Kidney-targeted renalase agonist prevents cisplatin-induced chronic kidney disease by inhibiting regulated necrosis and inflammation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE174014 | GEO | 2021/12/16
REPOSITORIES: GEO
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Project description:BackgroundRepeated administration of cisplatin causes CKD. In previous studies, we reported that the kidney-secreted survival protein renalase (RNLS) and an agonist peptide protected mice from cisplatin-induced AKI.MethodsTo investigate whether kidney-targeted delivery of RNLS might prevent cisplatin-induced CKD in a mouse model, we achieved specific delivery of a RNLS agonist peptide (RP81) to the renal proximal tubule by encapsulating the peptide in mesoscale nanoparticles (MNPs). We used genetic deletion of RNLS, single-cell RNA sequencing analysis, and Western blotting to determine efficacy and to explore underlying mechanisms. We also measured plasma RNLS in patients with advanced head and neck squamous cell carcinoma receiving their first dose of cisplatin chemotherapy.ResultsIn mice with CKD induced by cisplatin, we observed an approximate 60% reduction of kidney RNLS; genetic deletion of RNLS was associated with significantly more severe cisplatin-induced CKD. In this severe model of cisplatin-induced CKD, systemic administration of MNP-encapsulated RP81 (RP81-MNP) significantly reduced CKD as assessed by plasma creatinine and histology. It also decreased inflammatory cytokines in plasma and inhibited regulated necrosis in kidney. Single-cell RNA sequencing analyses revealed that RP81-MNP preserved epithelial components of the nephron and the vasculature and suppressed inflammatory macrophages and myofibroblasts. In patients receiving their first dose of cisplatin chemotherapy, plasma RNLS levels trended lower at day 14 post-treatment.ConclusionsKidney-targeted delivery of RNLS agonist RP81-MNP protects against cisplatin-induced CKD by decreasing cell death and improving the viability of the renal proximal tubule. These findings suggest that such an approach might mitigate the development of CKD in patients receiving cisplatin cancer chemotherapy.
| S-EPMC8819981 | biostudies-literature
Project description:Kidney-targeted renalase agonist prevents cisplatin-induced chronic kidney disease by inhibiting regulated necrosis and inflammation
| PRJNA727855 | ENA
Project description:Cisplatin is an effective chemotherapeutic agent, but significant nephrotoxicity limits its clinical use. Despite extensive investigation of the acute cellular and molecular responses to cisplatin, the mechanisms of progression from acute to chronic kidney injury have not been explored. We used functional and morphological metrics to establish a time-point when the transition from acute and reversible kidney injury to chronic and irreparable kidney disease is clearly established. In mice administered 1 or 2 doses of intraperitoneal cisplatin separated by 2 weeks, kidney function returned toward baseline two weeks after the first dose, but failed to return to normal two weeks following a second dose. Multiphoton microscopy revealed increased glomerular epithelial and proximal tubular damage in kidneys exposed to two doses of cisplatin compared with those exposed to a single dose. In contrast, there was no evidence of fibrosis, macrophage invasion, or decrease in endothelial cell mass in chronically diseased kidneys. Pathway analysis of microarray data revealed regulated necrosis as a key determinant in the development of chronic kidney disease after cisplatin administration. Western blot analysis demonstrated activation of proteins involved in necroptosis and increased expression of kidney injury markers, cellular stress response regulators, and upstream activators of regulated necrosis, including Toll-like receptors 2 and 4. These data suggest that unresolved injury and sustained activation of regulated necrosis pathways, rather than fibrosis, promote the progression of cisplatin-induced acute kidney injury to chronic kidney disease.
| S-EPMC6543531 | biostudies-literature
Project description:BACKGROUND: The renal function of chronic kidney disease (CKD) patients may be improved by a number of rehabilitative mechanisms. Swimming exercise training was supposed to be beneficial to its recovery. METHODOLOGY/PRINCIPAL FINDINGS: Doxorubicin-induced CKD (DRCKD) rat model was performed. Swimming training was programmed three days per week, 30 or 60 min per day for a total period of 11 weeks. Serum biochemical and pathological parameters were examined. In DRCKD, hyperlipidemia was observed. Active mesangial cell activation was evidenced by overexpression of PDGFR, P-PDGFR, MMP-2, MMP-9, ?-SMA, and CD34 with a huge amount collagen deposition. Apparent myofibroblast transdifferentiation implicating fibrogenesis in the glomerular mesangium, glomerulonephritis and glomeruloscelorosis was observed with highly elevated proteinuria and urinary BUN excretion. The 60-min swimming exercise but not the 30 min equivalent rescued most of the symptoms. To quantify the effectiveness of exercise training, a physical parameter, i.e. "the strenuosity coefficient" or "the myokine releasing coefficient", was estimated to be 7.154 × 10(-3) pg/mL-J. CONCLUSIONS: The 60-min swimming exercise may ameliorate DRCKD by inhibiting the transdifferentiation of myofibroblasts in the glomerular mesangium. Moreover, rehabilitative exercise training to rescue CKD is a personalized remedy. Benefits depend on the duration and strength of exercise, and more importantly, on the individual physiological condition.
