Mitigation of adriamycin (ADR)-induced nephropathy remains a significant challenge in clinical management. Brain-targeted administration of losartan demonstrates comparable nephroprotective effects at a 1:500 concentration relative to gavage administration. This study established an exosome-based nano-delivery platform (ExoACP) to reduce drug dosage for alleviating ADR-induced nephropathy. The platform was rigorously tested for toxicity and blood-brain barrier penetration. Additionally, the role and possible mechanism of ExoACP-Los in alleviating ADR-induced nephropathy in mice were investigated. ExoACP showed enhanced penetration in brain microvascular endothelial cells, with a 7.20-fold increase in uptake. In the ADR model, ExoACP-Los exhibited anti-inflammatory and anti-fibrotic effects by downregulating the renin-angiotensin system, reducing extracellular matrix deposition by nearly half. These findings suggest ExoACP-Los can alleviate ADR-induced nephropathy by enhancing targeted drug delivery to the brain while reducing losartan. Overall, ExoACP holds significant potential for future clinical applications in chronic nephropathy.

Although effective as a chemotherapeutic, the utility of Doxorubicin (Dox) is hampered by cardiotoxicity. Despite this, the ability to predict and guide monitoring of patients receiving Dox is hampered by a lack of effective biomarkers to identify susceptible patients and detect early signs of subclinical cardiotoxicity. Based on their well-established roles in the response to Dox and other chemotherapies, we performed a retrospective analysis of serum and plasma sphingolipids (SLs) from female patients with breast cancer (BC) undergoing anthracycline-containing therapy, correlating with cardiac parameters assessed by echocardiography. Results showed substantial changes in both plasma and serum SL species during therapy including ceramide (Cer), deoxydihydroCer, and dihydrosphingosine with reversion toward baseline after treatment. Linear mixed-effects model analysis revealed that baseline levels of a number of SLs correlated with adverse cardiac outcomes. Here, serum sphingosine-1-phosphate (S1P), dihydroS1P, and plasma Cer performed comparably to the prognostic value of pro-NT-BNP, an established biomarker of cardiotoxicity. Intriguingly, while pro-NT-BNP had no predictive value at mid- and post-therapy timepoints, serum S1P and dihydroS1P, and plasma Cer levels showed a correlation with adverse outcomes, particularly at the post-therapy timepoint. Finally, analysis of plasma and serum C16:C24-Cer ratios-previously linked with adverse cardiac outcomes-showed no correlation in the context of chemotherapy treatment. Overall, this pilot study provides initial evidence that plasma and serum SLs may have benefits as both prognostic and diagnostic biomarkers for female BC patients undergoing anthracycline-containing chemotherapy. Consequently, diagnostic SL measurements-recently implemented for metabolic-associated cardiac disorders-could have wider utility.

Podocytes are highly specialized, terminally differentiated cells in the glomerulus of the kidney and these cells play a central role in blood filtration. In this review, we comprehensively describe the cell biology of podocytes under healthy conditions and in glomerular disorders wherein podocyte injury is a major pathological mechanism. First, the molecular mechanisms that maintain podocyte actin cytoskeleton structure, permanent cell cycle exit, and metabolism under healthy conditions are described. Secondly, the mechanisms of podocyte injury, including genetic alterations and external insults that ultimately disrupt podocyte actin cytoskeleton dynamics or interrupt podocyte quiescence and mitochondrial metabolism are discussed. This understanding forms the basis of described potential therapeutic agents that act by modulating dysregulated podocyte cytoskeleton organization, prevent or reverse cell cycle re-entry, and re-establish normal mitochondrial energy production. Lastly, the application of modern techniques such as single cell RNA sequencing, super resolution microscopy, atomic force microscopy, and glomerular organoids is improving the resolution of mechanistic podocytopathy knowledge. Taken together, our review provides critical insights into the cellular and molecular mechanisms leading to podocyte loss, necessary for the advancement of therapeutic development in glomerular diseases.

Proteinuria is observed in various kidney diseases and is frequently associated with a compromised glomerular filtration barrier. Podocytes, as a crucial component of this barrier, play an essential role in preserving the kidney's normal filtration function. Podocytes are terminally differentiated cells that typically do not proliferate. However, certain harmful stimuli can trigger podocytes to re-enter the cell cycle. Due to its unique cytoskeletal structure, podocytes are unable to maintain the structure of the foot process and complete cell division at the same time, eventually form binucleated or multinucleated podocytes. Studies have found that podocytes re-entering the cell cycle are more susceptible to injury, and are prone to detachment from the basement membrane or apoptosis, which are accompanied by the widening of foot processes. This eventually leads to podocyte mitotic catastrophe and the development of proteinuria. Podocyte cell cycle disorders have previously been found mainly in focal segmental glomerulosclerosis and IgA nephropathy. In recent years, this phenomenon has been frequently identified in diabetic kidney disease and lupus nephritis. An expanding body of research has begun to investigate the mechanisms underlying podocyte cell cycle disorders, including cell cycle re-entry, cell cycle arrest, and mitotic catastrophe. This review consolidates the existing literature on podocyte cell cycle disorders in renal diseases and summarizes the molecules that trigger podocyte re-entry into the cell cycle, thereby providing new drug targets for mitigating podocyte damage. This is essential for alleviating podocyte injury, reducing proteinuria, and delaying the progression of kidney diseases.

Cellular senescence disrupts tissue homeostasis and diminishes physiological integrity, leading to the accumulation of senescent cells (SCs) in multiple senescence-associated diseases such as chronic kidney disease (CKD). Treatment of SCs has been approved to be a feasible approach to these diseases. However, curing SCs in different cell types remains challenging. In this study, we leveraged the high expression of glutaminase (GLS) in SCs to develop a drug delivery system utilizing γ-poly glutamic acid (γ-PGA) conjugated with octadecylamine (ODA) to encapsulate rapamycin (RP), resulting in a GLS-responsive drug delivery system, designated as RPPO. In a model of drug induced senescence, the γ-PGA component of RPPO was degraded by cellular GLS, facilitating the release of encapsulated RP and rejuvenating SCs by restoring the autophagic capacity. Additionally, in a model of CKD in mice, RPPO enhanced recovery by rejuvenating SCs, reducing fibrosis, and alleviating inflammation. Thus, this senescent cell-responsive drug delivery system presents a novel approach for the treatment of CKD.

