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Repeated intravenous injections of folic acid are associated with accelerated fibrosis and CKD in mice. Male CD1 mice received 2 intravenous doses of 125 mg/kg of folic acid (FA) or normal saline (control). (a) Mice were weighed every 2-7 days throughout the model and their weights are shown. FA treated mice were weighed more often as a safety precaution. (b) Sections from mouse kidneys were stained with picrosirius red (PSR) at day 0 (no FA) and other time points post 1 st FA injection as indicated (representative images shown).In the PSR panels the red stain indicates the presence of collagen in the tissue. In the PMT panels the tissue matrix is indicated by the level of blue stain. (c) The PSR (collagen fibre) staining was quantified using NIS Elements software as described in methods. (d) Collagen staining was also quantified from picro-Mallory trichrome (PMT) stained sections using NIS Elements software as described in methods and (e) Collagen content was assessed by tissue hydroxyproline content. (f) Blood urea Nitrogen (BUN) and (g) Serum creatinine were also quantified. 8-16 mice per treatment group. Each point is the result for a single animal. Statistically significant differences are represented as follows here and in all figures: *p < 0.05, **p < 0.01, ***p < 0.005.
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Chronic Kidney Disease is a growing problem across the world and can lead to end-stage kidney disease and cardiovascular disease. Fibrosis is the underlying mechanism that leads to organ dysfunction, but as yet we have no therapeutics that can influence this process. Ras monomeric GTPases are master regulators that direct many of the cytokines know...
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... the model to reduce death in the acute phase and accelerate fibrosis in the chronic phase by injecting 2 lower doses of folic acid (125 mg/kg), separated by 21 days. Each injection was associated with weight loss in the affected mice during the period of AKI, which eventually recovered reaching comparable weights as the control group by week 10 (Fig. 1a). There were no deaths in the AKI period. Over the following 9 weeks the animals developed progressive fibrosis and CKD (Fig. 1b-g). Picrosirius Red (PSR) staining highlights the increasing deposition of collagen fibres in the interstitium of the kidney over time in representative kidney sections (Fig. 1b). This deposition is quantified ...
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... (125 mg/kg), separated by 21 days. Each injection was associated with weight loss in the affected mice during the period of AKI, which eventually recovered reaching comparable weights as the control group by week 10 (Fig. 1a). There were no deaths in the AKI period. Over the following 9 weeks the animals developed progressive fibrosis and CKD (Fig. 1b-g). Picrosirius Red (PSR) staining highlights the increasing deposition of collagen fibres in the interstitium of the kidney over time in representative kidney sections (Fig. 1b). This deposition is quantified using sections from all animals in Fig. 1c. Increased collagen deposition was also demonstrated and quantified using ...
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... weights as the control group by week 10 (Fig. 1a). There were no deaths in the AKI period. Over the following 9 weeks the animals developed progressive fibrosis and CKD (Fig. 1b-g). Picrosirius Red (PSR) staining highlights the increasing deposition of collagen fibres in the interstitium of the kidney over time in representative kidney sections (Fig. 1b). This deposition is quantified using sections from all animals in Fig. 1c. Increased collagen deposition was also demonstrated and quantified using picro-Mallory trichrome staining (PMT) (Fig. 1d) and measurement of tissue hydroxyproline content (Fig. 1e). All three methods gave similar results. Renal function was also assessed ...
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... the AKI period. Over the following 9 weeks the animals developed progressive fibrosis and CKD (Fig. 1b-g). Picrosirius Red (PSR) staining highlights the increasing deposition of collagen fibres in the interstitium of the kidney over time in representative kidney sections (Fig. 1b). This deposition is quantified using sections from all animals in Fig. 1c. Increased collagen deposition was also demonstrated and quantified using picro-Mallory trichrome staining (PMT) (Fig. 1d) and measurement of tissue hydroxyproline content (Fig. 1e). All three methods gave similar results. Renal function was also assessed demonstrating significant renal impairment by day 85 with a 2.5 fold increase in ...
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... (PSR) staining highlights the increasing deposition of collagen fibres in the interstitium of the kidney over time in representative kidney sections (Fig. 1b). This deposition is quantified using sections from all animals in Fig. 1c. Increased collagen deposition was also demonstrated and quantified using picro-Mallory trichrome staining (PMT) (Fig. 1d) and measurement of tissue hydroxyproline content (Fig. 1e). All three methods gave similar results. Renal function was also assessed demonstrating significant renal impairment by day 85 with a 2.5 fold increase in blood urea nitrogen (BUN) and a doubling of serum creatinine (Fig. ...
