Model Of Chronic Kidney Disease Research Articles

Renal Macro- and Microcirculatory Perturbations in Acute Kidney Injury and Chronic Kidney Disease Associated with Heart Failure and Cardiac Surgery.

Chronic kidney disease (CKD) affects 50% of patients with heart failure. The pathophysiology of CKD in heart failure is proposed to be driven by macrocirculatory hemodynamic changes, including reduced cardiac output and elevated central venous pressure. However, our understanding of the renal microcirculation in heart failure and CKD remains limited. This is largely due to the lack of non-invasive techniques to assess the renal microcirculation in patients. Moreover, there is a lack of clinically relevant animal models of heart failure and CKD to advance our understanding of the timing and magnitude of renal microcirculatory dysfunction. Patients with heart failure and CKD commonly require cardiac surgery with cardiopulmonary bypass (CPB) to improve their prognosis. However, acute kidney injury (AKI) is a frequent unresolved clinical complication in these patients. There is emerging evidence that renal microcirculatory dysfunction, characterized by renal medullary hypoperfusion and hypoxia, plays a critical role in the pathogenesis of cardiac surgery-associated AKI. In this review, we consolidate the preclinical and clinical evidence of renal macro- and microcirculatory perturbations in heart failure and cardiac surgery requiring CPB. We also examine emerging biomarkers and therapies that may improve health outcomes for this vulnerable patient population by targeting the renal microcirculation.

Augmenter of liver regeneration inhibits renal fibrosis during acute kidney injury to chronic kidney disease transition by regulating autophagic flux

Augmenter of liver regeneration (ALR) is believed to protect against acute kidney injury (AKI). The objective of this study was to investigate the mechanisms of ALR in the transition from AKI to chronic kidney disease (CKD). ALR Conditional Knockout (CKO) mice were bilateral renal artery clamped to induce AKI and CKD. Serum creatinine, blood urea nitrogen, and uric acid were measured to reflect renal function. Renal histology was used to assess kidney damage. Transcriptome sequencing and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to identify differentially expressed genes (DEGs) and related pathways. TUNEL assay was conducted to assess apoptosis. Polymerase chain reaction and immunohistology were used to analyze autophagy-related factors and kidney fibrosis. AAV9-mRFP-GFP-LC3 was injected to observe autophagy flux. In the murine models of AKI and CKD, loss of ALR led to markedly reduced renal function and renal tubular pathology injury. Multiple autophagy-related pathways were found to be enriched in up-regulated DEGs in transcriptome sequencing of ALR CKO and control groups with AKI. Renal fibrosis was evident in ALR CKO mice, with marked suppression of Beclin-1, a factor associated with the initiation phase of autophagy, and ATG5, an important factor in the extension phase of autophagosomes. The marked accumulation of LC3 and SQSTM1/P62, which is associated with the formation of autophagosomes, was also observed, suggesting an impairment of autophagic processes. Correspondingly, the AAV9-mRFP-GFP-LC3 results indicated that decreased ALR led to the accumulation of autophagosomes and impaired autophagic lysosome generation. Collectively, these results suggested that ALR deficiency led to apoptosis and enhanced renal fibrosis by impairing autophagic flux, which in turn led to the transition of AKI to CKD.

A comparative review of murine models of repeated low-dose cisplatin-induced chronic kidney disease.

This Review evaluates various mouse and rat models of chronic kidney disease (CKD) that result from repeated low-dose cisplatin (RLDC) treatment while also discussing ethical considerations on the topic. Cisplatin can cause nephrotoxicity, and high doses of cisplatin can cause acute kidney injury. The RLDC regimen has been used in the treatment of solid organ cancers and has shown efficacy in reducing the occurrence of acute kidney injury in patients. However, prolonged treatments may lead to CKD. Mouse and rat models that effectively replicate the pathological features of CKD are invaluable for studying the mechanisms of the disease and exploring potential therapeutic interventions. Whereas administration of a single higher dose in some RLDC models may lead to higher mortality rates, a single lower dose may not replicate the fibrotic characteristics of CKD. Here we gathered information on mouse and rat models of RLDC-induced CKD and analyzed the impact of different variables, such as animal age, cisplatin dosage and administration frequency, on success rates, mortality rate and weight loss. Among the different models, weekly intraperitoneal administration of 8 mg/kg or 9 mg/kg of cisplatin for a total of 4 weeks in 12-week-old male C57BL/6 mice showed the most similar clinical characteristics of CKD while adhering to ethical requirements. In this Review, we suggest the best timings for both drug intervention and observation based on the biological traits of the model. Furthermore, given the limited research available on RLDC-induced CKD rat models, it is urgent to focus on developing RLDC methods that can induce detailed characteristics of CKD in rats.

