The study aimed to elucidate the molecular mechanisms underlying the protective effects of Compound Xueshuantong (CXst) in the context of diabetic nephropathy (DN), a major cause of kidney failure driven by podocyte injury and metabolic dysfunction. Given the critical role of the AMPK/mTOR signaling pathway in regulating cellular energy balance, autophagy, and mitochondrial health, we focused on its involvement in podocyte function and how it might be influenced by CXst. Through a series of experiments, we found that CXst treatment led to the upregulation of key proteins involved in autophagy, such as LC3 and p62, as well as proteins critical for mitochondrial function, like PGC-1α. These molecular changes helped to counteract the damaging effects of high glucose levels on podocytes, which are central to maintaining the filtration function of the kidneys. Additionally, CXst's ability to modulate the AMPK/mTOR pathway was shown to be a pivotal factor in its protective effects, as inhibition of AMPK significantly reduced these benefits. This comprehensive study provides strong evidence that CXst exerts its protective effects against DN by modulating the AMPK/mTOR pathway, thus preserving podocyte integrity and function. These findings suggest that CXst could be a promising candidate for the development of new therapeutic strategies for the treatment of DN, offering hope for better management of this challenging condition.

Chronic kidney disease (CKD) is influenced by inflammation, a critical factor in its progression. However, the underlying mechanism through which inflammation contributes to CKD is still obscure. The Klotho protein, which is predominantly found in the kidneys, is known for its protective functions, including anti-inflammatory, anti-aging, antioxidant, and anti-fibrotic effects. A myriad of studies have suggested that inflammation in CKD leads to a decrease in Klotho expression, diminishing Klotho protection capabilities and exacerbating kidney damage, thereby promoting CKD progression. These findings suggest that Klotho deficiency could be a crucial link between inflammation and CKD progression. However, the mechanism regarding their relationship is still unclear. The reduction in Klotho due to inflammation may be attributed to epigenetic mechanisms, such as DNA methylation, histone deacetylation, transcription factor, microRNA (miRNA) regulation and long non-coding RNA (lncRNA) regulation or non-epigenetic factors, such as endoplasmic reticulum (ER) stress and ER-associated degradation (ERAD), which affect Klotho protein metabolism. Through these pathways, inflammation triggers a decrease in Klotho expression, further driving CKD progression. Notably, Klotho also exerts a strong anti-inflammatory effect by inhibiting key inflammatory factors and pathways, suggesting that there is intricate crosstalk between inflammatory factors and Klotho in CKD. This review highlights how inflammation suppresses the expression of Klotho and further contributes to the development and exacerbation of CKD. By focusing on the interplay between inflammation and Klotho, the present review provides novel potential therapeutic strategies such as correcting epigenetic and non-epigenetic abnormalities for treating CKD by targeting this specific axis.

The α-klotho is crucial in diabetes and its related complications. This study seeks to explore the link between α-klotho levels and the risk of diabetic kidney disease (DKD) as well as all-cause and cardiovascular mortality among individuals with type 2 diabetes mellitus (T2DM).

The investigation involved 126 Chinese T2DM patients and 4,451 individuals from the National Health and Nutrition Examination Survey (NHANES) database. To evaluate the relationship between α-klotho levels and DKD risk, multivariate logistic regression was utilized. Additionally, restricted cubic spline (RCS) regression analysis was conducted to examine the nonlinear relationship between α-klotho levels and DKD incidence. RCS analysis was employed to explore the correlation between α-klotho and both all-cause and cardiovascular mortality.

In the Chinese cohort, α-klotho levels were notably elevated in T2DM group compared to DKD group. The NHANES data revealed a significant inverse relationship between α-klotho levels and DKD risk. Nonlinear analysis further illustrated a substantial nonlinear connection between α-klotho levels and DKD risk. Serum α-klotho levels below 880.78 pg/mL were linked to increased DKD risk in T2DM patients. When compared to the T2DM group, the DKD group had markedly higher all-cause and cardiovascular mortality rates, with the α-klotho low group (e.g., Q1) exhibiting lower survival compared to other groups. Cox regression findings indicated that elevated α-klotho levels could mitigate all-cause mortality in T2DM patients. The relationship between α-klotho levels and all-cause mortality was also nonlinear, with the minimal risk found at α-klotho levels between 776.95 pg/mL and 812.69 pg/mL, varying by gender.