The rat sub-total nephrectomy (SNx) is a functional model of general chronic kidney disease (CKD) where the main pathological driver is glomerular hypertension representative of several subtypes of CKD. Comprehensive transcriptomics and proteomics analyses on the SNx rats were performed to identify biomarkers in plasma or urine that correlate with kidney disease and functional kidney loss. Kidneys were subjected to collagen I and III staining for fibrosis scoring, SWATH-MS proteomics and bulk RNA-sequencing transcriptomics, with SWATH-MS also performed on plasma and urine. Differential expression analysis demonstrated significant dysregulation of genes and proteins involved in fibrosis, metabolism, and immune response in the SNx rats compared to controls. Gene ontology analysis of the intersecting genes and proteins from both studies demonstrated common biology between animal cohorts that reached the predefined kidney disease thresholds (serum creatinine > two-fold or proteinuria > three-fold increase over sham-operated). Thirteen significantly differential molecules were detected with consistent directional changes in both omics datasets. These molecules were detected independently in kidney (both RNA and protein) and urine (protein only), but not in plasma. Bioinformatics analysis enabled the identification of mechanistic CKD biomarkers including lumican and collagen alpha-1(III) chain, whose co-expression has previously been both implicated in fibrosis and detected in urine in CKD patients.

Podocytes are key components of the glomerular filtration barrier, and their injury leads to proteinuria, chronic kidney disease (CKD), and nephrotic syndrome. Effective treatments for these conditions are not well established, and prevention of podocyte injury is a crucial challenge. Nicotinamide (NAM), a form of vitamin B3, has been reported to exert beneficial effects in various renal disease models due to its antioxidant and anti-inflammatory properties and its ability to replenish nicotinamide adenine dinucleotide (NAD+). However, its impact on adriamycin (ADR)-induced nephropathy, a model of nephrotic syndrome caused by podocyte injury, remains unclear. We investigated the effects of NAM administration in a mouse model of ADR nephropathy. BALB/c mice were intravenously administered ADR to induce nephropathy. In the NAM-treated group, mice received 0.6% NAM in drinking water ad libitum starting 7 days before ADR administration. After 14 days, NAM treatment decreased albuminuria, glomerular sclerosis, and podocyte injury, and reduced inflammation and oxidative stress markers in the kidneys. NAM and NAD+ levels were decreased in ADR-treated kidneys, and the expression of the NAD+-consuming enzymes SIRT1 and poly(ADP-ribose) polymerase 1 (PARP-1) was decreased and increased, respectively. Nicotinamide N-methyltransferase expression was increased. NAM canceled these abnormalities. In cultured rat podocytes, NAD+ alleviated ADR-induced cytotoxicity, apoptosis, and inflammation. These findings suggest that NAM prevents ADR nephropathy and podocyte injury, likely through NAD+ replenishment.NEW & NOTEWORTHY Nephrotic syndrome can lead to end-stage kidney disease and cause severe complications. Currently, effective treatments for nephrotic syndrome have not been established, and new therapeutic approaches targeting podocyte injury are needed. Nicotinamide prevents podocyte injury in adriamycin-induced nephropathy in mice and ameliorates albuminuria, pathological changes, oxidative stress, and inflammation. Here, we provide evidence that pretreatment with nicotinamide can attenuate podocyte injury and subsequent nephropathy in mice.

Doxorubicin(DOX) is an anthracycline chemotherapeutic drug used in the treatment of a wide range of tumors. However, the nephrotoxicity has limited the clinical application of DOX. Fatty acid-binding protein 4 (FABP4), a key adipokine mainly expressed in adipocytes, is strongly associated with kidney dysfunction and kidney disease. This study aims to investigate the role of FABP4 in DOX-induced nephrotoxicity. In vivo experiments, the mice were divided into 4 groups randomly: CON group, DOX group, 4T1 group, and 4T1 + DOX group respectively. DOX was given by intraperitoneal injection at a dose of 15 mg/kg. The kidney function indicators, the morphology and lipid deposition in renal tissues and the preliminary mechanism were assessed. In vitro experiment, HK-2 cell was used to detect DOX-induced kidney cell injury with or without BMS309403. DOX caused renal dysfunction in both DOX group and 4T1 + DOX group, with a more severe kidney injury in DOX group. DOX also induced kidney lipid deposition, glycerophospholipids metabolism dysfunction, apoptosis accompanied by increased FABP4 and decreased Peroxisome Proliferator Activated Receptor- γ (PPAR-γ) levels in the kidney tissues. The decreased cell viability, increased apoptotic ratio, elevated protein levels of apoptosis and the lipid deposition caused by DOX were all alleviated by BMS309403. FABP4 mediated DOX induced kidney damage in normal mice and tumor-bearing mice by lipid metabolism disorders and cell apoptosis. This study may enhance the clinical management of DOX-induced kidney injury and provide new therapeutic targets and preventive strategies for the clinical application of DOX.

Podocyte injury leads to proteinuria and glomerular diseases. Different podocyte injuries have distinct mechanisms. It is desirable to use a regimen that targets the mechanism of a given podocyte injury for a specific and improved result. However, the mechanisms of the most podocyte injuries are largely elusive, preventing optimal drug choices. Here, we test the feasibility of combining kidney single-cell RNA-seq databases and the Connectivity Map database (CMAP) to predict drugs for a specific podocyte injury. We downloaded glomerular single-cell RNA-seq dataset of nephrotoxic serum (NTS)-treated and control mice from the GEO, and compared their podocyte gene expression, resulting in identification of genes with altered expression in NTS-treated podocytes. GO and KEGG enrichment of them revealed activations of podocyte injurious NFκB, TNFα, AGE-RAGE, apoptosis, cellular senescence, MAPK, and p53 pathways, and dedifferentiation. CMAP analysis of the genes ranked Forskolin top 3. Indeed, we found that NTS-treated mice developed massive proteinuria, which was prevented by Forskolin, accompanied by pathological improvement of podocytes. In treating overdose NTS-induced severe podocyte injury, Forskolin exhibited a comparable efficacy as glucocorticoids (methylprednisolone). In vitro, Forskolin prevented NTS-induced cellular injury in cultured podocytes as shown by cell viability and cytoskeletal integrity assays. Mechanistically, Forskolin inhibited STAT3, p53, NFκB, FAK, and TGF-β pathways, while upregulated podocyte essential genes, WT1, SYNPO, and VEGFA, independently of NTS. In conclusion, Forskolin protects podocytes by directly inhibiting harmful pathways and the associated genes while enhancing podocyte essential gene expression independently of insults, resulting in an efficacy comparable with that of glucocorticoids in NTS-treated mice.