Effectively simplified Adriamycin-induced chronic kidney disease mouse model: Retro-orbital vein injection versus tail-vein injection.

This study aimed to investigate the impact of administration routes in establishing the Adriamycin (ADR)-induced chronic kidney disease (CKD) model. Using BALB/c mice, we compared the effects of conventional tail-vein injection (TV10, 10 mg/kg) to those of retro-orbital sinus (orbital vein) injection (OV10, 10 mg/kg; OV8, 8 mg/kg). The results indicated that the OV10 group exhibited CKD pathology similar to the TV10 group, with both groups demonstrating significantly higher urinary albumin/creatinine ratio (p < 0.05), tubular injury (p < 0.05), and degree of renal fibrosis (p < 0.05) than the OV8 group. No significant differences were observed between the OV10 and TV10 groups in urinary albumin/creatinine ratio, tubular injury, and degree of renal fibrosis. These findings demonstrated that retro-orbital administration of 10 mg/kg ADR induces comparable effects to conventional tail-vein administration. This technique's technical simplicity may improve experimental efficiency, reproducibility, and animal welfare in CKD research. In conclusion, this study validates the utility of retro-orbital injection in CKD model establishment, demonstrating its potential to standardize and improve the reliability of future CKD research protocols.

Biomimetic wrinkled prebiotic microspheres with enhanced intestinal retention for hyperphosphatemia and vascular calcification.

It is urgent for patients with chronic kidney disease (CKD) to develop a robust and facile therapy for effective control of serum phosphate and reasonable regulation of gut microbiota, which are aiming to prevent cardiovascular calcification and reduce cardiovascular complications. Here, bioinspired by intestinal microstructures, we developed biomimetic wrinkled prebiotic-containing microspheres with enhanced intestinal retention and absorption for reducing hyperphosphatemia and vascular calcification of CKD model rats. The resultant CSM@5 microspheres exhibited favorable phosphate binding capacity in vitro and could effectively reduce serum concentration of phosphorous in vivo. Through increasing the beneficial bacteria and decreasing the harmful bacteria in the intestinal tract, these prebiotic microspheres can modulate intestinal microbiota and then ameliorate vascular calcification notably. This feasible and robust approach may offer a potential and effective strategy for the treatment of hyperphosphatemia of CKD and prevention of its cardiovascular complications.

Network pharmacology and multi-omics validation of the Jianpi-Yishen formula in the treatment of chronic kidney disease.

Chronic kidney disease (CKD) is a major global health problem. In clinical practice, the Chinese patent herbal medicine Jianpi-Yishen (JPYS) formula is commonly used to treat CKD. However, the molecular mechanisms by which JPYS targets and modulates the host immune response remain unclear. This study utilized network pharmacology, RNA sequencing (RNA-seq), and metabolic analyses using in vivo and in vitro models to investigate the impact of the JPYS formula on inflammation and the immune system. Specifically, the study focused on macrophage polarization and metabolic changes that may slow down the progression of CKD. A total of 14,946 CKD-related targets were identified from the GeneCards and Online Mendelian Inheritance in Man (OMIM) databases through network pharmacology analyses. 227 potential targets of the JPYS formula were predicted using the TCMSP database. Additionally, network diagram demonstrated that 11 targets were associated with macrophage activity. In vivo studies indicated that the JPYS formula could reduce blood urea nitrogen and serum creatinine in adenine-induced CKD rats. Furthermore, the formula inhibited inflammatory damage and abnormal macrophage infiltration in this CKD model. RNA-seq, proteomic and metabolic analyses identified the regulation of amino acid metabolism by betaine, specifically referring to glycine, serine, and threonine metabolism, as a key target of the JPYS formula in slowing the progression of CKD. In addition, in vitro studies suggested that JPYS may enhance tryptophan metabolism in M1 macrophage polarization and betaine metabolism in M2 macrophage polarization. The JPYS formula has been shown to have beneficial impact on CKD; a key mechanism is the mitigation of inflammatory damage through the interaction between amino acid metabolism and macrophage polarization. Of specific importance in this context are the roles of tryptophan in M1 polarization and betaine in M2 polarization.