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... fibres in the interstitium of the kidney over time in representative kidney sections (Fig. 1b). This deposition is quantified using sections from all animals in Fig. 1c. Increased collagen deposition was also demonstrated and quantified using picro-Mallory trichrome staining (PMT) (Fig. 1d) and measurement of tissue hydroxyproline content (Fig. 1e). All three methods gave similar results. Renal function was also assessed demonstrating significant renal impairment by day 85 with a 2.5 fold increase in blood urea nitrogen (BUN) and a doubling of serum creatinine (Fig. ...
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... and quantified using picro-Mallory trichrome staining (PMT) (Fig. 1d) and measurement of tissue hydroxyproline content (Fig. 1e). All three methods gave similar results. Renal function was also assessed demonstrating significant renal impairment by day 85 with a 2.5 fold increase in blood urea nitrogen (BUN) and a doubling of serum creatinine (Fig. ...
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... we demonstrate that K-Ras expression is also upregulated in folic acid-induced nephropathy in the acute and chronic phases between 1.5 and 2 fold at the mRNA level and by circa 25% at the protein level ( Fig. 2a,b and Supplementary Fig. S2). Although these increases in expression are modest in CFAN, they are associated with a marked increase in Ras activation, leading to increased GTP bound Ras and phosphorylation of ERK1/2, in both models ( Fig. 2c,d and Supplementary Fig. S1). In contrast there was no upregulation of the other Ras isoforms N-Ras and H-Ras (data not shown). ...
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... Total Kidney lysate from rats 16 days post UUO was subjected to western blotting for phosphorylated ERK 41/42 and compared with total ERK. A more complete image of this blot is shown in Supplementary Fig. S1. (d) Kidney sections from mice with CFAN (or untreated controls) were stained for GTP-bound (activated) Ras (left hand column) or phospho-ERK (right hand column). ...
Citations
... [70] It has been shown that silencing Kras signaling expression in a folic acid-induced renal fibrosis model and a unilateral ureteral obstruction model, thereby reducing ERK phosphorylation, significantly inhibits renal fibrosis and impairment of renal function. [71] The PI3K-AKT-mTOR signaling pathway plays a significant role in various cellular processes, including immune cell proliferation and differentiation, secretion of inflammatory cytokines, autophagy, and oxidative stress. [72] It has been observed that the PI3K/Akt signaling pathway can either inhibit GSK-3β or activate mTOR, depending on the specific cell type. ...
In order to investigate the potential link between Alzheimer's disease (AD) and chronic kidney disease (CKD), we conducted a comprehensive analysis using a bioinformatics approach. We downloaded AD and CKD datasets from the Gene Expression Omnibus database and analyzed differentially expressed genes and weighted gene co-expression networks to identify candidate genes for AD and CKD. We used a combination of the least absolute shrinkage and selection operator and random forest algorithms to select the shared genes. Subsequently, we shared genes and performed an immune infiltration analysis to investigate the association between different immune cell types and shared genes. Finally, we elucidated the relationship between the expression levels of the shared genes in disease samples and cells using single-cell analysis. Our analysis identified 150 candidate genes that may be primarily involved in immune inflammatory responses and energy metabolism pathways. We found that JunD Proto-Oncogene, ALF transcription elongation factor 1, and ZFP36 Ring Finger Protein Like 1 were the best co-diagnostic markers for AD and CKD based on the results of Least Absolute Shrinkage Selection Operator analysis and the random forest algorithm. Based on the results of immune infiltration analysis, macrophages and T-cells play a significant role in the progression of AD and CKD. Our scRNA-sequencing data showed that the 3 shared genes in AD were significantly expressed in astrocytes, excitatory neurons, oligodendrocytes, and MAIT cells. The 3 shared genes in CKD were significantly expressed in oligodendrocytes, neutrophils, fibroblasts, astrocytes, and T-cells. JunD Proto-Oncogene, ALF transcription elongation factor 1, and ZFP36 Ring Finger Protein Like 1 genes are the best diagnostic markers for AD and CKD.