Doxorubicin (DOX), an anthracycline chemotherapeutic agent, is extensively utilized in the clinical management of both solid and hematological malignancies. Nevertheless, the clinical application of this treatment is significantly limited by adverse reactions and toxicity that may arise during or after administration. Its cytotoxic effects are multifaceted, with cardiotoxicity being the most prevalent side effect. Furthermore, it has the potential to adversely affect other organs, including the brain, kidneys, liver, and so on. Notably, it has been reported that DOX may cause renal failure in patients and there is currently no effective treatment for DOX-induced kidney damage, which has raised a high concern about DOX-induced nephrotoxicity (DIN). Although the precise molecular mechanisms underlying DIN remain incompletely elucidated, prior research has indicated that reactive oxygen species (ROS) are pivotal in this process, triggering a cascade of detrimental pathways including apoptosis, inflammation, dysregulated autophagic flux, and fibrosis. In light of these mechanisms, decades of research have uncovered several DIN-associated signaling pathways and found multiple potential therapeutic agents targeting them. Thus, this review intends to delineate the DIN associated signaling pathways, including AMPK, JAKs/STATs, TRPC6/RhoA/ROCK1, YAP/TEAD, SIRTs, Wnt/β-catenin, TGF-β/Smad, MAPK, Nrf2/ARE, NF-κB, and PI3K/AKT, and to summarize their potential regulatory agents, which provide a reference for the development of novel medicines against DIN.

Although effective as a chemotherapy, the utility of Doxorubicin (Dox) is hampered by cardiotoxicity. Despite this, the ability to predict and guide monitoring of patients receiving Dox or other anthracyclines is hampered by a lack of effective biomarkers to identify susceptible patients, and to detect early signs of subclinical cardiotoxicity. Based on their well-established roles in the response to Dox and other chemotherapies, we performed a retrospective analysis of serum and plasma sphingolipids (SLs) from patients undergoing anthracycline-containing therapy, correlating with cardiac parameters assessed by echocardiography. Results showed there were substantial changes in both plasma and serum SL species during therapy including ceramide (Cer), deoxydihydroCer, and dihydrosphingosine with reversion towards baseline following treatment. Linear mixed-effects model analysis revealed that at baseline, a number of SLs correlated with adverse cardiac outcomes with serum sphingosine-1-phosphate (S1P) and dihydroS1P, and plasma Cer performing comparably to the prognostic value of pro-NT-BNP, an established biomarker of cardiotoxicity. Intriguingly, while pro-NT-BNP had no predictive value at mid- and post-therapy timepoints, serum S1P and dhS1P and plasma Cer levels showed correlation with adverse outcomes, particularly at the post-therapy timepoint. Finally, analysis of plasma and serum C16:C24- Cer ratios - previously reported as predictive of adverse cardiac outcomes - showed no correlation in the context of anthracycline treatment. Taken together, this pilot study provides supporting evidence that plasma and serum SLs may have benefit as both prognostic and diagnostic biomarkers for patients undergoing anthracycline-containing therapy. This suggests that diagnostic SL measurements - recently implemented for metabolic-associated cardiac disorders - could have wider utility.

Chronic kidney disease (CKD) is a worldwide public health problem. Podocyte damage is a hallmark of glomerular diseases including focal segmental glomerulosclerosis (FSGS) and one of the leading causes of CKD. Lysine methylation is a crucial post-translational modification. Beyond epidemic regulation, various lysine methyltransferases have been recently reported to participate in disease progression, including cancers and kidney diseases. Among them, Methyltransferase-like 10 (METTL10), is recognized as a gene associated with estimated glomerular filtration rate (eGFR) and CKD risk. However, its role in podocyte damage remains unclear. We identified the differentially expressed genes(DEGs)in podocyte injury by bioinformatics analysis. Patients diagnosed as idiopathic FSGS by renal biopsy were enrolled. Mouse model was established by Adriamycin(ADR) and urinary albumin/ creatinine ratio(UACR) was detected. Murine podocyte cell line was stimulated with ADR. We determined METTL10 was one of the significantly downregulated genes in damaged podocytes, confirmed the decreased glomerular expression of METTL10 in patients with idiopathic FSGS and in mice with ADR-induced nephrosis, respectively. Moreover, we found a negative correlation between glomerular METTL10 levels and UACR in mice. METTL10 was reduced in ADR-treated podocytes, accompanied by podocyte dedifferentiation (loss of synaptopodin, podocin, nephrin, WT-1) and acquisition of mesenchymal cell markers (snail, desmin, pax2). Knockdown of METTL10 promoted their dedifferentiation. METTL10 regulates podocyte dedifferentiation under damaging stimuli and protects podocytes.

This study is to investigate the therapeutical effect and mechanisms of human-derived adipose mesenchymal stem cells (ADSC) in relieving adriamycin (ADR)-induced nephropathy (AN). SD rats were separated into normal group, ADR group, ADR+Losartan group (20 mg/kg), and ADR + ADSC group. AN rats were induced by intravenous injection with adriamycin (8 mg/kg), and 4 d later, ADSC (2 × 105 cells/mouse) were administrated twice with 2 weeks interval time (i.v.). The rats were euthanized after the 6 weeks' treatment. Biochemical indicators reflecting renal injury, such as blood urea nitrogen (BUN), neutrophil gelatinase alpha (NGAL), serum creatinine (Scr), inflammation, oxidative stress, and pro-fibrosis molecules, were evaluated. Results demonstrated that we obtained high qualified ADSCs for treatment determined by flow cytometry, and ADSCs treatment significantly ameliorated renal injuries in DN rats by decreasing BUN, Scr and NGAL in peripheral blood, as well as renal histopathological injuries, especially protecting the integrity of podocytes by immunofluorescence. Furthermore, ADSCs treatment also remarkably reduced the renal inflammation, oxidative stress, and fibrosis in DN rats. Preliminary mechanism study suggested that the ADSCs treatment significantly increased renal neovascularization via enhancing proangiogenic VEGF production. Pharmacodynamics study using in vivo imaging confirmed that ADSCs via intravenous injection could accumulate into the kidneys and be alive at least 2 weeks. In a conclusion, ADSC can significantly alleviate ADR-induced nephropathy, and mainly through reducing oxidative stress, inflammation and fibrosis, as well as enhancing VEGF production.

Immune-mediated kidney diseases, including glomerulonephritis (GN), represent a diverse spectrum of disorders characterized by inflammation within the glomerulus and other renal compartments. Despite recent advances, the immunopathogenesis of these diseases remains incompletely understood. Current therapeutic approaches based on nonspecific immunosuppression often result in suboptimal outcomes and significant side effects, highlighting the need for tailored interventions. The complexity of the immune system extends beyond classical T-cell immunity, with the emergence of unconventional T cells - γδ T cells, NKT cells, and MAIT cells - that exhibit a semi-invariant nature and unique functions that bridge innate and adaptive immunity. γδ T cells exhibit unique homing and activation mechanisms and respond to different ligands, implying a multifaceted role in immune regulation. The understanding of γδ T-cell involvement in kidney disease lags behind conventional T-cell research. However, advances in immune cell analysis technologies offer promising avenues for elucidating their precise functions. This review synthesizes the current knowledge on γδ T cells in renal diseases, explores potential therapeutic strategies, and presents a roadmap for future research directions.