Targeted Polymer-Peptide Conjugates for E-Selectin Blockade in Renal Injury.

Leukocytes play a significant role in both acute kidney injury (AKI) and chronic kidney disease (CKD), contributing to pathogenesis and tissue damage. The process of leukocyte infiltration into the inflamed tissues is mediated by the interactions between the leukocytes and cell adhesion molecules (CAMs, i.e., E-selectin, P-selectin, and VCAM-1) present on the inner surface of the inflamed vasculature. Directly interfering with these interactions is a viable strategy to limit the extent of excessive inflammation; however, several small-molecule drug candidates failed during clinical translation. We hypothesized that a synthetic polymer presenting multiple copies of the high-affinity E-selecting binding peptide (P-Esbp) could block E-selectin-mediated functions and decrease leukocytes infiltration, thus reducing the extent of inflammatory kidney injury. P-Esbp was synthesized by conjugating E-selecting binding peptide (Esbp) to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer with reactive ester groups via aminolysis. The effects of P-Esbp treatment on kidney injury were investigated in two different models: AKI model (renal ischemia-reperfusion injury-RIRI) and CKD model (adenine-induced kidney injury). We found that the mRNA levels of E-selectin were up-regulated in the kidney following acute and chronic tissue injury. P-Esbp demonstrated an extended half-life time in the bloodstream, and the polymer accumulated significantly in the liver, lungs, and kidneys within 4 h post injection. Treatment with P-Esbp suppressed the up-regulation of E-selectin in mice with RIRI and attenuated the inflammatory process. In the adenine-induced CKD model, the use of the E-selectin blocking copolymer had little impact on the progression of kidney injury, owing to the compensating function of P-selectin and VCAM-1. Our findings provide valuable insights into the interconnection between CAMs and compensatory mechanisms in controlling leukocyte migration in AKI and CKD. The combination of multiple CAM blockers, given simultaneously, may provide protective effects for preventing excessive leukocyte infiltration and control renal injury.

Runx2-NLRP3 axis orchestrates matrix stiffness-evoked vascular smooth muscle cell inflammation.

Arterial stiffening is a hallmark of chronic kidney disease (CKD)-related cardiovascular events and is primarily attributed to the elevated matrix stiffness. Stiffened arteries are accompanied by low-grade inflammation, but the causal effects of matrix stiffness on inflammation remain unknown. For analysis of the relationship between arterial stiffness and vascular inflammation, pulse-wave velocity (PWV) and aortic inflammatory markers were analyzed in an adenine-induced mouse model of CKD in chronological order. Compared with their control littermates, mice with CKD showed elevated arterial stiffness at the early stage of disease progression, which preceded the onset of vascular inflammation. Correspondingly, the increase of matrix stiffness induced vascular smooth muscle cells (VSMCs) to transdifferentiate into an inflammatory phenotype, as indicated by the increased expression and secretion of MCP-1, IL-6, IL-1β, and IL-18. RNA-sequencing analysis of stiff matrix-cultured VSMCs and bioinformatics analysis with the ChIP-Atlas database revealed the potential involvement of the transcription factor Runx2. The expression and the nuclear localization of Runx2 were significantly increased in stiff matrix-cultured VSMCs. High-throughput ChIP-sequencing and promoter luciferase assays further revealed that NLRP3 was directly transcriptionally regulated by Runx2. The inhibition of Runx2 or NLRP3 inflammasome abrogated the proinflammatory effect of matrix stiffening on VSMCs. Together, these data revealed that arterial stiffness precedes vascular inflammatory responses in CKD mice and that the Runx2-NLRP3 axis orchestrates matrix stiffness and the VSMC inflammatory phenotype, which may contribute to the pathogenic role in arterial stiffness-related vascular inflammation and CKD-related cardiovascular complications.NEW & NOTEWORTHY As a hallmark of chronic kidney disease (CKD), arterial stiffening is related to increased vascular inflammation and cardiovascular morbidity, whereas the underlying mechanism is unclear. The study demonstrates that increased arterial stiffness precedes the onset of vascular inflammation, and matrix stiffness stimulates the transdifferentiation of vascular smooth muscle cells (VSMCs) to an inflammatory phenotype via activating Runx2-NLRP3 signaling, which provides novel insights into CKD-related cardiovascular disorder treatment.

