Model Of Kidney Disease Research Articles

The Heparinoid Sevuparin Improves Anemia and Kidney Status in a Mouse Model of Chronic Kidney Disease

The control of systemic iron availability is essential to sustain the different needs of the body, without causing iron overload disease or deficiency (anemia) meaning that iron is highly regulated and the master regulator is hepcidin. High levels of hepcidin induce ferroportin degradation, inhibiting iron release from enterocytes and macrophages resulting in an internal iron deficiency, which underlies anemia of chronic diseases (ACD). Patients with chronic kidney disease (CKD) often have ACD due to a combination of inflammation, erythropoietin (EPO) insufficiency/unresponsiveness, elevated hepcidin levels, reduced kidney function and decreased iron availability. Treatments involve erythropoiesis-stimulating agents, that in a longer perspective often fail to ameliorate the anemia, highlighting the need for new therapeutic tools. Interestingly, it has been reported that hepcidin suppression improves anemia in rodent models of CKD, suggesting that normalising hepcidin levels may be a means to treat anemia in CKD and in general in ACD. It is known that heparins are potent hepcidin suppressors; sevuparin, a novel, clinical stage, low-molecular weight heparinoid compound with substantially reduced anticoagulant activity is a promising candidate drug to control hepcidin expression in patients with CKD. The authors previously found that sevuparin strongly suppressed basal, BMP6- and IL6-dependent hepcidin expression in vitro with a maximum effect after 6h (90% reduction) persisting for at least 16h. The hepcidin lowering effect of sevuparin was confirmed also in healthy mice. Furthermore, in healthy volunteers, a single dose of subcutaneous sevuparin caused a significant reduction of about 50% (3 mg/kg) and 80% (9 mg/kg) of serum hepcidin after 12 and 24h, respectively, providing a robust translational context to the sevuparin effects on hepcidin levels. The aim of the present work was to investigate the effect of sevuparin on hepcidin, hemoglobin and the kidney status in a CKD mouse model of high hepcidin anemia. Mice fed with “adenine rich diet” (ARD) (0.2% adenine; 0.9% phosphorus; 0.6% calcium; 20% casein) developed moderate or severe signs of kidney damage as manifested by weight loss, increased serum creatinine, high hepcidin levels, low serum iron and anemia (hemoglobin ≤ 12.5 g/dL) after 7-9 weeks. After the onset of CKD, the mice were chronically treated with PBS or sevuparin (10 mg/kg/daily) subcutaneously for 3 or 6 weeks alone or in combination with erythropoietin (EPO) administered intraperitoneally (50 U/mouse twice a week in the first 3 weeks followed by 3 weeks and then 25 U/mouse once a week to simulate EPO hypo-responsiveness). Sevuparin was provided by Modus Therapeutics AB, Sweden, whereas EPO was used in the form of the commercially available darbapoietin alfa (ARANESP ®). Sevuparin treatment alone increased hemoglobin, hematocrit and weight (Hb 11-12 g/dL; Ht 20%; 22 g vs baseline values of Hb 9-10 g/dL; Ht 18%; 14.5 g PBS) with adjoining modest decreases of serum hepcidin and creatinine. The reduction of creatinine was supported by a concomitant improvement of the kidney status visible as a reduction of collagen deposits indicative of reduced fibrosis compared to the mice treated with PBS only. The EPO/sevuparin combination showed a strong reduction from control of serum hepcidin levels (292 ng/mL vs 1382 ng/mL) after 3 weeks of treatment whereas after 6 weeks levels were increased up to 2000 ng/mL suggesting that the chronic treatment with EPO is not optimal, as observed in patients. Interestingly the concomitant benefit on anemia at 3w (about Hb 18 g/dL, Ht 54%) for the combination remained stable at 6w, further supported by the maintained high Ret-He (about 15.62 pg); suggesting a phased dependency on hepcidin in the development of CKD anemia. Furthermore, the improvement of the kidney status (histology and function) was also maintained throughout combination treatment. Our data in this mouse CKD model add new insights to the role of hepcidin in the development of CKD anemia over time. Furthermore, the results are promising and support further mechanistic and clinical studies to elucidate the therapeutic role for sevuparin as a treatment in anemia of inflammatory and/or chronic diseases in monotherapy or in combination with EPO and to explore its role in kidney protection.