Doxorubicin (DOX) is a cytotoxic anthracycline used to treat a variety of cancers. Cardiotoxicity, hepatotoxicity, and nephrotoxicity are adverse effects of DOX, that limit prognosis. The study aims to determine if diosmin (DIOS) and coenzyme Q10 (CoQ10) alone or in combination protect rats against DOX-induced liver and kidney damage. Adult male rats were assigned randomly in five groups. An intraperitoneal injection of DOX (2.5 mg/kg) was given to the DOX group every other day for three weeks, whereas a normal control group received the vehicle. Diosmin group received oral DIOS (100 mg/kg), Co-Q10 group received oral CoQ10 (10 mg/kg) and combination group received oral DIOS and CoQ10 daily for three weeks concomitantly with DOX. Sera and tissues were obtained 24 hours after last DOX injection. Serum aspartate transaminase (AST), alanine transaminase (ALT), creatinine, urea, total bilirubin and direct bilirubin were detected with hepatic and renal reduced glutathione (GSH), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α) and nuclear factor kappa-B (NF-κB). Histopathology and morphometry of liver and kidney were assessed. DOX exerted significant hepatorenal toxicity via elevation of liver and kidney functions, inducing oxidative stress by reducing GSH and elevating MDA, triggering renal and hepatic TNF-α and NF-kB. DIOS and CoQ10 modulated hepatic and renal functions, oxidative stress and inflammatory biomarkers. DIOS-CoQ10 combination treatment showed significant improvement in histopathology of liver and kidney along with morphometry compared to DOX group. In conclusion, combining DIOS and CoQ10 exhibited synergistic protective activity against DOX-induced hepatic and renal insult via their antioxidant and anti-inflammatory properties.

Podocyte loss in glomeruli is a fundamental event in the pathogenesis of chronic kidney diseases. Currently, mitotic catastrophe (MC) has emerged as the main cause of podocyte loss. However, the regulation of MC in podocytes has yet to be elucidated. The current work aimed to study the role and mechanism of p53 in regulating the MC of podocytes using adriamycin (ADR)-induced nephropathy. In vitro podocyte stimulation with ADR triggered the occurrence of MC, which was accompanied by hyperactivation of p53 and cyclin-dependent kinase (CDK1)/cyclin B1. The inhibition of p53 reversed ADR-evoked MC in podocytes and protected against podocyte injury and loss. Further investigation showed that p53 mediated the activation of CDK1/cyclin B1 by regulating the expression of Wee1. Restraining Wee1 abolished the regulatory effect of p53 inhibition on CDK1/cyclin B1 and rebooted MC in ADR-stimulated podocytes via p53 inhibition. In a mouse model of ADR nephropathy, the inhibition of p53 ameliorated proteinuria and podocyte injury. Moreover, the inhibition of p53 blocked the progression of MC in podocytes in ADR nephropathy mice through the regulation of the Wee1/CDK1/cyclin B1 axis. Our findings confirm that p53 contributes to MC in podocytes through regulation of the Wee1/CDK1/Cyclin B1 axis, which may represent a novel mechanism underlying podocyte injury and loss during the progression of chronic kidney disorder.

Diabetic nephropathy results from chronic (or uncontrolled) hyperglycemia and is the leading cause of kidney failure. The kidney's glomerular podocytes are highly susceptible to diabetic injury and subsequent non-reversible degeneration. We generated a human induced pluripotent stem (iPS) cell-derived model of diabetic podocytopathy to investigate disease pathogenesis and progression. The model recapitulated hallmarks of podocytopathy that precede proteinuria including retraction of foot processes and podocytopenia (detachment from the extracellular matrix (ECM)). Moreover, hyperglycemia-induced injury to podocytes exacerbated remodeling of the ECM. Specifically, mature podocytes aberrantly increased expression and excessively deposited collagen (IV)α1α1α2 that is normally abundant in the embryonic glomerulus. This collagen (IV) imbalance coincided with dysregulation of lineage-specific proteins, structural abnormalities of the ECM, and podocytopenia - a mechanism not shared with endothelium and is distinct from drug-induced injury. Intriguingly, repopulation of hyperglycemia-injured podocytes on decellularized ECM scaffolds isolated from healthy podocytes attenuated the loss of synaptopodin (a mechanosensitive protein associated with podocyte health). These results demonstrate that human iPS cell-derived podocytes can facilitate in vitro studies to uncover the mechanisms of chronic hyperglycemia and ECM remodeling and guide disease target identification.

Pegylated liposomal doxorubicin (PLD) has emerged as a recent innovation within the realm of antineoplastic agents, distinguished by its incorporation of doxorubicin within the liposomal bilayer. Given the low risk of cardiotoxicity, the clinical use of PLD has been expanding. We encountered a patient who underwent extended PLD therapy for recurrent malignancy and subsequently developed PLD-associated thrombotic microangiopathy, which was diagnosed by a detailed pathophysiological assessment. This case underscores the importance of considering thrombotic microangiopathy as a potential differential diagnosis in patients presenting with unexplained hypertension and renal impairment during prolonged PLD monotherapy.

This study aimed to develop a treatment for chronic kidney disease (CKD) by investigating whether transplantation of biofabricated adipose-derived mesenchymal cell (AMC) sheets could improve renal tissue and function. Thirty-nine 10-week-old male Sprague-Dawley rats underwent the harvesting of adipose tissues and right nephrectomy. AMCs that were collected from adipose tissues were labeled and cultured on temperature-responsive dishes, and applied to a gelatin hydrogel sheet. Subsequently, two identical AMC-gelatin sheets were attached together to biofabricate a bilayered AMC-gelatin sheet. Further, 3 weeks after nephrectomy, the renal artery and vein of the left kidney were clamped, and the kidney was sprayed with liquid nitrogen for 60 seconds. The biofabricated AMC sheet was autologously transplanted into the renal capsule of the cryo-injured region (n = 14). Control rats were given acellular sheet (n = 25). One day before and four weeks after transplantation, blood and 24-hour urinary specimens were collected. Histological analysis of the experimental kidneys was performed four weeks after transplantation. Four weeks after transplantation, in the acellular control-transplanted rats, creatinine clearance levels tended to increase, while serum creatinine levels significantly increased. However, in the biofabricated AMC sheet-transplanted rats, creatinine clearance levels significantly increased, and serum creatinine levels remained unchanged and were significantly lower than that of the control rats. The ratio of damaged to undamaged renal tubules in the AMC sheet-transplanted rats was lower than that in the control rats. In addition, the occupancy rate of fibrotic areas in the renal cortex under the AMC sheet-transplanted regions was significantly lower than that in the control regions. After transplantation, while the expressions of transforming growth factor-beta 1 and hypoxia-inducible factor-1 alpha were observed in both the control- and AMC sheet-transplanted regions, these expressions tended to be lower in the AMC sheet-transplanted rats than in the control rats. The labeled transplanted AMCs were detected in the transplanted regions, with some of them also showing positive staining for the vascular endothelial growth factor antibody. In conclusion, the biofabricated AMC sheets improved renal functions by ameliorating renal tubule disorders and renal fibrosis. Therefore, biofabricated AMC sheets would serve as a potential treatment for CKD.