An integrated proteomic and phosphoproteomic landscape of chronic kidney disease.

The prevalence of chronic kidney disease (CKD) is gradually rising worldwide. Patients often remain asymptomatic for an extended period, leaving them unaware of their condition, which can lead to progressing to end-stage renal disease and cause significant economic burden. Improved understanding of CKD pathogenesis can enhance early detection and facilitate advances in drug development. Here, we performed proteomic and phosphoproteomic analyses of the mouse unilateral ureteral obstruction model to explore the molecular mechanisms of chronic kidney injury. 474 significantly differentially expressed proteins and 96 significantly differentially expressed phosphoproteins were screened, respectively. Chronic kidney injury involves complex metabolic pathways such as citrate cycle and hematopoietic system in proteome, and mitochondrial oxidative phosphorylation suppression is a notable alteration. The phosphoproteomic analysis revealed a significant upregulation in epithelial mesenchymal transition and P53 pathways, with a corresponding increase in the phosphorylation of Jun at serine 73. Utilizing HK2 cells, we observed that the reduction oxidative phosphorylation was consistently associated with an augmentation in oxidative stress, which subsequently activated Jun and induced apoptosis. Proteins that act as hubs in these pathways may be candidate targets for CKD intervention. These findings contribute significantly to the current understanding of CKD and provide valuable insights for future studies. SIGNIFICANCE: Chronic kidney disease (CKD) incidence rising annually with varied etiologies, kidney often irreversibly fibrotic, the treatment options are limited and often ineffective due to deficient understanding of renal fibrosis mechanisms. Despite the extensive efforts and numerous omics studies conducted on renal fibrosis, to date, no study has been undertaken to investigate the role of phosphorylated proteins in UUO models. Previously, we performed a comprehensive transcriptome and proteome analysis based on the CKD model, but the potential alterations in the phosphoproteome were not addressed. Here, an integrated proteomic and phosphoproteomic landscape of CKD was completed, which was the the first phosphoproteomic profiles of UUO model. Phosphoproteomic profile suggests that the epithelial mesenchymal transition and P53 pathways is significantly activated in mouse models of kidney injury, and the core protein Jun played a key role in CKD. And a preliminary correlation between P-Jun and oxidative phosphorylation was found base on HK2 cells. Our work contributes to a deeper understanding of the disease characteristics and molecular mechanisms of CKD. Identifying potential CKD targets from proteome and phosphoproteome may provide valuable insights for early diagnosis and treatment of CKD.

Curcumin modulated gut microbiota and alleviated renal fibrosis in 5/6 nephrectomy-induced chronic kidney disease rats.

Increasing evidence suggests that dysbiosis of gut microbiota exacerbates chronic kidney disease (CKD) progression. Curcumin (CUR) has been reported to alleviate renal fibrosis in animal models of CKD. However, the relationship between CUR and gut microbiome in CKD remains unclear. This study aims to investigate the potential anti-renal fibrosis effects of CUR from the gut microbiota perspective. A 5/6 nephrectomy (5/6Nx) rat model was used to explore the therapeutic effect of CUR on renal fibrosis. Tight junction protein expression levels were measured to assess intestinal barrier function. 16S rRNA sequencing was employed to evaluate changes in gut microbiota composition, and metabolomics was utilized to detect alterations in plasma metabolites. The administration of CUR significantly ameliorated renal fibrosis and inhibited inflammation in 5/6Nx rats. Additionally, CUR markedly improved the expression of tight junction proteins and local colon inflammation. CUR also positively reconstructed gut microbiota, significantly increasing the abundance of beneficial bacteria, such as Lachnospiraceae_NK4A136_group, Eubacterium_siraeum_group, and Muribaculaceae was significantly increased. Metabolomics revealed that CUR reduced uremic retention solutes and elevated Vitamin D and short-chain fatty acids (SCFAs). Spearman correlation analysis indicated that gut genera enriched by CUR were positively correlated with Vitamin D and SCFA and negatively correlated with chronic renal injury biomarkers. Mechanistically, we found inhibition of the LPS/TLR4/NF-κB and TGF-β1/Smads pathway in CUR-treated rats. Our study indicates that CUR has the potential to modulate gut microbiota composition, and that this modulation may contribute to the anti-fibrosis effects of CUR.