... Farnesyl thiosalicylic acid (FTS) is a specific inhibitor of the proto-oncogene Ras. It has been reported that FTS can inhibit Transforming growth factor (TGF) by inhibiting the EMT process-β 1 induced activation of NRK-49F in renal fibroblasts and may have therapeutic potential in treating renal fibrosis (117)(118)(119)(120). However, its application is hindered by its water insolubility and low bioavailability. ...
With the development of nanotechnology, nanoparticles have been used in various industries. In medicine, nanoparticles have been used in the diagnosis and treatment of diseases. The kidney is an important organ for waste excretion and maintaining the balance of the internal environment; it filters various metabolic wastes. Kidney dysfunction may result in the accumulation of excess water and various toxins in the body without being discharged, leading to complications and life-threatening conditions. Based on their physical and chemical properties, nanoparticles can enter cells and cross biological barriers to reach the kidneys and therefore, can be used in the diagnosis and treatment of chronic kidney disease (CKD). In the first search, we used the English terms “Renal Insufficiency, Chronic” [Mesh] as the subject word and terms such as “Chronic Renal Insufficiencies,” “Chronic Renal Insufficiency,” “Chronic Kidney Diseases,” “Kidney Disease, Chronic,” “Renal Disease, Chronic” as free words. In the second search, we used “Nanoparticles” [Mesh] as the subject word and “Nanocrystalline Materials,” “Materials, Nanocrystalline,” “Nanocrystals,” and others as free words. The relevant literature was searched and read. Moreover, we analyzed and summarized the application and mechanism of nanoparticles in the diagnosis of CKD, application of nanoparticles in the diagnosis and treatment of renal fibrosis and vascular calcification (VC), and their clinical application in patients undergoing dialysis. Specifically, we found that nanoparticles can detect CKD in the early stages in a variety of ways, such as via breath sensors that detect gases and biosensors that detect urine and can be used as a contrast agent to avoid kidney damage. In addition, nanoparticles can be used to treat and reverse renal fibrosis, as well as detect and treat VC in patients with early CKD. Simultaneously, nanoparticles can improve safety and convenience for patients undergoing dialysis. Finally, we summarize the current advantages and limitations of nanoparticles applied to CKD as well as their future prospects.
... Some studies have explored the role of circRNA_30032 in renal fibrosis and its mechanism using TGF-β1-induced BUMPT cells as an in vitro model (Yi et al., 2021). The analysis showed that circRNA_30032 mediated TGF-β1-induced renal fibrosis by sponging miR-96-5p and increasing the expression of profibrotic proteins, including HBEGF, KRAS, type I collagen, type III collagen and fibronectin (Newbury et al., 2019;Yang et al., 2020a;Zeng et al., 2016). These results suggest that circRNA_30032 promotes renal fibrosis via the miR-96-5p/HBEGF/KRAS axis (Yi et al., 2021). ...
Fibrosis is the ultimate pathological feature of many chronic diseases, and ageing a major risk factor for fibrotic diseases. Current therapies are limited to those that reduce the rate of functional decline in patients with mild to moderate disease, but few interventions are available to specifically target the pathogenesis of fibrosis. In this context, new treatments that can significantly improve survival time and quality of life for these patients are urgently needed. In this review, we outline both the synthesis and metabolism of lipids and lipoproteins associated with ageing-associated renal fibrosis and the prominent contribution of lipids and lipidomics in the discovery of biomarkers that can be used for the prevention, diagnosis, and treatment of renal ageing and fibrosis. Next, we describe the effect of dyslipidaemia on ageing-related renal fibrosis and the pathophysiological changes in the kidney caused by dyslipidaemia. We then summarize the enzymes, transporters, transcription factors, and RNAs that contribute to dysregulated lipid metabolism in renal fibrosis and discuss their role in renal fibrosis in detail. We conclude by discussing the progress in research on small molecule therapeutic agents that prevent and treat ageing and ageing-associated renal fibrosis by modulating lipid metabolism. A growing number of studies suggest that restoring aberrant lipid metabolism may be a novel and promising therapeutic strategy to combat age-ing and ageing-associated renal fibrosis.
... In this study, we adopted a FA nephropathy model of 14 days. Newbury et al. used a chronic FA nephropathy model (12 weeks) and revealed that inhibition of Kirsten-Ras reduces fibrosis and protects against renal dysfunction (Newbury et al., 2019). In this respect, further investigation is required for assessing whether pharmacological inhibition of STING/TBK1 has a role in a longer term of FA nephropathy model. ...