Podocytopathies encompass kidney diseases where direct or indirect podocyte injury leads to proteinuria or nephrotic syndrome. Although Semaphorin3A (Sema3A) is expressed in podocytes and tubular cells in adult mammalian kidneys and has a common effect on the progression of podocyte injury, its mechanism remains unclear. Previous studies have shown increased Sema3A expression in various glomerulopathies, indicating a gap in understanding its role. In this study, analysis of human data revealed a positive correlation between the levels of urinary Sema3A and Podocalyxin (PCX), suggesting a close relationship between Sema3A and podocyte loss. Furthermore, the impact of Adriamycin on podocytes was investigated. Adriamycin induced podocyte migration and apoptosis, along with an increase in Sema3A expression, all of which were ameliorated by the inhibition of Sema3A. Importantly, TRPC5 was found to increase the overexpression of Sema3A in podocytes. A TRPC5 inhibitor, AC1903, alleviated podocyte migration and apoptosis, inhibiting the formation of lamellar pseudopodia in the podocyte cytoskeleton by lowering the expression of Rac1. Furthermore, AC1903 relieved massive albuminuria and foot process effacement in the kidneys of Adriamycin-treated mice in vivo. In conclusion, our findings suggest that Sema3A may impact the cytoskeletal stability of podocytes through TRPC5 ion channels, mediated by Rac1, ultimately leading to foot process effacement. Notably, AC1903 demonstrates the potential to reverse Adriamycin-induced foot process fusion and urine protein. These results contribute to a deeper understanding of the mechanisms involved in podocytopathies and highlight the therapeutic potential of targeting the Sema3A-TRPC5 pathway.

Peptide drug discovery for the treatment of chronic kidney disease (CKD) has attracted much attention in recent years due to the urge to find novel drugs and mechanisms to delay the progression of the disease. In this study, we identified a novel short peptide (named YR-7, primary sequence 'YEVEDYR') from the natural Fibroin protein, and demonstrated that it significantly alleviated pathological renal changes in ADR-induced nephropathy. PANX1 was identified as the most notably upregulated component by RNA-sequencing. Further analysis showed that YR-7 alleviated the accumulation of lipid droplets via regulation of the lipid metabolism-related proteins PPAR α and PANK1. Using chemical proteomics, fluorescence polarization, microscale thermophoresis, surface plasmon resonance, and molecular docking, YR-7 was proven to directly bind to β-barrel domains of TGM2 protein to inhibit lipid accumulation. TGM2 knockdown in vivo increased the protein levels of PPAR α and PANK1 while decreased the levels of fibrotic-related proteins to alleviate nephropathy. In vitro, overexpression TGM2 reversed the protective effects of YR-7. Co-immunoprecipitation indicated that TGM2 interacted with PANX1 to promote lipid deposition, and pharmacological inhibition or knockdown of PANX1 decreased the levels of PPAR α and PANK1 induced by ADR. Taken together, our findings revealed that TGM2-PANX1 interaction in promoting lipid deposition may be a new signaling in promoting ADR-induced nephropathy. And a novel natural peptide could ameliorate renal fibrosis through TGM2-PANX1-PPAR α/PANK1 pathway, which highlight the potential of it in the treatment of CKD.

Peroxisome proliferator-activated receptor-alpha (PPAR-α) and its exogenous activators (fibrates) promote autophagy. However, whether the deleterious effects of PPAR-α deficiency on doxorubicin (DOX)-induced podocytopathy are associated with reduced autophagy remains to be clarified. We investigated the mechanisms of PPAR-α in DOX-induced podocytopathy and tubular injury in PPAR-α knockout (PAKO) mice and in a murine podocyte cell line. DOX-treated PAKO mice showed higher serum levels of triglycerides and non-esterified fatty acids and more severe podocytopathy than DOX-treated wild-type mice, as evidenced by higher urinary levels of proteins and podocalyxin at 3 days to 2 weeks and higher blood urea nitrogen and serum creatinine levels at 4 weeks. Additionally, there was an increased accumulation of p62, a negative autophagy marker, in the glomerular and tubular regions in DOX-treated PAKO mice at Day 9. Moreover, DOX-treated PAKO mice showed more severe glomerulosclerosis and tubular damage and lower podocalyxin expression in the kidneys than DOX-treated control mice at 4 weeks. Furthermore, DOX treatment increased p-p53, an apoptosis marker, and cleaved the caspase-3 levels and induced apoptosis, which was ameliorated by fenofibrate, a PPAR-α activator. Fenofibrate further enhanced AMPK activation and autophagy under fed and fasting conditions. Conclusively, PPAR-α deficiency enhances DOX-induced podocytopathy, glomerulosclerosis, and tubular injury, possibly by reducing autophagic activity in mouse kidneys.

Nephrotic syndrome(NS) has emerged as a worldwide public health problem. Renal fibrosis is the most common pathological change from NS to end-stage renal failure, seriously affecting the prognosis of renal disease. Although tremendous efforts have been made to treat NS, specific drug therapies to delay the progression of NS toward end-stage renal failure are limited. Epimedium is generally used to treat kidney disease in traditional Chinese medicine. Icariin is a principal active component of Epimedium.

We used Sprague Dawley rats to establish NS models by injecting doxorubicin through the tail vein. Then icariin and prednisone were intragastric administration. Renal function was examined by an automatic biochemical analyzer. Pathology of the kidney was detected by Hematoxylin-Eosin and Masson staining respectively. Furthermore, RT-PCR, Enzyme-Linked Immunosorbent Assay, Immunohistochemistry, Western Blot and Terminal-deoxynucleotidyl Transferase Mediated Nick End Labeling staining were employed to detect the proteins related to pyroptosis and EMT. HK-2 cells exposed to doxorubicin were treated with icariin, and cell viability was assessed using the MTT. EMT was assessed using Enzyme-Linked Immunosorbent Assay and Western Blot.

The study showed that icariin significantly improved renal function and renal fibrosis in rats. In addition, icariin effectively decreased NOD-like receptor thermal protein domain associated protein 3,Caspase-1, Gasdermin D, Ly6C, and interleukin (IL)-1β. Notably, treatment with icariin also inhibited the levels of TGF-β, α-SMA and E-cadherin.