Aquaporin-2 in the early stages of the adenine-induced chronic kidney disease model.

Chronic kidney disease (CKD) is one of the leading health problems in the world. It is silent in the early stages and gradually progresses, inducing renal physiological and structural alterations. Moreover, CKD is associated with impaired life quality, increased risk for cardiovascular diseases, and reduced life expectancy. Different CKD animal models differ in underlying etiology, time of onset, and associated diseases. The 0.25% adenine diet induces progressive kidney damage, constituting an adequate model mimicking human CKD. Vasopressin (VP) was postulated as a mediator of CKD, mainly acting through its V2 receptors. However, the molecular mechanisms involved in the pathogenesis of this condition and its progression still are not entirely understood. This study aimed to evaluate if AQP2 expression is altered in an adenine-induced model of CKD in rats at early stages of development (two weeks) and to assess a potential beneficial effect of Tolvaptan (a V2 receptor antagonist) treatment. We showed an increased renal medullary AQP2 expression at two weeks of adenine administration. This increase was mainly cytoplasmic, explaining the increased urinary volume of CKD rats and suggesting a possible non-canonical role for AQP2. In addition, Tolvaptan effectively inhibited the V2 receptor in both control and CKD rats, decreasing AQP2 expression and increasing diuresis. Moreover, Tolvaptan slightly reduced BUN and plasma creatinine. On the other hand, the renal alterations induced by adenine in CKD rats were not prevented by Tolvaptan.

Inhibition of PKM2 by shikonin impedes TGF-β1 expression by repressing histone lactylation to alleviate renal fibrosis.

Macrophage-myofibroblast transition (MMT) plays a significant role in the progression of renal fibrosis in chronic kidney disease (CKD), making inhibition of MMT a promising therapeutic strategy. Pyruvate kinase M2 (PKM2) and its metabolite lactate are implicated in the pathogenesis of renal fibrosis; however, the mechanisms through which they contribute to this process remain poorly understood. To investigate the effects of PKM2 inhibition by shikonin on renal fibrosis and the underly mechanisms. Mice were subjected to unilateral ureteral obstruction (UUO) to establish a CKD model. Renal fibrosis was assessed using histochemistry and western blotting. The MMT and histone lactylation levels were evaluated by immunofluorescence and western blotting. The interaction between the Tgfb1 promoter and lactylated histone H3 (K18) was examined using chromatin Immunoprecipitation (ChIP). PKM2 expression was significantly elevated in the renal tubular cells of UUO mouse kidneys, resulting in increased pyruvate and lactate production. Similarly, lactate levels were elevated in TGF-β1-treated TCMK-1 cells and in the serum of CKD patients. In UUO mice, treatment with shikonin, a potent PKM2 inhibitor, effectively reduced lactate production, alleviated renal fibrosis, decreased TGF-β1 expression, and suppressed the MMT process. Mechanistic studies revealed that lactate treatment stimulates Tgfb1 expression in TCMK-1 cells. Consequently, TGF-β1 in conditioned media from lactate-treated TCMK-1 cells promoted M2 macrophage polarization and upregulated fibrotic gene expression in RAW264.7 cells. Pharmacological intervention demonstrated that TGF-β1 activates the Smad3 pathway to drive the MMT process. In TCMK-1 cells, both lactate treatment and PKM2 overexpression induced Tgfb1 expression by promoting histone H3K18 lactylation. Our findings indicate that PKM2-induced excessive lactate production renal tubular cells contributes to renal fibrosis. Lactate promotes histone lactylation, leading to TGF-β1 expression in these cells, which subsequently activates the Smad3 pathway in macrophages, driving the MMT and fibrosis in the kidney. Therefore, targeting PKM2, as with shikonin treatment, may represent an effective therapeutic strategy for managing renal fibrosis in CKD.

Effects of renal denervation on the course of cardiorenal syndrome: insight from studies with fawn-hooded hypertensive rats.