METTL3/YTHDF2 m6A axis mediates the progression of diabetic nephropathy through epigenetically suppressing PINK1 and mitophagy.

This research aimed to investigate the specific mechanism of methyltransferase like 3 (METTL3) in the progression of diabetic kidney disease (DKD). The model of diabetic kidney disease was established with HK-2 cells and mice in vitro and in vivo. The N6 methyladenosine (m6A) contents in the cells and tissues were detected with a commercial kit and the m6A levels of PTEN induced putative kinase 1 (PINK2) were detected with a MeRIP kit. The mRNA and protein levels were determined with RT-qPCR and western blot. The ROS, TNF-α, and IL-6 levels were assessed with ELISA. The cell proliferative ability was measured by a CCK-8 assay and cell apoptosis was determined with TUNEL staining. The HE and Masson staining was performed to observe the renal morphology. The RIP assay was conducted to detect the interaction between METTL3/YTHDF2 and PINK1. The m6A content and METTL3 levels were prominently elevated in diabetic kidney disease. METTL3 silencing promoted the cell growth and the expression of LC3 II, PINK1, and Parkin, while inhibiting the cell apoptosis and the expression of LC3 I and p62 in the high glucose (HG) stimulated HK-2 cells. METTL3 silencing also decreased the ROS, TNF-α, and IL-6 levels in diabetic kidney disease. PINK1 silencing neutralized the function of sh-METTL3 in the HG stimulated HK-2 cells. The HE and Masson staining showed that METTL3 silencing alleviated the kidney injury induced by DKD. METTL3 silencing decreased the m6A levels of PINK1, while increased the mRNA levels of PINK1 which depended on YTHDF2. METTL3 silencing could inhibit the progression of diabetic nephropathy in vivo and in vitro by regulating the m6A modification of PINK1, which depends on YTHDF2. Our research lays the theoretical foundation for the precise treatment of diabetic kidney disease and the development of targeted drugs in the future.

Validation of Townes As Mice As a Model of Chronic Kidney Disease and Venous Thrombosis Associated with Sickle Cell Trait