There exists a notable association between α-klotho levels and DKD risk, along with mortality in T2DM patients, with varying effects based on gender. These results highlight the potential importance of α-klotho as both a biomarker and a therapeutic target.

Cellular senescence is a hallmark of aging and contributes to age-related diseases, including diabetic nephropathy (DN). Additionally, macrophage-mediated inflammation has been linked with DKD. Therefore, we investigated the effect of macrophage depletion on kidney cell senescence in DN, focusing on the relationship between the GDF-15 and Klotho signaling pathways. Wistar albino rats (n = 24) were divided into four groups: healthy control, liposomal clodronate (LC)-treated healthy, diabetic, and LC-treated diabetic groups. Rats in the LC-treated healthy, diabetic, and LC-treated diabetic groups were intravenously administered LC once a week for 4 weeks. Rat models of type 2 diabetes were successfully established via the administration of streptozotocin and a high-fat diet, as evidenced by increased blood glucose levels, kidney weight to body weight (KW/BW) ratio, serum albumin, creatinine, and urea levels, kidney damage, and oxidative stress. However, LC-mediated macrophage depletion reduced the KW/BW ratio, improved serum and oxidative parameters, decreased inflammatory markers (IL-6 and TNF-α), and ameliorated oxidative stress. Additionally, LC treatment promoted macrophage polarization towards the anti-inflammatory phenotype, downregulated GDF-15 expression, upregulated Klotho expression, and ameliorated kidney damage. In conclusion, macrophage depletion combats kidney senescence by modulating Klotho and GDF-15, indicating their potential as novel targets in DN treatment.

Tripterygium wilfordii is a traditional Chinese medicine used to treat rheumatic diseases, with properties such as clearing heat, detoxifying, dispelling wind, and relieving pain. In recent years, its active compound, celastrol, garnered significant attention for its potential therapeutic effects on metabolic diseases. Celastrol exhibits bioactivities such as regulating metabolic functions and anti-inflammatory effects, positioning it as a promising candidate for the treatment of obesity, diabetes, atherosclerosis (AS), and non-alcoholic fatty liver disease (NAFLD).

This review aims to explore the pharmacological mechanisms of celastrol in metabolic diseases, focusing on its anti-inflammatory mechanisms and metabolic regulation effects, providing theoretical support for further investigation of its therapeutic potential in metabolic diseases.

Literature was retrieved from PubMed, Web of Science, Scopus, Cochrane, and Google Scholar. This review primarily focuses on anti-inflammatory mechanisms of celastrol, its metabolic regulation, and toxicity studies, by systematically analyzing its effects in obesity, diabetes, AS, and NAFLD, providing scientific evidence for its potential clinical applications.

Celastrol regulates multiple signaling pathways, particularly inhibiting NF-κB and activating AMPK, reducing the production of pro-inflammatory cytokines and improving insulin sensitivity, enhancing its therapeutic potential in metabolic diseases. Additionally, celastrol regulates adipogenesis and energy metabolism by influencing key transcription factors such as PPARγ and SREBP-1c. Numerous studies highlight its role in alleviating oxidative stress and improving mitochondrial function, further enhancing its metabolic benefits.

In summary, celastrol holds great promise as a multi-target therapeutic agent for metabolic diseases, offering anti-inflammatory, metabolic regulatory, and antioxidative benefits. Despite these, challenges remain for the clinical application of celastrol due to its poor bioavailability and potential toxicity. Advanced formulation strategies and targeted delivery systems are urgently needed to overcome challenges related to bioavailability and clinical translation.

To comprehensively assess evidence from published systematic review and meta-analyses (SRMAs) on the genetics of vascular diabetes complications.

A systematic literature search conducted in Medline and Embase identified 63 non-overlapping SRMAs. We re-conducted meta-analyses to compare diabetes with and without complications using multiple genetic models; evaluated associations using Venice criteria and Bayesian false-discovery probability (BFDP); and graded as highly credible, credible, and not credible. We also contrasted highly credible and credible associations to recent genome-wide association studies (GWASs).