| S-EPMC3384651 | biostudies-other
Project description:Cisplatin is widely used for the treatment of solid tumors and its antitumor effects are well established. However, a known complication of cisplatin administration is acute kidney injury (AKI). In this study, we examined the role of TEA domain family member 1 (TEAD1) in the pathogenesis of cisplatin-induced AKI. TEAD1 expression was upregulated in tubular epithelial cells of kidneys with cisplatin-induced AKI. TEAD1 floxed mice (TEAD1CON) mice treated with cisplatin developed tubular cell damage and impaired kidney function. In contrast, proximal tubule specific TEAD1 knockout (TEAD1PKO) mice treated with cisplatin had enhanced tubular cell damage and kidney dysfunction. Additionally, TEAD1PKO mice treated with cisplatin had augmented necroptotic cell death and inflammatory response compared to TEAD1CON mice with cisplatin. Knockdown of TEAD1 in mouse tubular epithelial cells showed increased intracellular ROS levels, reduced ATP production and impaired mitochondrial bioenergetics compared to control cells treated with cisplatin. Mechanistically, TEAD1 interacts with peroxisomal proliferator-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, to promote mitochondrial function. Taken together, our results indicate TEAD1 plays an important role in the pathogenesis of cisplatin-induced AKI through regulation of necroptosis and inflammation, which is associated with mitochondrial metabolism. Therefore, TEAD1 may represent a novel therapeutic target for cisplatin-induced AKI.
| S-EPMC11705647 | biostudies-literature
Project description:In this study, we investigated the nephroprotective effects of Umbelliferone (UMB) against cisplatin-induced acute kidney injury (AKI). C57BL/6J mice were treated with cisplatin via a single intraperitoneal injection (25 mg/kg) with or without UMB (40 mg/kg/day) by gavage. Renal function, apoptosis, oxidative stress, inflammation, and mitochondrial function were analyzed to evaluate kidney injury. In vitro, human proximal tubule epithelial cells were treated with cisplatin, with or without UMB, for 24 h. Western blotting and immunohistochemistry were performed to explore the mechanisms underlying the nephroprotective effects of UMB. Cisplatin-induced renal dysfunction, including increases in blood urea nitrogen, serum creatinine, and renal tubular injury indices (NGAL and KIM-1), were significantly attenuated by UMB treatment, along with renal phenotypic changes and renal tubular injury, as evidenced by improved renal histology. Moreover, NRF2 was activated by UMB pretreatment, along with the inhibition of oxidative stress and inflammatory response, as evidenced by decreased levels of antioxidant genes and inflammatory cytokines in cisplatin-induced AKI. Our results demonstrate that UMB can protect against cisplatin-induced nephrotoxicity, which is mediated by the NRF2 signaling pathway via antioxidant and anti-inflammatory activities, suggesting the clinical potential of UMB for the treatment of AKI.
| S-EPMC10686806 | biostudies-literature
Project description:The use of cisplatin, a chemotherapy drug, is often limited due to its renal side effects such as acute kidney injury (AKI). However, there are no validated medications to prevent or treat cisplatin-induced AKI. Oridonin is the major bioactive component of Isodon rubescens (Rabdosia rubescens) and exhibits anticancer, antioxidative, and anti-inflammatory effects. Recent studies have shown that oridonin alleviated a variety of inflammatory diseases, including renal diseases, in rodents. This study was aimed at investigating the potential renoprotective effect of oridonin on cisplatin-induced AKI. Male C57BL/6 mice were administered with cisplatin (20 mg/kg) with or without oridonin (15 mg/kg). Oridonin administration to mice after cisplatin injection attenuated renal dysfunction and histopathological changes. Upregulation of tubular injury markers was also suppressed by oridonin. Mechanistically, oridonin suppressed lipid peroxidation and reversed the decreased ratio of reduced to oxidized glutathione in cisplatin-injected mice. The increase in cisplatin-induced apoptosis was also alleviated by the compound. Moreover, oridonin inhibited cytokine overproduction and attenuated immune cell infiltration in cisplatin-injected mice. Altogether, these data demonstrated that oridonin alleviates cisplatin-induced kidney injury via inhibiting oxidative stress, apoptosis, and inflammation.