Individuals with sickle cell trait (SCT) are heterozygous carriers of the sickle beta-globin gene. Systematic analyses of large cohort studies over the past decade have established that SCT is a risk factor for a limited number of complications, most notably chronic kidney disease (CKD) and venous thrombosis (VT). SCT red blood cells (RBCs) can undergo sickling, although the degree and duration of hypoxia required to produce sickling are much greater than in sickle cell disease due to the lower intra-erythrocyte sickle hemoglobin beta (HbS) concentration of 25-45%. Hypoxia-mediated HbS polymerization can be enhanced by cellular dehydration, hyperosmolarity and/or acidosis that may be encountered in the renal inner medulla. Furthermore, prolonged exposure of SCT RBCs to profound hypoxia, such as in the nidus of a venous clot, will also result in sickling. The objective of this study was to determine if Townes AS mice manifest kidney dysfunction analogous to their SCT human counterparts. Furthermore, we evaluated whether VT was more pronounced in a well-described model of inferior vena cava (IVC) stasis. We used humanized male sickle cell trait (AS) and age-matched genetic control (AA) mice (n=7-16). Analysis of urinary renal biomarkers (albuminuria, proteinuria, kidney injury marker 1 (KIM-1), osmolality) and kidney function (transcutaneous measurement of glomerular filtration rate (GFR)) were conducted at 4-week intervals from 8 to 40 weeks of age. VT was induced by complete occlusion of the IVC in AA and AS mice. Sickling of RBCs was determined by histological and electron microscopy analysis of the IVC clot. Senicapoc, an oral Gardos channel inhibitor, was administered twice daily (20mg/kg, bid) for 2 weeks to prevent AS RBC dehydration and subsequent sickling. Human HbS accounts for 30.1% of total Hb expression in AS mice. Consistent with human SCT, peripheral blood counts did not differ from AA controls. Basal plasma thrombin-antithrombin complex levels were also not different between AA and AS mice. We performed a longitudinal study of renal structure and function in AA and AS mice over 40 weeks. At 8 weeks of age, AS mice exhibited no differences in any parameter compared to AA controls. However, AS mice subsequently developed albuminuria and a moderate but statistically significant increase in GFR (Figure 1). At 36 and 40 weeks of age, we observed progressive loss of kidney function demonstrated by statistically significant decreased GFR accompanied by a significant increase in albuminuria in AS mice (Figure 1). Over time, proteinuria gradually increased in AS mice, and had doubled by 40 weeks of age compared to AA controls (4.6 ±1.1 vs. 2.3 ±0.4 mg/24h, p<0.05). Increased levels of urinary KIM-1, a marker of tubular damage, were observed in AS mice throughout the duration of the study, with the highest levels at 16 weeks (228.3 ± 32.6 pg/24h vs. 53.8 ± 8.5 pg/24h, respectively, p˂0.05). Urine osmolality was not different at 8 weeks of age, but progressively declined in AS mice with statistically significant changes vs. controls starting at 24 weeks until the end of study (1946 ±63 vs. 2672 ±135 mOsm/kg at 40 weeks, p=0.002). Histologic analysis confirmed glomerular injury (congestion, glomerulosclerosis) and tubular injury (medullary congestion, interstitial fibrosis) in 40 week old AS mice. Following 24 hours of IVC stasis, thrombus weight was significantly increased (p<0.01) in AS mice (mean±SEM; 29.0 mg +/- 1.7; n=8) compared to AA controls (20.0 mg ± 1.7; n=7). Histologic and electron microscopic evaluation demonstrated that severe hypoxia (pO 2 ≈ 10 mm Hg) present in the nidus of venous thrombi was associated with extensive sickling of RBCs in AS mice. To determine if the enhancement of VT observed in AS mice was mediated by RBC sickling, mice were pretreated with Senicapoc or vehicle. Compared to vehicle-treated AS mice (27.3 mg ± 2.2 n=9) pre-treatment with Senicapoc significantly reduced (p<0.05) clot weight (18.1mg ± 1.1; n=7) to that observed in untreated AA controls. In aggregate, our data demonstrate that Townes AS murine nephropathy closely mimics the renal abnormalities (impaired urinary concentration and albuminuria with later onset loss of GFR) described in humans with SCT. Furthermore, we have established a mouse model of the venous thrombotic complications associated with SCT and have demonstrated that hypoxia-induced sickling of RBCs may contribute to enhanced VT observed in AS mice.

Effects of cerium oxide nanoparticles on adenine-induced chronic kidney disease model rats.

Cerium oxide, particularly in nanoparticle form (nanoceria), has been investigated for biomedical applications as a promising new agent for treating several pathologies. The aim of the present study was to characterize the pharmacologic effects of nanoceria in an animal model of chronic kidney disease. We created the chronic kidney disease animal model by feeding rats a 0.25% adenine diet. Male Wistar rats were divided into five groups: normal diet, 0.25% adenine diet, or adenine diet containing three different doses or durations of nanoceria treatment. Blood was collected weekly from the tail veins of each rat and analyzed for renal function markers. After 5 weeks, various biochemical markers in serum, plasma, and urine were also analyzed. In the adenine-treated group, body weight was significantly decreased, and the kidneys lost much of their healthy reddish color and became lumpy and white in appearance. In addition, levels of serum creatinine, blood urea nitrogen, and plasma uremic toxins were significantly increased in adenine-treated rats compared with controls. Renal functional and structural damage in adenine diet model rats tended to be ameliorated by nanoceria ingestion. The high-dose cerium-treated group maintained reddish areas in the kidneys, and the increases in biomarker levels of creatinine, blood urea nitrogen, and inorganic phosphorus were markedly reduced, regardless of treatment duration. Ingestion of nanoceria may be effective for improving or preventing renal damage caused by adenine. Geriatr Gerontol Int 2024; 24: 88-95.