It is confirmed that icariin can improve renal function and alleviate renal fibrosis by inhibiting pyroptosis and the mechanism may be related to epithelial-to-mesenchymal transition. Icariin treatment might be recommended as a new approach for NS.

Kidney diseases have become an important global health concern due to their high incidence, inefficient diagnosis, and poor prognosis. Devising direct methods, especially imaging means, to assess renal function is the key for better understanding the mechanisms of various kidney diseases and subsequent development of effective treatment. Herein, we developed a fluorinated ferrous chelate-based sensitive probe, 1,7-DO2A-Fe(II)-F18 (Probe 1), for 19F magnetic resonance imaging (MRI). This highly fluorinated probe (containing 18 chemically equivalent 19F atoms with a fluorine content at 35 wt %) achieves a 15-time enhancement in signal intensity compared with the fluorine-containing ligand alone due to the appropriately regulated 19F relaxation times by the ferrous ion, which significantly increases imaging sensitivity and reduces acquisition time. Owing to its high aqueous solubility, biostability, and biocompatibility, this probe could be rapidly cleared by kidneys, which provides a means for monitoring renal dysfunction via 19F MRI. With this probe, we accomplish in vivo imaging of the impaired renal dysfunction caused by various kidney diseases including acute kidney injury, unilateral ureteral obstruction, and renal fibrosis at different stages. Our study illustrates the promising potential of Probe 1 for in vivo real-time visualization of kidney dysfunction, which is beneficial for the study, diagnosis, and even stratification of different kidney diseases. Furthermore, the design strategy of our probe is inspiring for the development of more high-performance 19F MRI probes for monitoring various biological processes.

Focal segmental glomerular sclerosis (FSGS) is a histological lesion characterized by sclerosis in sections (segmental) of some glomeruli (focal) in association with podocyte injury. Historically, FSGS has often been characterized as a disease, but it is a heterogeneous entity based on etiology, clinical course, and therapeutic approach. A unifying feature is podocyte injury and loss, which can be primary or the result of secondary maladaptive responses to glomerular stressors. FSGS has been demonstrated over time to carry a large health burden and remains a leading glomerular cause of ESRD globally. Recent clinical practice guidelines highlight the unmet scientific need for better understanding of disease pathogenesis, particularly for immunologic etiologies, as well as more targeted therapeutic drug development. In this review, we will discuss the current FSGS classification scheme, pathophysiologic mechanisms of injury, and treatment guidelines, along with emerging and investigational therapeutics.

Regular exercise training can lead to several health benefits, reduce mortality risk, and increase life expectancy. On the other hand, a sedentary lifestyle is a known risk factor for chronic diseases and increased mortality. Acute kidney injury (AKI) and chronic kidney disease (CKD) represent a significant global health problem, affecting millions of people worldwide. The progression from AKI to CKD is well-recognized in the literature, and exercise training has emerged as a potential renoprotective strategy. Thus, this article aims to review the main molecular mechanisms underlying the renoprotective actions of exercise training in the context of AKI and CKD, focusing on its antioxidative, anti-inflammatory, anti-apoptotic, anti-fibrotic, and autophagy regulatory effects. For that, bibliographical research was carried out in Medline/PubMed and Scielo databases. Although the pathophysiological mechanisms involved in renal diseases are not fully understood, experimental studies demonstrate that oxidative stress, inflammation, apoptosis, and dysregulation of fibrotic and autophagic processes play central roles in the development of tissue damage. Increasing evidence has suggested that exercise can beneficially modulate these mechanisms, potentially becoming a safe and effective non-pharmacological strategy for kidney health protection and promotion. Thus, the evidence base discussed in this review suggests that an adequate training program emerges as a valuable tool for preserving renal function in experimental animals, mainly through the production of antioxidant enzymes, nitric oxide (NO), irisin, IL-10, and IL-11. Future research can continue to explore these mechanisms to develop specific guidelines for the prescription of exercise training in different populations of patients with kidney diseases.

In recent years, chronic kidney disease (CKD) has emerged as an increasingly significant issue due to the growing prevalence and high treatment costs. While recorded the positive diuretic effect of Schoenoplectus tabernaemontani, there is a lack of reports on its efficacy in treating CKD. The pharmacological effects and mechanisms of Schoenoplectus tabernaemontani rhizomes aqueous extracts (STE) in CKD were investigated by inducing a rodent model of CKD via injection of Adriamycin (ADR; 7.5 mg/kg) into the tail vein of Wistar rats. In summary, our findings suggest that STE has a beneficial effect on anti-renal fibrosis and can reverse ADR-induced renal injury by suppressing oxidative stress and inflammation. Therefore, STE holds promising potential as a treatment option for CKD.

Approximately 30% of steroid-resistant nephrotic syndromes are attributed to monogenic disorders that involve 27 genes. Mutations in KANK family members have also been linked to nephrotic syndrome; however, the precise mechanism remains elusive. To investigate this, podocyte-specific Kank1 knockout mice were generated to examine phenotypic changes. In the initial assessment under normal conditions, Kank1 knockout mice showed no significant differences in the urinary albumin-creatinine ratio, blood urea nitrogen, serum creatinine levels, or histological features compared to controls. However, following kidney injury with adriamycin, podocyte-specific Kank1 knockout mice exhibited a significantly higher albumin-creatinine ratio and a significantly greater sclerotic index than control mice. Electron microscopy revealed more extensive foot process effacement in the knockout mice than in control mice. In addition, KANK1-deficient human podocytes showed increased detachment and apoptosis following adriamycin exposure. These findings suggest that KANK1 may play a protective role in mitigating podocyte damage under pathological conditions.

Insulin signaling to the glomerular podocyte via the insulin receptor (IR) is critical for kidney function. In this study we show that near-complete knockout of the closely related insulin-like growth factor 1 receptor (IGF1R) in podocytes is detrimental, resulting in albuminuria in vivo and podocyte cell death in vitro. In contrast, partial podocyte IGF1R knockdown confers protection against doxorubicin-induced podocyte injury. Proteomic analysis of cultured podocytes revealed that while near-complete loss of podocyte IGF1R results in the downregulation of mitochondrial respiratory complex I and DNA damage repair proteins, partial IGF1R inhibition promotes respiratory complex expression. This suggests that altered mitochondrial function and resistance to podocyte stress depends on the level of IGF1R suppression, the latter determining whether receptor inhibition is protective or detrimental. Our work suggests that the partial suppression of podocyte IGF1R could have therapeutic benefits in treating albuminuric kidney disease.