Highly credible evidence was discovered for single nucleotide polymorphisms (SNPs) rs1024611 at MCP-1 gene and SNP rs3025039 at VEGF gene with diabetic retinopathy (DR) in type 2 diabetes; SNP rs2268388 at ACACB gene, insertion/deletion (Ins/Del) variant at ACE gene, SNP rs1801133 at MTHFR gene, and SNP rs7903146 at TCF7L2 gene with diabetic kidney disease (DKD) in type 2 diabetes; and SNP rs4880 at SOD2 gene with diabetic peripheral neuropathy (DPN) in type 1 diabetes. Combining type 1 and 2 diabetes, highly credible evidence was discovered for insertion/deletion variant at ACE gene, SNP rs759853 at AKR1B1 gene, SNP rs1044498 at ENPP1 gene and DKD, and SNP rs1617640 at EPO gene for the combined endpoint of DR and DKD. None of these associations was directly replicated in the latest GWASs for DR and DKD, however, another SNP, rs55853916 at TCF7L2 gene had been detected as a GWAS hit for DKD.

This umbrella review rigorously assessed evidence on the genetics of vascular diabetes complications, complemented findings in recent GWASs and yielded insight into the optimal selection of genetic models for the design of GWASs on vascular diabetes complications. Mechanistic or bioinformatic studies are warranted to further assess the role of these genes in the pathology of vascular diabetes complications and their potential as drug targets.

PROSPERO: CRD42022384423.

Renal tubular epithelial cells (RTECs) apoptosis is the key factor in the development of diabetic kidney disease (DKD). Endoplasmic reticulum stress (ERS) leading to mitochondrial Ca2+ overload is one of the causes of apoptosis in RTECs. Corni Fructus (CF) is an herbal medicine, developed and applied as a functional food, and it is commonly used to treat DKD. Cornuside (Cor) is one of the main chemical components in CF. This research seeks to investigate the function of Cor in DKD and delve into its possible mechanisms. Cor significantly improved renal function and ameliorated renal pathological changes of db/db mice. Bioinformatics analyses suggested that the modulation of endoplasmic reticulum-induced intrinsic apoptosis pathway was a primary mechanism by which Cor ameliorated DKD. TUNEL assays and flow cytometry assays indicated that Cor effectively inhibited RTECs apoptosis in db/db mice and AGE-induced HK-2 cells. Further experimental studies showed that Cor mitigated ERS by inhibiting the activation of PERK/ATF4/CHOP signal pathway and down-regulation of VDAC1 protein expression, thus alleviating mitochondrial Ca2+ overload. More importantly, Cor directly targeted NEDD4 to facilitate VDAC1 degradation. Notably, the silencing of NEDD4 nearly abolished Cor's inhibitory effects on mitochondrial Ca2+ overload and apoptosis. In conclusion, Cor modulated Ca2+ homeostasis by alleviating ERS and targeting NEDD4, thus mitigating apoptosis of RTECs in DKD. These findings indicate that Cor has the potential for the treatment and drug development of DKD.

This paper aims to investigate m6A modification during DKD progression. We evaluated m6A regulators expression in peripheral blood mononuclear cells, whole kidney tissue, glomerular, and tubulointerstitial samples. CIBERSORT and single-sample gene set enrichment analysis analyzed glomerular immune characteristics. Logistic-LASSO regression were used to develop the m6A regulators model that can identify early DKD. Consensus clustering algorithms were used to classify DKD in glomerular samples into m6A modified subtypes based on the expression of m6A regulators. Gene set variation analysis algorithm was used to evaluate the functional pathway enrichment of m6A modified subtypes. Weighted gene co-expression network analysis and protein-protein interaction networks identified m6A modified subtype marker genes. The Nephroseq V5 tool was used to evaluate the correlation between m6A modified subtypes marker genes and renal function. DKD patients' m6A regulators expression differed from the control group in various tissue types. DKD stages have various immune characteristics. The m6A regulators model with YTHDC1, METTL3, and ALKBH5 better identified early DKD. DKD was divided into two subtypes based on the expression of 26 m6A regulators. Subtype 1 was enriched in myogenesis, collagen components, and cytokine receptor interaction, while subtype 2 was enriched in protein secretion, proliferation, apoptosis, and various signaling pathways (e.g., TGFβ signaling pathway, PI3K/AKT/mTOR pathway, and etc.). Finally, AXIN1 and GOLGA4 were identified as possible biomarkers associated with glomerular filtration rate. From the viewpoint of m6A modification, the immune characteristics and molecular mechanisms of DKD at various stages are different, and targeted treatment would improve efficacy.