Combination of chronic kidney disease (CKD) and heart failure (HF) results in extremely high morbidity and mortality. The current guideline-directed medical therapy is rarely effective and new therapeutic approaches are urgently needed. The study was designed to examine if renal denervation (RDN) will exhibit long-standing beneficial effects on the HF- and CKD-related morbidity and mortality. Fawn-hooded hypertensive rats (FHH) served as a genetic model of CKD and fawn-hooded low-pressure rats (FHL) without CKD served as controls. HF was induced by creation of aorto-caval fistula (ACF). RDN was performed 28 days after creation of ACF and the follow-up period was 70 days. ACF FHH subjected to sham-RDN had survival rate of 34 % i.e. significantly lower than 79 % observed in sham-denervated ACF FHL. RDN did not improve the condition and the final survival rate, both in ACF FHL and in ACF FHH. In FHH basal albuminuria was markedly higher than in FHL, and further increased throughout the study. RDN did not lower albuminuria and did not reduce renal glomerular damage in FHH. In these rats creation of ACF resulted in marked bilateral cardiac hypertrophy and alterations of cardiac connexin-43, however, RDN did not modify any of the cardiac parameters. Our present results further support the notion that kidney damage aggravates the HF-related morbidity and mortality. Moreover, it is clear that in the ACF FHH model of combined CKD and HF, RDN does not exhibit any important renoprotective or cardioprotective effects and does not reduce mortality. Key words Chronic kidney disease, Heart failure, Renal denervation, Fawn-hooded hypertensive rats.

Screening of active components in Astragalus mongholicus Bunge and Panax notoginseng formula for anti-fibrosis in CKD: nobiletin inhibits Lgals1/PI3K/AKT signaling to improve renal fibrosis

The Astragalus mongholicus Bunge and Panax notoginseng formula (A&P) has been clinically shown to effectively slow down the progression of chronic kidney disease (CKD) and has demonstrated significant anti-fibrosis effects in experimental CKD model. However, the specific active ingredients and underlying mechanism are still unclear. The active ingredients of A&P were analyzed by Ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-HR-MS). A mouse model of CKD was constructed by 5/6 nephrectomy. Renal function was assessed by creatinine and urea nitrogen. Real-time PCR and Western Blot were performed to detect the mRNA and protein changes in kidney and cells. An in vitro fibrotic cell model was constructed by TGF-β induction in TCMK-1 cells. The results showed that thirteen active ingredients of A&P were identified by UPLC-HR-MS, nine of which were identified by analysis with standards, among which the relative percentage of NOB was high. We found that NOB treatment significantly improved renal function, pathological damage and reduced the expression level of fibrotic factors in CKD mice. The results also demonstrated that Lgals1 was overexpressed in the interstitial kidney of CKD mice, and NOB treatment significantly reduced its expression level, while inhibiting PI3K and AKT phosphorylation. Interestingly, overexpression of Lgals1 significantly increased fibrosis in TCMK1 cells and upregulated the activity of PI3K and AKT, which were strongly inhibited by NOB treatment. NOB is one of the main active components of A&P. The molecular mechanism by which NOB ameliorates renal fibrosis in CKD may be through the inhibition of Lgals1/PI3K/AKT signaling pathway.

Protective Effects of Tormentic Acid on Unilateral Ureteral Obstruction-Induced Renal Injury, Inflammation, and Fibrosis: A Comprehensive Approach to Reducing Oxidative Stress, Apoptosis, and Ferroptosis.

Chronic kidney disease (CKD) progresses through mechanisms involving inflammation, fibrosis, and oxidative stress, leading to the gradual structural and functional deterioration of the kidneys. Tormentic acid (TA), a triterpenoid compound with known anti-inflammatory and antioxidant properties, shows significant potential in counteracting these pathological processes. This study explored the protective role of TA in a unilateral ureteral obstruction (UUO)-induced CKD model. Mice received TA through intraperitoneal injections at a dosage of 5 mg/kg per day for 8 consecutive days, commencing a day before the UUO procedure. The TA treatment significantly improved both structural and functional kidney injury. It suppressed cytokine expression and reduced immune cell infiltration, inhibited the activation of the mitogen-activated protein kinase cascade, and alleviated endoplasmic reticulum stress. Moreover, TA displayed potent anti-fibrotic effects by reversing epithelial-to-mesenchymal transition and inhibiting Smad2/3 activation, reducing extracellular matrix deposition. TA also mitigated oxidative stress by attenuating lipid peroxidation and boosting antioxidant defenses. Additionally, it inhibited apoptosis and ferroptosis by reducing oxidative stress and modulating key cell death markers. Collectively, these findings indicate that TA provides comprehensive renoprotection in the UUO model by effectively targeting inflammation, fibrosis, oxidative stress, and tubular cell death in CKD progression.