Glomerulonephritis (GN) is characterized by podocyte injury or glomerular filtration dysfunction, which results in proteinuria and eventual loss of kidney function. Progress in studying the mechanism of GN, and developing an effective therapy, has been limited by the absence of suitable in vitro models that can closely recapitulate human physiological responses. We developed a microfluidic glomerulus-on-a-chip device that can recapitulate the physiological environment to construct a functional filtration barrier, with which we investigated biological changes in podocytes and dynamic alterations in the permeability of the glomerular filtration barrier (GFB) on a chip. We also evaluated the potential of GN-mimicking devices as a model for predicting responses to human GN. Glomerular endothelial cells and podocytes successfully formed intact monolayers on opposite sides of the membrane in our chip device. Permselectivity analysis confirmed that the chip was constituted by a functional GFB that could accurately perform differential clearance of albumin and dextran. Reduction in cell viability resulting from damage was observed in all serum-induced GN models. The expression of podocyte-specific marker WT1 was also decreased. Albumin permeability was increased in most models of serum-induced IgA nephropathy (IgAN) and membranous nephropathy (MN). However, sera from patients with minimal change disease (MCD) or lupus nephritis (LN) did not induce a loss of permeability. This glomerulus-on-a-chip system may provide a platform of glomerular cell culture for in vitro GFB in formation of a functional three-dimensional glomerular structure. Establishing a disease model of GN on a chip could accelerate our understanding of pathophysiological mechanisms of glomerulopathy.

Investigating the role of podocytes in proteinuric disease is imperative to address the increasing global burden of chronic kidney disease (CKD). Studies strongly implicate increased levels of monocyte chemoattractant protein-1 (MCP-1/CCL2) in proteinuric CKD. Since podocytes express the receptor for MCP-1 (i.e., CCR2), we hypothesized that podocyte-specific MCP-1 production in response to stimuli could activate its receptor in an autocrine manner, leading to further podocyte injury. To test this hypothesis, we generated podocyte-specific MCP-1 knockout mice (Podo-Mcp-1fl/fl) and exposed them to proteinuric injury induced by either angiotensin II (Ang II; 1.5 mg/kg/d, osmotic minipump) or Adriamycin (Adr; 18 mg/kg, intravenous bolus). At baseline, there were no between-group differences in body weight, histology, albuminuria, and podocyte markers. After 28 days, there were no between-group differences in survival, change in body weight, albuminuria, kidney function, glomerular injury, and tubulointerstitial fibrosis. The lack of protection in the knockout mice suggests that podocyte-specific MCP-1 production is not a major contributor to either Ang II- or Adr-induced glomerular disease, implicating that another cell type is the source of pathogenic MCP-1 production in CKD.

Heterogeneous nuclear ribonucleoprotein F (HnRNP F) is a key regulator for nucleic acid metabolism; however, whether HnRNP F expression is important in maintaining podocyte integrity is unclear. Nephroseq analysis from a registry of human kidney biopsies was performed. Age- and sex-matched podocyte-specific HnRNP F knockout (HnRNP FPOD KO) mice and control (HnRNP Ffl/fl) were studied. Podocytopathy was induced in male mice (more susceptible) either by adriamycin (ADR)- or low-dose streptozotocin treatment for 2 or 8 weeks. The mouse podocyte cell line (mPODs) was used in vitro. Nephroseq data in three human cohorts were varied greatly. Both sexes of HnRNP FPOD KO mice were fertile and appeared grossly normal. However, male 20-week-old HnRNP FPOD KO than HnRNP Ffl/fl mice had increased urinary albumin/creatinine ratio, and lower expression of podocyte markers. ADR- or diabetic- HnRNP FPOD KO (vs. HnRNP Ffl/fl) mice had more severe podocytopathy. Moreover, methyltransferase-like 14 (Mettl14) gene expression was increased in podocytes from HnRNP FPOD KO mice, further enhanced in ADR- or diabetic-treated HnRNP FPOD KO mice. Consequently, this elevated Mettl14 expression led to sirtuin1 (Sirt1) inhibition, associated with podocyte loss. In mPODs, knock-down of HnRNP F promoted Mettl14 nuclear translocation, which was associated with podocyte dysmorphology and Sirt1 inhibition-mediated podocyte loss. This process was more severe in ADR- or high glucose- treated mPODs. Conclusion: HnRNP F deficiency in podocytes promotes podocytopathy through activation of Mettl14 expression and its nuclear translocation to inhibit Sirt1 expression, underscoring the protective role of HnRNP F against podocyte injury.

Podocytes play a critical role in the formation and maintenance of the glomerular filtration barrier and injury to these cells can lead to a breakdown of the glomerular barrier causing permanent damage leading to progressive chronic kidney disease. Matured podocytes have little proliferative potential, which makes them critical cells from a health perspective, but also challenging cells to maintain in vitro. Differentiating podocyte-like cells from induced pluripotent stem cells (iPSC) provides a novel and continuous source of cells. Here, we investigated the effect of a 24-h exposure to eight compounds, including the known glomerular toxins doxorubicin and pamidronate, on transcriptomic alterations in iPSC derived podocytes. Doxorubicin (50 nM), pamidronate (50 μM), sodium arsenite (10 μM), and cyclosporine A (15 μM) had a strong impact on the transcriptome, gentamicin (450 μg/ml), lead chloride (15 μM) and valproic acid (500 μM) had a mild impact and busulfan (50 μM) exhibited no impact. Gene alterations and pathways analysis provided mechanistic insight for example, doxorubicin exposure affected the p53 pathway and dedifferentiation, pamidronate activated several pathways including HIF1alpha and sodium arsenite up-regulated oxidative stress and metal responses. The results demonstrate the applicability of iPSC derived podocytes for toxicological and mechanistic investigations.

Proteinuria is recognized as a risk factor for the exacerbation of chronic kidney disease. Modified Huangqi Chifeng decoction (MHCD) has distinct advantages in reducing proteinuria. Our previous experimental results have shown that MHCD can inhibit excessive autophagy. However, the specific mechanism by which MHCD regulates autophagy needs to be further explored.

In this study, in vivo and in vitro experiments were conducted to further clarify the protective mechanism of MHCD on the kidney and podocytes by regulating autophagy based on phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK)/mTOR signaling pathways.

By a single injection via the tail vein, Sprague-Dawley rats received Adriamycin (5 mg/kg) to establish a model of proteinuria nephropathy. They were divided into control, model, MHCD, 3-methyladenine (3 MA), 3 MA + MHCD, and telmisartan groups and were administered continuously for 6 weeks. The MHCD-containing serum was prepared, and a model of podocyte injury induced by Adriamycin (0.2 μg/mL) was established.