Diabetic kidney disease (DKD) is a main complication of diabetes mellitus. experimental in vitro validation and Network pharmacology were used in this study to explore the potential mechanism of Huangkui capsules (HKC) in treating DKD. First, we used CCK8 to analyze the optimal drug concentration of HKC. Next, we used flow cytometry, ELISA, Scratch test, and immunofluorescence to examine the apoptosis, oxidative stress, inflammatory factors, and fibrotic factors (FN and α-SMA) expression in HK-2 cells. Thereafter, in order to determine the potential molecular mechanisms underlying the therapeutic effect of HKC in DKD. Compounds contained in HKC were explored by UPLC-Q-TOF-MS/MS. SwissTargetPrediction was utilized for predicting potential gene targets of these compounds. OMIM, DisGeNet and GeneCards databases were employed to identify DKD-related genes. Meanwhile, the association of compounds with DKD genes was examined by protein-protein interaction, GO and KEGG analysis. Finally, molecular docking and molecular dynamics simulation were adopted for further validation. The results showed that HKC had 40 active ingredients, 1051 possible gene targets, and 133 DKD-HKC intersection genes. IL6, TNF, GAPDH, AKT1, PPARG, and TP53 were candidate hub genes by which HKC exerted its anti-DKD function based on molecular docking, molecular dynamics simulation and experimental results. To conclude, this study sheds more lights on the possible pharmacological activities of HKC in DKD and a foundation for further clinical application.

Recent advancements in tissue engineering and regenerative medicine have introduced promising strategies to address tissue and organ deficiencies. This review highlights the critical role of short peptides, particularly their ability to self-assemble into matrices that mimic the extracellular matrix (ECM). These low molecular weight peptides exhibit target-specific activities, modulate gene expression, and influence cell differentiation pathways. They are stable, programmable, non-cytotoxic, biocompatible, biodegradable, capable of crossing the cell membrane and easy to synthesize. This review underscores the importance of peptide structure and concentration in directing stem cell differentiation and explores their diverse biomedical applications. Peptides such as Aβ1-40, Aβ1-42, RADA16, A13 and KEDW are discussed for their roles in modulating stem cell differentiation into neuronal, glial, myocardial, osteogenic, hepatocyte and pancreatic lineages. Furthermore, this review delves into the underlying signaling mechanisms, the chemistry and design of short peptides and their potential for engineering biocompatible materials that mimic stem cell microenvironments. Short peptide-based biomaterials and scaffolds represent a promising avenue in stem cell therapy, tissue engineering, and regenerative medicine.

Diabetic nephropathy is a severe chronic complication characterized by cytotoxicity, inflammation, and fibrosis, ultimately leading to renal failure. This study systematically investigated the effects of the PARP1 inhibitor PJ-34 on high glucose-induced cytotoxicity, inflammation, and fibrosis in HK-2 cells, as well as its improvement on neuropathic pain response and transforming growth factor β (TGFβ) expression in a type 1 diabetes mellitus diabetic nephropathy mouse model. Through cellular and animal experiments, we observed that PJ-34 significantly enhanced the proliferative capacity of cells damaged by high glucose, reduced apoptosis, and decreased the release of proinflammatory factors TGFα, interleukin-6, and interleukin-1β. In the type 1 diabetes mellitus nephropathy mouse model, the administration of PJ-34 substantially improved parameters of neuropathic pain, alleviated renal tissue damage, reduced indicators of renal functional impairment-inhibited renal fibrosis, and reduced the key protein expression in the epithelial-mesenchymal transition process, acting through the regulation of the TGFβ/Smads signaling pathway. This study elucidated the mechanism of action of the PARP1 inhibitor PJ-34 as a potential therapeutic agent for diabetic nephropathy, offering a novel strategy for its treatment.

This study evaluates the utility of serum s-αKlotho levels as a quantifiable biomarker for overwork.