Higher beta-hydroxybutyrate ketone levels associated with a slower kidney function decline in ADPKD.

Dysregulated energy metabolism is a recently discovered key feature of autosomal dominant polycystic kidney disease (ADPKD). Cystic cells depend on glucose and are poorly able to use other energy sources such as ketone bodies. Raising ketone body concentration reduced disease progression in animal models of polycystic kidney diseases. Therefore, we hypothesized that higher endogenous plasma beta-hydroxybutyrate (BHB) concentrations are associated with reduced disease progression in patients with ADPKD. We analyzed data from 670 patients with ADPKD participating in the Developing Intervention Strategies to Halt Progression of ADPKD (DIPAK) cohort, a multi-center prospective observational cohort study. BHB was measured at baseline using nuclear magnetic resonance spectroscopy. Participants were excluded if they had type 2 diabetes, were using disease-modifying drugs (e.g. tolvaptan, somatostatin analogs), were not fasting or had missing BHB levels, leaving 521 participants for the analyses. Linear regression analyses were used to study cross-sectional associations and linear mixed-effect modeling for longitudinal associations. Of the participants, 61% were female, with an age of 47.3±11.8 years, a height-adjusted total kidney volume (htTKV) of 834 [interquartile range (IQR) 495-1327] mL/m and an estimated glomerular filtration rate (eGFR) of 63.3±28.9mL/min/1.73 m2. The median concentration of BHB was 94 (IQR 68-147) µmol/L. Cross-sectionally, BHB was associated neither with eGFR nor with htTKV. Longitudinally, BHB was positively associated with eGFR slope {B=0.35mL/min/1.73 m2 [95% confidence interval (CI) 0.09 to 0.61], P=.007}, but not with kidney growth. After adjustment for potential confounders, every doubling in BHB concentration was associated with an improvement in the annual rate of eGFR by 0.33mL/min/1.73 m2 (95% CI 0.09 to 0.57, P=.008). These observational analyses support the hypothesis that interventions that raise BHB concentration could reduce the rate of kidney function decline in patients with ADPKD.

A systematic review and meta-analysis of prediction models for incident heart failure and chronic kidney disease in community-based electronic health records

Abstract Background Heart failure (HF) and chronic kidney disease (CKD) share common pathophysiological pathways,(1) and disease-modifying therapies.(2-4) A model that identifies a high-risk population for HF and CKD in primary care electronic health records (EHRs) could facilitate population-based screening initiatives. Purpose To provide an overview of prediction models for incident HF and/or CKD that have been validated in community-based EHR cohorts, to determine common predictive variables, and synthesise discriminatory abilities. Methods We performed a systematic review of prediction models derived, validated and/or augmented for either HF and/or CKD prediction in community-based electronic health records cohorts using Medline and Embase through 25 September 2022. Measures of discrimination were extracted and pooled by Bayesian meta-analysis, with heterogeneity assessed through a 95% prediction interval (PI). Risk of bias was assessed using Prediction model Risk Of Bias Assessment Tool (PROBAST). Results From 15 106 unique records we included 29 studies. We identified 36 models that had been developed and/or validated for incident HF, and 16 for incident CKD, though not one had been simultaneously validated for both outcomes in the same study. Machine learning methodology had been used to develop 25 models for incident HF prediction, and 2 models for CKD. Overall, 71% of model results were at high risk of bias predominantly driven by high risk of bias in the analysis domain. Calibration was infrequently reported for prediction models for incident HF, especially those developed through machine learning, but well-reported for prediction models of incident CKD. Age was included in almost every model (Figure 1), hypertension and diabetes were included in more than 70% of models, and markers of vascular risk or manifest disease were also frequently used. For prediction models of incident HF the summary c-statistic was 0.814 (95% CI 0.707-0.883, n = 54 reports) with a 95% PI 0.612-0.949 demonstrating a large amount of heterogeneity between studies. For prediction models for incident CKD the summary c-statistic was 0.833 (95% CI 0.804-0.859, n = 27 reports) with a 95% PI 0.672-0.945 demonstrating a large amount of heterogeneity between studies. In sensitivity analysis where model results at high risk of bias were excluded, the summary c-statistic for prediction models for incident HF was 0.878 (95% CI 0.841-0.914, 95% PI 0.780-0.957, n = 5 reports), and for CKD was 0.856 (95% CI 0.814-0.892, 95% PI 0.685-0.968, n = 13 reports). Conclusions Models for prediction of incident HF and CKD in community-based electronic health records show good discrimination performance and high risk of bias. Common predictors for incident CKD and HF suggest there are opportunities to unify prediction for these two common and treatable diseases.Figure 1:Shared predictors