Renal fibrosis is an important pathological biomarker of chronic kidney disease (CKD). Stimulator of interferon genes/TANK binding kinase 1 (STING/TBK1) axis has been identified as the main regulator of innate immune response and closely related to fibrotic disorder. However, the role of STING/TBK1 signaling pathway in kidney fibrosis is still unknown. In this study, we investigated the effect of pharmacological inhibition of STING/TBK1 signaling on renal fibrosis induced by folic acid (FA). In mice, TBK1 was significantly activated in interstitial cells of FA-injured kidneys, which was markedly inhibited by H-151 (a STING inhibitor) treatment. Specifically, pharmacological inhibition of STING impaired bone marrow-derived fibroblasts activation and macrophage to myofibroblast transition in folic acid nephropathy, leading to reduction of extracellular matrix proteins expression, myofibroblasts formation and development of renal fibrosis. Furthermore, pharmacological inhibition of TBK1 by GSK8612 reduced myeloid myofibroblasts accumulation and impeded macrophage to myofibroblast differentiation, resulting in less deposition of extracellular matrix protein and less severe fibrotic lesion in FA-injured kidneys. In cultured mouse bone marrow-derived monocytes, TGF-β1 activated STING/TBK1 signaling. This was abolished by STING or TBK1 inhibitor administration. In addition, GSK8612 treatment decreased levels of α-smooth muscle actin and extracellular matrix proteins and prevents bone marrow-derived macrophages to myofibroblasts transition in vitro. Collectively, our results revealed that STING/TBK1 signaling has a critical role in bone marrow-derived fibroblast activation, macrophages to myofibroblasts transition, and kidney fibrosis progression.
... Although daily oral intake of folic acid (5-15 mg) did not show adverse effects in healthy people [51], folic acid at very high doses can be renal toxic. It was reported that single or multiple injections of high-dose folic acid (125-250 mg/kg BW) caused tubular necrosis, oxidative stress and increased creatinine levels in rodents [52][53][54]. On the other hand, low-dose folic acid had beneficial effects on the cardiovascular system, and improved hyperhomocysteinemia and diabetes [23,45,55,56]. ...
Oxidative stress is a major mediator of adverse outcomes in acute kidney injury (AKI). Deficiency of micronutrients, such as folate, is common in AKI. Our previous study reported that AKI impaired kidney reabsorption of folate and decreased plasma folate level in rats. The present study investigated the effect of 5-methyltetrahydrofolate (5-MTHF), a biologically active form of folate/folic acid, on AKI-impaired kidney function and oxidative stress. Sprague-Dawley rats developed AKI after kidney ischemia (45 min) and reperfusion (24 h). Injection of 5-MTHF (3 µg/kg body weight) improved kidney function and attenuated oxidative stress with a restoration of glutathione and a reduction of lipid peroxidation in the kidney. Injection of 5-MTHF activated transcription factor Nrf2 and increased the expression of glutathione synthesizing enzymes, superoxide dismutase-1 and heme oxygenase-1 in the kidney. Simulated ischemia-reperfusion through hypoxia-reoxygenation increased oxidative stress in proximal tubular cells. Incubation of cells with 5-MTHF alleviated cell injury and increased antioxidant enzyme expression and intracellular glutathione levels. Inhibition of Nrf2 expression through siRNA transfection abolished the effect of 5-MTHF against oxidative stress. These results suggest that low-dose folic acid can improve kidney function through activation of Nrf2 and restoration of antioxidant defence. Micronutrient supplements may improve clinical outcomes in AKI.
... It has been shown that H-Ras-GTPases are expressed during fibrosis and play pivotal roles in regulating both proliferation of cell and TGF-β induced EMT [61,71]. The Ras-induced ERK1/2 pathway (Raf/MEK/ERK) is typically activated by ET-1 [66], TGF-β [72], and growth factors through their receptors, which can mobilize adaptor proteins such as Shc and Grb2, and guanine nucleotide exchange factors (GEFs) like Sos. ...