Antihypertensive Effects of a Sodium Thiosulfate-Loaded Nanoparticle in a Juvenile Chronic Kidney Disease Rat Model.

Sodium thiosulfate (STS), a precursor of hydrogen sulfide (H2S), has demonstrated antihypertensive properties. Previous studies have suggested that H2S-based interventions can prevent hypertension in pediatric chronic kidney disease (CKD). However, the clinical application of STS is limited by its rapid release and intravenous administration. To address this, we developed a poly-lactic acid (PLA)-based nanoparticle system for sustained STS delivery and investigated whether weekly treatment with STS-loaded nanoparticles (NPs) could protect against hypertension in a juvenile CKD rat model. Male Sprague Dawley rats, aged three weeks, were fed a diet containing 0.5% adenine for three weeks to induce a model of pediatric CKD. STS-loaded NPs (25 mg/kg) were administered intravenously during weeks 6, 7, and 8, and at week 9, all rats were sacrificed. Treatment with STS-loaded NPs reduced systolic and diastolic blood pressure by 10 mm Hg and 8 mm Hg, respectively, in juvenile CKD rats. The protective effect of STS-loaded NPs was linked to increased renal expression of H2S-producing enzymes, including cystathionine γ-lyase (CSE) and D-amino acid oxidase (DAO). Additionally, STS-loaded NP therapy restored nitric oxide (NO) signaling, increasing L-arginine levels, which were disrupted in CKD. Furthermore, the beneficial effects of STS-loaded NPs were associated with inhibition of the renin-angiotensin system (RAS) and the enhancement of the NO signaling pathway. Our findings suggest that STS-loaded NP treatment provides sustained STS delivery and effectively reduces hypertension in a juvenile CKD rat model, bringing us closer to the clinical translation of STS-based therapy for pediatric CKD-induced hypertension.

The Ability of AST-120 to Lower the Serum Indoxyl Sulfate Level Improves Renal Outcomes and the Lipid Profile in Diabetic and Nondiabetic Animal Models of Chronic Kidney Disease: A Meta-Analysis.

The therapeutic benefit of the oral adsorbent drug AST-120 in chronic kidney disease (CKD) is related to an indoxyl sulfate (IS)-lowering action. Diabetes and dyslipidemia might worsen kidney damage in CKD. However, it is not known whether AST-120 influences lipid abnormalities as well as renal function in patients with CKD and diabetes. The objective of the present meta-analysis was to evaluate the efficacy of AST-120 treatment in CKD using data from preclinical studies. Mixed-effect or random-effect models were used to estimate the standardized mean difference (SMD) and the 95% confidence interval (CI). Publication bias was assessed with a funnel plot and Egger's test. The potential influence of some variables (the dose and duration of AST-120 treatment, the animal species, and the CKD model's diabetic status) was evaluated in subgroup analyses. Treatment with AST-120 was associated with a significantly lower IS level in animals with CKD (SMD = -1.75; 95% CI = -2.00, -1.49; p < 0.001). Significant improvements in markers of renal function and the lipid profile were also observed. In subgroup analyses of the cholesterol level, the diabetic status, the AST-120 dose, and the animal species were found to be influential factors. AST-120 lowered serum IS and triglyceride levels and improved renal function in animal models of CKD independent of diabetes status. However, AST-120's ability to lower the total cholesterol level was more prominent in animals with diabetic CKD.

Transgenic augmentation of erythroferrone in mice ameliorates anemia in adenine-induced chronic kidney disease.

Anemia is a common and disabling complication of chronic kidney disease (CKD). Current therapies can be burdensome, and full correction of anemia is limited by cardiovascular side effects. New approaches that may offer additional therapeutic options are needed. We explored the anti-anemic effects of erythroferrone, an erythroid hormone that induces iron mobilization by suppressing the master iron-regulatory hormone hepcidin. In a preclinical murine model of adenine-induced CKD, transgenic augmentation of erythroferrone mobilized iron, increased hemoglobin concentrations by approximately 2 g/dl, and modestly improved renal function without affecting systemic or renal inflammation, fibrosis, or markers of mineral metabolism. This study supports the concept that therapeutic augmentation of erythroferrone is a promising approach for alleviating CKD-associated anemia.