| S-EPMC9034941 | biostudies-literature
Project description:Ischemia reperfusion injury (IRI) of the kidney results in interferon regulatory factor 4 (IRF4)-mediated counter-regulation of the acute inflammatory response. Beyond that, IRF4 exerts important functions in controlling the cytokine milieu, T-cell differentiation, and macrophage polarization. The latter has been implicated in tissue remodeling. It therefore remains elusive what the role of IRF4 is in terms of long-term outcome following IRI. We hypothesized that an inability to resolve chronic inflammation in Irf4 -/- mice would promote chronic kidney disease (CKD) progression. To evaluate the effects of IRF4 in chronic upon acute injury in vivo, a mouse model of chronic injury following acute IRI was employed. The expression of Irf4 increased within 10 days after IRI in renal tissue. Both mRNA and protein levels remained high up to 5 weeks upon IRI, suggesting a regulatory function in the chronic phase. Mice deficient in IRF4 display increased tubular cell loss and defective clearance of infiltrating macrophages. These phenomena were associated with increased expression of pro-inflammatory macrophage markers together with reduced expression of alternatively activated macrophage markers. In addition, IRF4-deficient mice showed defective development of alternatively activated macrophages. Hints of a residual M1 macrophage signature were further observed in human biopsy specimens of patients with hypertensive nephropathy vs. living donor specimens. Thus, IRF4 restricts CKD progression and kidney fibrosis following IRI, potentially by enabling M2 macrophage polarization and restricting a Th1 cytokine response. Deteriorated alternative macrophage subpopulations in Irf4 -/- mice provoke chronic intrarenal inflammation, tubular epithelial cell loss, and renal fibrosis in the long course after IRI in mice. The clinical significance of these finding for human CKD remains uncertain at present and warrants further studies.
| S-EPMC6781770 | biostudies-literature
Project description:In the aged patients suffering from acute kidney injury, the risk for progression to chronic kidney disease and mortality is high. Aging accompanied by glomerulosclerosis, interstitial inflammation, and fibrosis might be one of the underlying mechanisms for vulnerability. In addition to sustained activation of the renin-angiotensin system, persistent chronic inflammation with tertiary lymphoid tissue formation is more common and is associated with disease progression in the aged kidney after acute injury. Based on recent laboratory evidence that young blood can rejuvenate the brain, muscle, and heart, we were intrigued by the possible protective effect of young plasma on acute kidney injury in aged mice. Here, we demonstrated that young plasma from 2-month-old mice could attenuate chronic kidney disease progression in 15-month-old mice subjected to acute kidney injury induced by ischemia-reperfusion. In the aged mice after acute kidney injury, young plasma administration decreased tubulointerstitial injury, fibrosis, and tertiary lymphoid tissue formation in kidneys assessed on day 28 after acute injury despite no significant beneficial effect on injury severity and survival. Mechanistically, young plasma inhibited angiotensin II-activated chemokines in pericytes that were responsible for tertiary lymphoid tissue formation. In summary, our data provide evidence that young plasma attenuates the transition from acute kidney injury to chronic kidney disease in aged mice. The therapeutic potential of young plasma infusion or exchange in the aged patients suffering acute kidney injury needs to be addressed in clinical trials.
| S-EPMC11567270 | biostudies-literature
Project description:Cisplatin is extensively used to treat malignancies. However, its clinical use is always limited due to the serious side effects, especially the nephrotoxicity. Matrine (MAT), a tetracyclic quinolizine alkaloid found in sophora genus, exerts multiple pharmacological roles, including anti-oxidative stress, anti-inflammation and anti-apoptosis, but the role of MAT on acute kidney injury (AKI) has not been evaluated. Here, we found that MAT potently inhibited cell injury induced by cisplatin in HK2 cells in vitro, which was associated with the inhibition of oxidative injury and NF-κB-mediated inflammation. Moreover, MAT treatment could activate the SIRT3/OPA1 axis and subsequently suppress the mitochondrial fragmentation and improve mitochondrial function. More importantly, SIRT3 knockdown suppressed the deacetylation of OPA1, which blocked the protective role of MAT on cisplatin-induced cell injury. In vivo, MAT treatment alleviated renal dysfunction, histological damage and inflammation induced by cisplatin in mice. Furthermore, consistent with the founding in vitro, MAT also activated SIRT3-mediated deacetylation of OPA1 and alleviated mitochondrial dysfunction in AKI mice. Our study proved that MAT protected against cisplatin-induced AKI by synergic anti-oxidative stress and anti-inflammation actions via SIRT3/OPA1-mediated improvement of mitochondrial function, suggesting that MAT may be a novel and effective strategy for AKI.
| S-EPMC9258713 | biostudies-literature