Mitochondrial and contractile dysfunction in a swine model of early chronic kidney disease

Abstract Background Numerous clinical trials have demonstrated that patients with kidney damage have an increased chance of developing heart failure, and the risk is compounded in people with diabetes. Cardiac remodeling occurs at very early stages of kidney injury but studies undertaken to pinpoint the common biomarkers of cardiorenal signaling are still inadequate, which may be due to the fact that research done on rodent models does not fully reflect the complexity of the disease. We and our collaborators established swine models for diabetes (DM- insulin gene INS mutation) and chronic kidney disease (CKD- renal microembolisation) to overcome the translational gap associated with rodent models. Purpose In order to provide mechanistic as well as therapeutic insights, we used proteomic analyses to elucidate the pathophysiological effects of DM and CKD on the heart. Methods We used microspheres to embolise both kidneys of wild type and diabetic swine at 10-12 weeks of age and 6 months later we performed quantitative LC-MS-MS based proteomic analyses of left ventricular tissue from these four groups (wild type (WT), wild type with CKD (WT_CKD), diabetic (DM) and diabetic with CKD (DM_CKD). STRING bioinformatics software was used to identify significantly enriched pathways. Results Masson Trichrome staining confirmed the presence of kidney damage and fibrosis in CKD animals (Fig1 A). Quantitative proteomic analysis detected significant differences in the left ventricle of the WT or DM swine when compared to those with CKD using a volcano plot (Fig1B,C). STRING pre-ranked functional analysis showed pathway enrichments in both the comparisons (Fig2A,B). We found that proteins involved in the remodeling of the extracellular matrix (ECM), such as C3, F9, Col6A2, and FBN1, were downregulated in both groups (WT CKD and DM CKD as compared to WT and DM respectively). Interestingly, in WT_CKD we found that mitochondrial proteins like cytochrome oxidase (MT-CO2) and ATP5 synthase subunit were downregulated suggesting mitochondrial dysfunction. Strong indicators of this dysfunction include pathways with altered regulation of reactive oxygen species like hydrogen peroxide and substantial downregulation of contractile proteins like phospholamban, which maintains the Ca2+ homeostasis. DM_CKD on the other hand when compared to DM suggested presence of an inflammatory milieu with alterations of metabolic, wound healing and immune cell regulation pathways. Conclusions Our proteomic data in swine model provides strong evidence that mild CKD can induce early alterations in contractile proteins of the heart due to mitochondrial dysfunction along with ECM remodeling. In the presence of diabetes, metabolic and immune cells play a more predominant role in early part of the disease. Thus, we aim to further our understanding by applying our proteomic findings in conjunction with functional hemodynamic data in this swine model of cardiorenal disease.Figure 1Figure 2