Systemic sclerosis (SSc) is a disease of connective tissue with high rate of morbidity and mortality highlighted by extreme fibrosis affecting various organs such as the dermis, lungs, and heart. Until now, there is no specific cure for the fibrosis occurred in SSc disease. The SSc pathogenesis is yet unknown, but transforming growth factor beta (TGF-β), endothelin-1 (ET-1), and Ras-ERK1/2 cascade are the main factors contributing to the tissue fibrosis through extracellular matrix (ECM) accumulation. Several studies have hallmarked the association of ET-1 with or without TGF-β and Ras-ERK1/2 signaling in the development of SSc disease, vasculopathy, and fibrosis of the dermis, lungs, and several organs. Accordingly, different clinical and experimental studies have indicated the potential therapeutic role of ET-1 and Ras antagonists in these situations in SSc. In addition, ET-1 and connective tissue growth factor (CTGF) as a cofactor of the TGF-β cascade play a substantial initiative role in inducing fibrosis. Once initiated, TGF-β alone or in combination with ET-1 and CTGF can activate several kinase proteins such as the Ras-ERK1/2 pathway that serve as the fundamental factor for developing fibrosis. Furthermore, Salirasib is a synthetic small molecule that is able to inhibit all Ras forms. Therefore, it can be used as a potent therapeutic factor for fibrotic disorders. So, this review discusses the role of TGF-β/ET-1/Ras signaling and their involvement in SSc pathogenesis, particularly in its fibrotic situation.
... 148 If left untreated, CKD will develop and can be studied more than 4 weeks or beyond after FA injection ( Figure 1). 55 Multiple injections of a lower dose of FA (125-150 mg/kg body weight) 150,151 or a single injection of lower dose of FA (less than 200 mg/kg body weight) can also produce symptoms of kidney disease that can be used to investigate the pathological mechanisms of AKI or CKD. 152 Note: This table is not meant to cover all the animal models of kidney injury in the literature. ...
The kidneys are a vital organ that is vulnerable to both acute kidney injury (AKI) and chronic kidney disease (CKD) which can be caused by numerous risk factors such as ischemia, sepsis, drug toxicity and drug overdose, exposure to heavy metals, and diabetes. In spite of the advances in our understanding of the pathogenesis of AKI and CKD as well AKI transition to CKD, there is still no available therapeutics that can be used to combat kidney disease effectively, highlighting an urgent need to further study the pathological mechanisms underlying AKI, CKD, and AKI progression to CKD. In this regard, animal models of kidney disease are indispensable. This article reviews a widely used animal model of kidney disease, which is induced by folic acid (FA). While a low dose of FA is nutritionally beneficial, a high dose of FA is very toxic to the kidneys. Following a brief description of the procedure for disease induction by FA, major mechanisms of FA‐induced kidney injury are then reviewed, including oxidative stress, mitochondrial abnormalities such as impaired bioenergetics and mitophagy, ferroptosis, pyroptosis, and increased expression of fibroblast growth factor 23 (FGF23). Finally, application of this FA‐induced kidney disease model as a platform for testing the efficacy of a variety of therapeutic approaches is also discussed. Given that this animal model is simple to create and is reproducible, it should remain useful for both studying the pathological mechanisms of kidney disease and identifying therapeutic targets to fight kidney disease. Folic acid induced animal model of kidney disease was reviewed along with the mechanisms of the pathogenesis involved. This model can provide an important platform for the testing of a variety of therapeutic approaches that are designed to fight kidney disease including both acute kidney injury and chronic kidney disease.
... 9,10 Knockdown of K-Ras by antisense oligonucleotide prevented renal fibrosis in folate-induced CKD mice. 11 In H-Ras knockout mice, UUO induced lower EMT and renal interstitial fibrosis. 10 EMT in the progression of renal fibrosis can be suppressed by inhibiting the transmission of Ras/Raf1/p38 MAPK signaling pathway. ...
... 14 FTS has been reported to inhibit the growth of H-Ras and K-Ras transformed fibroblasts in vitro. 10,11 FTS has also been shown to alleviate inflammation and fibrosis in chemically induced liver fibrosis in rats. 15,16 FTS could suppress TGF-β1 induced renal fibroblasts NRK-49F activation by inhibiting the EMT process. ...
