitro and in vivo Pkd1del models are known to be implicated in ADPKD pathways, including PI3K-AKT, MAPK, Hippo, calcium, Wnt, and TGF-β signaling. We hypothesize that increased activation of selected genes in renal epithelial cells early upon Pkd1 gene disruption may disturb the balance in signaling and may contribute to cyst formation.
... Previous studies have shown that renal tubular epithelial cells (RTEC) injury and oxidative stress are important reasons for the formation of calcium oxalate crystals [7]. In other studies, we found that inhibition of ERK signaling pathway could induce the cells apoptosis in autosomal dominant polycystic kidney disease and related to RTEC dysfunction and attrition [8,9]. Evidence showed silencing of Mucin 4 (MUC4) could decreased the activation of Extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway [10]. ...
Background/aims:
Nephrolithiasis plagues a great number of patients all over the world. Increasing evidence shows that the extracellular signal-regulated kinase (ERK) signaling pathway and renal tubular epithelial cell (RTEC) dysfunction and attrition are central to the pathogenesis of kidney diseases. Mucin 4 (MUC4) is reported as an activator of ERK signaling pathway in epithelial cells. In this study, using rat models of calcium oxalate (CaOx) nephrolithiasis, the present study aims to define the roles of MUC4 and ERK signaling pathway as contributors to oxidative stress and CaOx crystal formation in RTEC.
Methods:
Data sets of nephrolithiasis were searched using GEO database and a heat flow map was drawn. Then MUC4 function was predicted. Wistar rats were prepared for the purpose of model establishment of ethylene glycol and ammonium chloride induced CaOx nephrolithiasis. In order to assess the detailed regulatory mechanism of MUC4 silencing on the ERK signaling pathway and RTEC, we used recombinant plasmid to downregulate MUC4 expression in Wistar rat-based models. Samples from rat urine, serum and kidney tissues were reviewed to identify oxalic acid and calcium contents, BUN, Cr, Ca2+ and P3+ levels, calcium crystal formation in renal tubules and MUC4 positive expression rate. Finally, RT-qPCR, Western blot analysis, and ELISA were employed to access oxidative stress state and CaOx crystal formation in RTEC.
Results:
Initially, MUC4 was found to have an influence on the process of nephrolithiasis. MUC4 was upregulated in the CaOx nephrolithiasis model rats. We proved that the silencing of MUC4 triggered the inactivation of ERK signaling pathway. Following the silencing of MUC4 or the inhibition of ERK signaling pathway, the oxalic acid and calcium contents in rat urine, BUN, Cr, Ca2+ and P3+ levels in rat serum, p-ERK1/2, MCP-1 and OPN expressions in RTEC and H2O2 and MDA levels in the cultured supernatant were downregulated, but the GSH-Px, CAT and SOD levels in the cultured supernatant were increased. Moreover, MUC4 silencing or ERK signaling pathway inactivation may decrease the formation of CaOx crystals.
Conclusion:
Taken together, silencing of MUC4 can inactivate the ERK signaling pathway and further restrain oxidative stress and CaOx crystal formation in RTEC. Thus, MUC4 represents a potential investigative focus target in nephrolithiasis.
... The speculated mechanism is vascular endothelial growth factor blockade. 45 Research with animal models has not shown a correlation between celecoxib administration and improved renal function, and the safety and efficacy of this form of therapy in ADPKD cannot be determined at this time. ...
Purpose:
Promising developments in the search for effective pharmacotherapies for autosomal-dominant polycystic kidney disease (ADPKD) are reviewed.
Summary:
The formation and development of cysts characteristic of ADPKD result in inexorable renal and extrarenal manifestations that give rise to more rapid disease progression and more widespread complications than are seen with other forms of chronic kidney disease. To date, no agent has gained Food and Drug Administration marketing approval for use in patients with ADPKD, complicating efforts to meet the medical needs of this population. Although definitive ultrasonographic diagnostic strategies are available, molecular screening approaches lack sufficient evidence and patient outcomes data to support broad clinical application. Recently completed and ongoing clinical trials point to a number of encouraging platforms for evidence-based ADPKD management. Tolvaptan therapy significantly improved cyst burden and slowed disease progression among patients with early-stage ADPKD in a large-scale trial, while somatostatin therapies may also be useful in halting disease progression and managing comorbid polycystic liver disease. Stem cell research and nanomedicine might represent novel approaches to gaining comprehensive insights on ADPKD and, ultimately, to targeting the disease's origins, thereby making restoration of kidney function possible.
Conclusion:
A number of pharmacotherapy approaches to ADPKD management show promise but are unlikely to be curative, fueling interest among researchers in finding new applications for nanomedicine and stem cell technologies that can slow ADPKD progression and better control complications of the disease.
... The MAPK/ERK signaling pathway is also involved in the development of renal fibrosis [62,63]. Pretreatment with curcumin blocked angiotensin II-(Ang-II-) induced profibrotic responses in renal tubular epithelial cells [64]. ...
Curcumin, a polyphenol derived from the turmeric, has received attention as a potential treatment for renal fibrosis primarily because it is a relatively safe and inexpensive compound that contributes to kidney health. Here, we review the literatures on the applications of curcumin in resolving renal fibrosis in animal models and summarize the mechanisms of curcumin and its analogs (C66 and (1E,4E)-1,5-bis(2-bromophenyl) penta-1,4-dien-3-one(B06)) in preventing inflammatory molecules release and reducing the deposition of extracellular matrix at the priming and activation stage of renal fibrosis in animal models by consulting PubMed and Cnki databases over the past 15 years. Curcumin exerts antifibrotic effect through reducing inflammation related factors (MCP-1, NF- κ B, TNF- α , IL-1 β , COX-2, and cav-1) and inducing the expression of anti-inflammation factors (HO-1, M6PRBP1, and NEDD4) as well as targeting TGF- β /Smads, MAPK/ERK, and PPAR- γ pathways in animal models. As a food derived compound, curcumin is becoming a promising drug candidate for improving renal health.
... Our results demonstrated that Cx / PLGA promotes apoptosis in a murine mammary tumor. Other authors describe that binding of PGs to its receptor promotes evasion of apoptosis by increasing Survivin and Bcl-2 (Konturek et al., 2006) or through inhibition of VEGF signaling pathway / VEGFR-2 / Raf-1 / MAPK / ERK (Xu et al., 2012). ...
Although, antineoplastic therapies have now been developed reduction of tumor progression, it is necessary to find new therapeutic alternatives to suppress angiogenesis. Thus celecoxib (Cx) has been used for its antiangiogenic action in combination with certain polymeric compounds such as poly (lactic co-glycolic acid) (PLGA) acid, which help to improve the bioavailability and avoid effects of long drug administrations. For this purpose we used a murine tumor model induced by mammary adenocarcinoma cells resistant to chemotherapy (TA3-MTXR). CX/PLGA inhibits the microvascular density, VEGF expression and cell proliferation in addition to increased apoptosis (P <0.0001). Cx reduces tumor progression in a concentration of 1000 ppm associated with PLGA, reducing cell proliferation, the presence of VEGF and promoting apoptosis of multiresistant TA3 tumor cells.