Diagnosis of Chronic Kidney Disease Using Machine Learning Algorithm

A large percentage of people globally suffer from chronic kidney disease (CKD), a serious health concern. Effective diagnosis, treatment, and referral of CKD depend heavily on early identification and prediction of the disease. However, it is difficult to evaluate and derive significant insights from health data due to its vast and complicated nature. Engineers and medical researchers are using data mining techniques and machine learning algorithms to create predictive models for chronic kidney disease (CKD) in an effort to address this issue. The goal of this research is to create and validate predictive models for chronic kidney disease (CKD) based on a variety of clinical factors, including albuminuria, age, diet, eGFR, and pre-existing medical problems. The objective is to estimate the likelihood of renal failure, which may necessitate kidney dialysis or a transplant, and to evaluate the degree of kidney disease. With the use of this knowledge, patients and healthcare providers should be able to make well-informed decisions about diagnosis, treatment, and lifestyle changes. Patterns in the gathered data can be found, and future incidence of CKD or other related diseases can be predicted, by utilising MLT such as ANN and data mining techniques. Finding novel characteristics linked to the onset of renal disease and adding more trustworthy data from CKD patients. The best algorithm to categorise the data as CKD or NOT_CKD is chosen throughout the design process, and the data is then classified according to this differentiation. Estimated glomerular filtration rate (eGFR), which offers important details about the patient's current kidney function, is used to classify cases of chronic kidney disease. By combining complete patient data with machine learning algorithms, this research advances the diagnosis of chronic kidney disease (CKD) and improves patient outcomes.

Elucidating the Function of a Novel Arg-1+/Clec4d+ Scar-Associated Monocyte-Derived Macrophage Population in Driving Fibrosis in Kidney Disease Models

Elucidating the Function of a Novel Arg-1+/Clec4d+ Scar-Associated Monocyte-Derived Macrophage Population in Driving Fibrosis in Kidney Disease Models

Feasibility and impact of ketogenic dietary interventions in polycystic kidney disease: KETO-ADPKD—a randomized controlled trial

Ketogenic dietary interventions (KDIs) are beneficial in animal models of autosomal-dominant polycystic kidney disease (ADPKD). KETO-ADPKD, an exploratory, randomized, controlled trial, is intended to provide clinical translation of these findings (NCT04680780). Sixty-six patients were randomized to a KDI arm (ketogenic diet [KD] or water fasting [WF]) or the control group. Both interventions induce significant ketogenesis on the basis of blood and breath acetone measurements. Ninety-five percent (KD) and 85% (WF) report the diet as feasible. KD leads to significant reductions in body fat and liver volume. Additionally, KD is associated with reduced kidney volume (not reaching statistical significance). Interestingly, the KD group exhibits improved kidney function at the end of treatment, while the control and WF groups show a progressive decline, as is typical in ADPKD. Safety-relevant events are largely mild, expected (initial flu-like symptoms associated with KD), and transient. Safety assessment is complemented by nuclear magnetic resonance (NMR) lipid profile analyses.

Small Molecule Inhibition of APOL1 Reverses Albuminuria in a Chronic Mouse Model of APOL1-Mediated Kidney Disease

Small Molecule Inhibition of APOL1 Reverses Albuminuria in a Chronic Mouse Model of APOL1-Mediated Kidney Disease

Renal Cell Type-Associated Therapeutic Effects of Semaglutide in a Mouse Model of Hypertension-Accelerated Diabetic Kidney Disease

Renal Cell Type-Associated Therapeutic Effects of Semaglutide in a Mouse Model of Hypertension-Accelerated Diabetic Kidney Disease

Ultrasound and 3D Imaging Characterisation of a Rat Model of Polycystic Kidney Disease

Ultrasound and 3D Imaging Characterisation of a Rat Model of Polycystic Kidney Disease

Total and Phosphoproteomic Analyses in Kidneys from an Authentic Mouse Model of Human Autosomal Dominant Polycystic Kidney Disease

Total and Phosphoproteomic Analyses in Kidneys from an Authentic Mouse Model of Human Autosomal Dominant Polycystic Kidney Disease

Combination Therapy with Lisinopril and Dapagliflozin Rescues GFR Decline and Glomerular Damage in the KKAy Mouse Model of Diabetic Kidney Disease

Combination Therapy with Lisinopril and Dapagliflozin Rescues GFR Decline and Glomerular Damage in the KKAy Mouse Model of Diabetic Kidney Disease

Role of CD44 expressed in renal tubules during maladaptive repair in renal fibrogenesis in an allopurinol-induced rat model of chronic kidney disease.