Apocynin and Hyperbaric Oxygen Therapy Improve Renal Function and Structure in an Animal Model of CKD.

Chronic kidney disease (CKD) is a progressive pathological condition which results in the severe fibrosis of the kidneys. However, the mechanisms of CKD progression and fibrogenesis remain unclear. We wanted to examine the effects that apocynin and hyperbaric oxygen therapy (HBOT) have on renal function and structure in animals with CKD induced through 5/6 nephrectomy (5/6 Nx-L). Male Wistar rats were divided in 5 groups (n = 8/group) as follows: control-sham-operated rats; Nx-L-rats with 5/6 Nx-L; APO-5/6 Nx-L + apocynin treatment; HBOT-5/6 Nx-L + hyperbaric oxygen treatment, and APO+HBOT-5/6 Nx-L, treated with both treatments. All treatments started 4 weeks after the final step of CKD induction and lasted for 4 weeks. At the end of the experiment, urine samples were collected for the proteinuria assessment and the mean arterial pressure (MAP) was measured. Kidneys were collected for histopathological, Western blot, and immunohistochemical analyses. All treatments significantly decreased MAP compared to the Nx-L group (p < 0.001). In the APO and APO+HBOT groups, the level of proteinuria was decreased compared to the Nx-L group (p < 0.05 and p < 0.01, respectively). All examined treatments significantly decreased the intensity of lesions in the kidney compared to those observed in the Nx-L group (p < 0.001). Isolated treatments with apocynin and HBOT induced a significant decrease in desmin expression compared to the Nx-L group (p < 0.05); meanwhile, they did not affect the levels of fibronectin (FN) and hypoxia-inducible factor-1α (HIF-1α). Combined treatment did not affect desmin expression levels; however, it induced a significant increase in fibronectin expression compared to Nx-L (p < 0.001). Apocynin treatment decreased BP and protein loss, and it improved renal morphology at least partly through the downregulation of desmin expression without changing FN and HIF-1α. Hyperbaric oxygen therapy improved hypertension but failed to significantly affect the level of proteinuria. Combined treatment (apocynin and HBOT) normalized blood pressure (BP) values, renal function, and improved kidney structure by modulating FN and HIF-1α, without affecting desmin protein expression. Further studies are needed to elucidate the mechanisms of slowing down the progression of CKD in this experimental model.

Chronic Kidney Disease-associated Lung Injury Is Mediated by Phosphate-induced MAPK/AKT Signaling.

Chronic kidney disease (CKD) is associated with systemic phosphate elevations, called hyperphosphatemia. Translational studies have shown that hyperphosphatemia contributes to CKD-associated inflammation and injury in various tissues, including the kidney, heart, liver, and parathyroid gland. Mechanisms underlying pathologic actions of elevated phosphate on cells are not well understood but seem to involve uptake of phosphate through sodium phosphate cotransporters and phosphate-induced signaling via FGFR1 (fibroblast growth factor receptor 1). Clinical studies indicate patients with CKD are more likely to develop inflammatory and restrictive lung diseases, such as fibrotic interstitial lung diseases, and here we aimed to determine whether hyperphosphatemia can cause lung injury. We found that a mouse model of CKD and hyperphosphatemia, induced by an adenine-rich diet, develops lung fibrosis and inflammation. Elevation of systemic phosphate concentration by administration of a high-phosphate diet in a mouse model of primary lung inflammation and fibrosis, induced by bleomycin, exacerbated lung injury in the absence of kidney damage. Our invitro studies identified increases of proinflammatory cytokines in human lung fibroblasts exposed to phosphate elevations. Phosphate activated ERK 1/2 (extracellular signal-related kinase 1/2) and PKB/AKT (protein kinase B) signaling, and pharmacological inhibition of ERK, AKT, FGFR1, or sodium phosphate cotransporters prevented phosphate-induced proinflammatory cytokine upregulation. In addition, inhibition of FGFR1 or sodium phosphate cotransporters decreased the phosphate-induced activation of ERK and AKT. Our study suggests that phosphate can directly target lung fibroblasts and induce an inflammatory response and that hyperphosphatemia in CKD and non-CKD models contributes to lung injury. Phosphate-lowering strategies might protect from CKD-associated lung injury.