MHCD reduced the 24-h urine protein levels and relieved pathological kidney damage. During autophagy in the kidneys of rats with Adriamycin-induced nephropathy, the PI3K/AKT/mTOR signaling pathway is inhibited, while the AMPK/mTOR signaling pathway is activated. MHCD antagonized these effects, thereby inhibiting excessive autophagy. MHCD alleviated Adriamycin-induced podocyte autophagy, as demonstrated using Pik3r1 siRNA and an overexpression plasmid for Prkaa1/Prkaa2. Furthermore, MHCD could activate the PI3K/AKT/mTOR signaling pathway while suppressing the AMPK/mTOR signaling pathway.

This study demonstrated that MHCD can activate the interaction between the PI3K/AKT/mTOR and the AMPK/mTOR signaling pathways to maintain autophagy balance, inhibit excessive autophagy, and play a role in protecting the kidneys and podocytes.

Podocytes, specialized postmitotic cells, are central players in various kidney-related diseases. Zebrafish have become a valuable model system for studying podocyte biology because they are genetically easy to manipulate, transparent, and their glomerular structure is similar to that of mammals. This review provides an overview of the knowledge of podocyte biology in zebrafish larvae, with particular focus on their essential contribution to understanding the mechanisms that underlie kidney diseases as well as supporting drug development. In addition, special attention is given to advances in live-imaging techniques allowing the observation of dynamic processes, including podocyte motility, podocyte process behavior, and glomerulus maturation. The review further addresses the functional aspects of podocytes in zebrafish larvae. This includes topics such as glomerular filtration, ultrastructural analyses, and evaluation of podocyte response to nephrotoxic insults. Studies presented in this context have provided important insights into the maintenance and resistance of the glomerular filtration barrier in zebrafish larvae and explored the potential transferability of these findings to mammals such as mice, rats, and most importantly, humans. The recent ability to identify potential therapeutic targets represents a promising new way to identify drugs that could effectively treat podocyte-associated glomerulopathies in humans. In summary, this review gives an overview about the importance of zebrafish as a model for podocyte-related disease and targeted drug development. It also highlights the key role of advanced imaging techniques in transparent zebrafish larvae, improving our understanding of glomerular diseases and the significant potential for translation of these findings to humans.

In this study, we aim to unveil the potential of itaconyl chondroitin sulfate nanogel (ICSNG) in tackling chronic kidney diseases triggered by the administration of CDDP and doxorubicin (Adriamycin, ADR). To that end, the new drug delivery system (ICSNG) was initially prepared, characterized, and loaded with the target drugs. Thereafter, the in-vivo studies were performed using five equally divided groups of 100 male Sprague-Dawley (SD) rats. Biochemical evaluation and immunohistochemistry studies have revealed the renal toxicity and the ameliorative effects of ICSNG on renal function. When ICSNG-based treatments were contrasted with the CDDP and ADR infected groups, they significantly increased paraoxonase-1 (PON-1), superoxide dismutase (SOD), catalase (CAT) and albumin activity and significantly decreased nitric oxide (NO), tumor necrosis factor alpha (TNF-α), creatinine, urea, and cyclooxygenase-2 (COX-2) activity (p < 0.001). The findings of the current study imply that ICSNG may be able to lessen renal inflammation and damage in chronic kidney disorders brought on by the administration of CDDP and ADR. Interestingly, according to the estimated selectivity indices, the ICSNG-encapsulated drugs have demonstrated superior selectivity for cancer MCF-7 cells, over healthy HSF cells, in comparison to the bare drugs.

Arteriovenous fistulas (AVFs) have long been used as dialysis access in patients with end-stage renal disease; however, their maturation and long-term patency still fall short of clinical needs. Rodent models are irreplaceable to facilitate the study of mechanisms and provide reliable insights into clinical problems. The ideal rodent AVF model recapitulates the major features and pathology of human disease as closely as possible, and pre-induction of the uremic milieu is an important addition to AVF failure studies. Herein, we review different surgical methods used so far to create AVF in rodents, including surgical suturing, needle puncture, and the cuff technique. We also summarize commonly used evaluations after AVF placement. The aim was to provide recent advances and ideas for better selection and induction of rodent AVF models. At the same time, further improvements in the models and a deeper understanding of AVF failure mechanisms are expected.

Patients with end-stage kidney disease (ESKD) require dialysis or transplantation for their survival. There are few experimental animal models mimicking the human situation in which the animals are dependent on dialysis for their survival. We developed a peritoneal dialysis (PD) system for rats to enable long-term treatment under controlled conditions.

Rats were chemically nephrectomised using orellanine to render them uremic. Two studies were performed, the first with highly uremic rats on PD for 5 days, and the other with moderately uremic rats on PD for 21 days. Blood and dialysate samples were collected repeatedly from the first study and solute concentrations analysed. Based on these values, dialysis parameters were calculated together with generation rates allowing for kinetic modelling of the effects of PD. In the second study, the general conditions of the rats were evaluated during a longer dialysis period.

For rats with estimated glomerular filtration rate (GFR) 5-10% of normal (moderately uremic rats), five daily PD cycles kept the rats in good condition for 3 weeks. For highly uremic rats (GFR below 3% of normal), more extensive dialysis is needed to maintain homeostasis and our simulations show that a six daily and four nightly PD cycles should be needed to keep the rats in good condition.

In conclusion, the PD system described in this study can be used for long-term studies of PD on uremic dialysis-dependent rats mimicking the human setting. To maintain whole body homeostasis of highly uremic rats, intense PD is needed during both day and night.

Nephrotic syndrome (NS) is one of the reasons of end-stage kidney disease, and elucidating the pathogenesis and offer new treatment options is important. Oxidative stress might trigger pathogenesis systemically or isolated in the kidneys. Octreotide (OCT) has beneficial antioxidant effects. We aimed to investigate the source of oxidative stress and the effect of OCT on experimental NS model.

Twenty-four non-uremic Wistar albino rats were divided into 3 groups. Control group, 2 mL saline intramuscular (im); NS group, adriamycin 5 mg/kg intravenous (iv); NS treatment group, adriamycin 5 mg/kg (iv) and OCT 200 mcg/kg (im) were administered at baseline (Day 0). At the end of 21 days, creatinine and protein levels were measured in 24-hour urine samples. Erythrocyte and renal catalase (CAT) and thiobarbituric acid reactive substance (TBARS) were measured. Renal histology was also evaluated.

There was no significant difference among the 3 groups in terms of CAT and TBARS in erythrocytes. Renal CAT level was lowest in NS group, and significantly lower than the control group. In treatment group, CAT level significantly increased compared with NS group. In terms of renal histology, tubular and interstitial evaluations were similar in all groups. Glomerular score was significantly higher in NS group compared with control group and it was significantly decreased in treatment group compared to NS group.

Oxidative stress in NS might be due to the decrease in antioxidant protection mechanism in kidney. Octreotide improves antioxidant levels and histology in renal tissue and might be a treatment option.