The kidney is a major target organ for the adverse effects of pharmaceuticals; renal tubular epithelial cells (TECs) are particularly vulnerable to drug-induced toxicity. TECs have regenerative capacity; however, maladaptive repair of TECs after injury leads to renal fibrosis, resulting in chronic kidney disease (CKD). We previously reported the specific expression of CD44 in failed-repair TECs of rat CKD model induced by ischemia reperfusion injury. Here, we investigated the pathophysiological role of CD44 in renal fibrogenesis in allopurinol-treated rat CKD model. Dilated or atrophic TECs expressing CD44 in fibrotic areas were collected by laser microdissection and subjected to microarray analysis. Gene ontology showed that extracellular matrix (ECM)-related genes were upregulated and differentiation-related genes were downregulated in dilated/atrophic TECs. Ingenuity Pathway Analysis identified CD44 as an upstream regulator of fibrosis-related genes, including Fn1, which encodes fibronectin. Immunohistochemistry demonstrated that dilated/atrophic TECs expressing CD44 showed decreases in differentiation markers of TECs and clear expression of mesenchymal markers during basement membrane attachment. In situ hybridization revealed an increase in Fn1 mRNA in the cytoplasm of dilated/atrophic TECs, whereas fibronectin was localized in the stroma around these TECs, supporting the production/secretion of ECM by dilated/atrophic TECs. Overall, these data indicated that dilated/atrophic TECs underwent a partial epithelial-mesenchymal transition (pEMT) and that CD44 promoted renal fibrogenesis via induction of ECM production in failed-repair TECs exhibiting pEMT. CD44 was detected in the urine and serum of APL-treated rats, which may reflect the expression of CD44 in the kidney.

Enteroendocrine cells and gut hormones as potential targets in the crossroad of the gut-kidney axis communication.

Recent studies suggest that disruptions in intestinal homeostasis, such as changes in gut microbiota composition, infection, and inflammatory-related gut diseases, can be associated with kidney diseases. For instance, genomic investigations highlight how susceptibility genes linked to IgA nephropathy are also correlated with the risk of inflammatory bowel disease. Conversely, investigations demonstrate that the use of short-chain fatty acids, produced through fermentation by intestinal bacteria, protects kidney function in models of acute and chronic kidney diseases. Thus, the dialogue between the gut and kidney seems to be crucial in maintaining their proper function, although the factors governing this crosstalk are still emerging as the field evolves. In recent years, a series of studies have highlighted the significance of enteroendocrine cells (EECs) which are part of the secretory lineage of the gut epithelial cells, as important components in gut-kidney crosstalk. EECs are distributed throughout the epithelial layer and release more than 20 hormones in response to microenvironment stimuli. Interestingly, some of these hormones and/or their pathways such as Glucagon-Like Peptide 1 (GLP-1), GLP-2, gastrin, and somatostatin have been shown to exert renoprotective effects. Therefore, the present review explores the role of EECs and their hormones as regulators of gut-kidney crosstalk and their potential impact on kidney diseases. This comprehensive exploration underscores the substantial contribution of EEC hormones in mediating gut-kidney communication and their promising potential for the treatment of kidney diseases.

Ouabain enhances renal cyst growth in a slowly progressive mouse model of autosomal dominant polycystic kidney disease.