Background
Renal fibrosis is the common pathway in chronic kidney diseases progression to end-stage renal disease, but to date, no clinical drug for its treatment is approved. It has been demonstrated that the inhibitor of proto-oncogene Ras, farnesylthiosalicylic acid (FTS), shows therapeutic potential for renal fibrosis, but its application was hindered by the water-insolubility and low bioavailability. Hence, in this study, we improved these properties of FTS by encapsulating it into bovine serum albumin nanoparticles (AN-FTS) and tested its therapeutic effect in renal fibrosis.
Methods
AN-FTS was developed using a classic emulsification-solvent ultrasonication. The pharmacokinetics of DiD-loaded albumin nanoparticle were investigated in SD rats. The biodistribution and therapeutic efficacy of AN-FTS was assessed in a mouse model of renal fibrosis induced by unilateral ureteral obstruction (UUO).
Results
AN-FTS showed a uniform spherical shape with the size of 100.6 ± 1.12 nm and PDI < 0.25. In vitro, AN-FTS displayed stronger inhibitory effects on the activation of renal fibroblasts cells NRK-49F than free FTS. In vivo, AN-FTS showed significantly higher peak concentration and area under the concentration-time curve. After intravenous administration to UUO-induced renal fibrosis mice, AN-FTS accumulated preferentially in the fibrotic kidney, and alleviated renal fibrosis and inflammation significantly more than the free drug. Mechanistically, the improved anti-fibrosis effect of AN-FTS was associated with greater inhibition in renal epithelial-to-mesenchymal transformation process via Ras/Raf1/p38 signaling pathway.
Conclusion
The study reveals that AN-FTS is capable of delivering FTS to fibrotic kidney and showed superior therapeutic efficacy for renal fibrosis.
... They demonstrated that the ASO-induced knockdown of K-Ras isoform led to a 50% reduction of folic acid-induced kidney fibrosis, assessed by Masson's trichrome and Sirius red. K-Ras knockdown also prevented renal failure evaluated by plasma creatinine levels and BUN [122]. In vivo experimental models of kidney fibrosis have demonstrated a clear involvement of H-Ras, and perhaps a more relevant role of K-Ras in kidney fibrosis [53,121]. ...
... Antisense technology has become a powerful tool used in basic research and promising in clinical therapy [123]. As we have mentioned previously, K-Ras isoform has been knocked down using ASO in in vivo experimental models, showing a strong reduction of kidney fibrosis in rats after the UUO model [121] or mice after folic acid administration [122]. ...
Many different regulatory mechanisms of renal fibrosis are known to date, and those related to transforming growth factor-β1 (TGF-β1)-induced signaling have been studied in greater depth. However, in recent years, other signaling pathways have been identified, which contribute to the regulation of these pathological processes. Several studies by our team and others have revealed the involvement of small Ras GTPases in the regulation of the cellular processes that occur in renal fibrosis, such as the activation and proliferation of myofibroblasts or the accumulation of extracellular matrix (ECM) proteins. Intracellular signaling mediated by TGF-β1 and Ras GTPases are closely related, and this interaction also occurs during the development of renal fibrosis. In this review, we update the available in vitro and in vivo knowledge on the role of Ras and its main effectors, such as Erk and Akt, in the cellular mechanisms that occur during the regulation of kidney fibrosis (ECM synthesis, accumulation and activation of myofibroblasts, apoptosis and survival of tubular epithelial cells), as well as the therapeutic strategies for targeting the Ras pathway to intervene on the development of renal fibrosis.
... Both increase in proportion to the dose of FAN, with the 250 mg/kg dose resulting in severe acute kidney injury with significant increase (greater than double) in circulating markers and histological evidence of acute tubular necrosis at 48 hours post injection. If the animals survive, the FAN model is also commonly used to study renal fibrosis (key finding in chronic kidney disease) that develops 7-14 days after injection [14,35] and continues to progress weeks thereafter and can be exacerbated with repeated administration of FA [36,37]. ...
Acute Kidney Injury (AKI) is a poor prognosis in hospitalized patients that is associated with high degree of mortality. AKI is also a major risk factor for development of chronic kidney disease. Despite these serious complications associated with AKI there has not been a great amount of progress made over the last half-century. Here we have outlined and provided details on variety of mouse models of AKI. Some of the mouse models of AKI are renal pedicle clamping (ischemia reperfusion injury), Cisplatin induced nephrotoxicity, sepsis (LPS, cecal slurry, and cecal ligation and puncture), folic acid, and rhabdomyolysis. In this chapter we describe in detail the protocols that are used in our laboratories.