Renal cyst progression in autosomal dominant polycystic kidney disease (ADPKD) is highly dependent on agents circulating in blood. We have previously shown, using different in vitro models, that one of these agents is the hormone ouabain. By binding to Na+-K+-ATPase (NKA), ouabain triggers a cascade of signal transduction events that enhance ADPKD cyst progression by stimulating cell proliferation, fluid secretion, and dedifferentiation of the renal tubular epithelial cells. Here, we determined the effects of ouabain in vivo. We show that daily administration of ouabain to Pkd1RC/RC ADPKD mice for 1-5 mo, at physiological levels, augmented kidney cyst area and number compared with saline-injected controls. Also, ouabain favored renal fibrosis; however, renal function was not significantly altered as determined by blood urea nitrogen levels. Ouabain did not have a sex preferential effect, with male and female mice being affected equally. By contrast, ouabain had no significant effect on wild-type mice. In addition, the actions of ouabain on Pkd1RC/RC mice were exacerbated when another mutation that increased the affinity of NKA for ouabain was introduced to the mice (Pkd1RC/RCNKAα1OS/OS mice). Altogether, this work highlights the role of ouabain as a procystogenic factor in the development of ADPKD in vivo, that the ouabain affinity site on NKA is critical for this effect, and that circulating ouabain is an epigenetic factor that worsens the ADPKD phenotype.NEW & NOTEWORTHY This work shows that the hormone ouabain enhances the progression of autosomal dominant polycystic kidney disease (ADPKD) in vivo. Ouabain augments the size and number of renal cysts, the kidney weight to body weight ratio, and kidney fibrosis in an ADPKD mouse model. The Na+-K+-ATPase affinity for ouabain plays a critical role in these effects. In addition, these outcomes are independent of the sex of the mice.

Ferroptosis is involved in passive Heymann nephritis in rats

Ferroptosis is found to be involved in some experimental models of kidney diseases, but its role in membrane nephropathy (MN) is still unclear. The purpose of this study is to explore whether ferroptosis occurred in MN, and the role of ferritinophagy. In this study, passive Heymann nephritis (PHN) rats were induced by single tail vein injection of anti-Fx1A serum, and normal rats were used as control. The changes of 24 h urinary protein, serum biochemical parameters, renal pathological damage, iron content, lipid peroxidation parameters, ferroptosis markers, and ferritinophagy markers were evaluated in the two groups. Compared with the control group, PHN rats showed obvious proteinuria, hypoproteinemia, and hyperlipidemia. Besides, more severe renal pathological damage and higher Fe2+ levels were observed in PHN rats, and the levels of malondialdehyde (MDA) increased significantly, while the levels of superoxide Dismutase (SOD) and glutathione (GSH) decreased. In addition, the expression of glutathione peroxidase 4 (GPX4) in renal tissues of PHN rats decreased significantly, while the expression of transferrin receptor (TFR) and acyl-CoA synthetase long-chain family member 4 (ACSL4) increased. The expression of microtubule associated protein 1 light chain 3 (LC3) II/LC3I and nuclear receptor coactivator 4 (NCOA4) increased significantly. Therefore, our study shows that ferroptosis is involved in the pathological damage of MN, and companied by activation of ferritinophagy.

Animal Models of Kidney Disease: Challenges and Perspectives.

Kidney disease is highly prevalent and affects about 850 million people worldwide. It is also associated with high morbidity and mortality, and current therapies are incurable and often ineffective. Animal models are indispensable for understanding the pathophysiology of various kidney diseases and for preclinically testing novel remedies. In the last two decades, rodents continue to be the most used models for imitating human kidney diseases, largely due to the increasing availability of many unique genetically modified mice. Despite many limitations and pitfalls, animal models play an essential and irreplaceable role in gaining novel insights into the mechanisms, pathologies and therapeutic targets of kidney disease. In this review, we highlight commonly used animal models of kidney diseases by focusing on experimental acute kidney injury, chronic kidney disease, and diabetic kidney disease. We briefly summarize the pathological characteristics, advantages and drawbacks of some widely used models. Emerging animal models such as mini-pig, salamander, zebrafish and drosophila, as well as human-derived kidney organoids and kidney-on-a-chip are also discussed. Undoubtedly, careful selection and utilization of appropriate animal models is of vital importance in deciphering the mechanisms underlying nephropathies and evaluating the efficacy of new treatment options. Such studies will provide a solid foundation for future diagnosis, prevention and treatment of human kidney diseases.