Frontline medical workers aged 20-55 years from Yiling People's Hospital of Yichang were recruited. Criteria included nonsmokers, non-heavy drinkers, no chronic medication use, and no acute illnesses recently. Participants worked over 10 hours per day, 60 hours weekly, and had at least 3 years of experience. A control group was matched except for work conditions. Data were collected through surveys, and serum levels were measured.

Significant differences in serum Klotho were found between overwork and control groups. The overwork group had higher median s-αKlotho levels (49.99 pg/mL) compared to controls (27.88 pg/mL).

Overworked medical workers exhibited elevated serum s-αKlotho, suggesting s-αKlotho as a potential biomarker for overwork. Future research should use multicenter designs with larger samples to validate findings.

In this review, we examine the significance of multi-omics technologies in understanding the plethora of intricate processes that activate gastrointestinal (GI) injury repair. Multi-omics, which includes genomics, transcriptomics, proteomics, and metabolomics, allows intricate mapping of cellular responses and molecular pathways involved in GI repair. We highlight the potential of multi-omics to discover previously unknown therapeutic targets or elucidate the molecular basis of the pathogenesis of GI. Furthermore, we explore the possibilities of integrating omics data to improve prediction models, and summarize the state-of-the-art technological developments and persisting obstacles that hinder the translation of multi-omics into clinical practice. Finally, innovative multi-omics approaches that can improve patient outcomes and advance therapeutic strategies in GI medicine are discussed.

Uremia (UR) is caused by increased UR-related toxins in the bloodstream. We explored the mechanism of enterogenous toxin methylmalonic acid (MMA) in calcium-phosphorus metabolic disorder in UR rats via the Wnt/β-catenin pathway.

The UR rat model was established by 5/6 nephrectomy. The fecal bacteria of UR rats were transplanted into Sham rats. Sham rats were injected with exogenous MMA or Salinomycin (SAL). Pathological changes in renal/colon tissues were analyzed. MMA concentration, levels of renal function indicators, serum inflammatory factors, Ca2+/P3+, and parathyroid hormone, intestinal flora structure, fecal metabolic profile, intestinal permeability, and glomerular filtration rate (GFR) were assessed. Additionally, rat glomerular podocytes were cultured, with cell viability and apoptosis measured.

Intestinal flora richness and diversity in UR rats were decreased, along with unbalanced flora structure. Among the screened 133 secondary differential metabolites, the MMA concentration rose, showing the most significant difference. UR rat fecal transplantation caused elevated MMA concentration in the serum and renal tissues of Sham rats. The intestinal flora metabolite MMA or exogenous MMA promoted intestinal barrier impairment, increased intestinal permeability, induced glomerular podocyte loss, and reduced GFR, causing calcium-phosphorus metabolic disorder. The intestinal flora metabolite MMA or exogenous MMA induced inflammatory responses and facilitated glomerular podocyte apoptosis by activating the Wnt/β-catenin pathway, which could be counteracted by repressing the Wnt/β-catenin pathway.

Enterogenous toxin MMA impelled intestinal barrier impairment in UR rats, enhanced intestinal permeability, and activated the Wnt/β-catenin pathway to induce glomerular podocyte loss and reduce GFR, thus aggravating calcium-phosphorus metabolic disorder.

Diabetic nephropathy (DN) is a prevalent global renal illness and one of the main causes of end-stage renal disease (ESRD). FGF21 has been shown to ameliorate diabetic nephropathy, and in addition FGF-21-treated mice impeded mitogenicity, whereas it is unclear whether FGF21 can influence DN progression by regulating the cell cycle in diabetic nephropathy.

In order to create a diabetic model, STZ injections were given to C57BL/6J mice for this investigation. Then, FGF21 was administered, and renal tissue examination and pathological observation were combined with an assessment of glomerular injury, inflammation, oxidative stress, and the fibrinogen system in mice following the administration of the intervention. Furthermore, we used db/db mice and FGF21 direct therapy for 8 weeks to investigate changes in fasting glucose and creatinine expression as well as pathological changes in glomeruli glycogen deposition, fibrosis, and nephrin expression. To investigate the mechanism of action of FGF21 in the treatment of glycolytic kidney, transcriptome sequencing of renal tissues and KEGG pathway enrichment analysis of differential genes were performed.

The study's findings demonstrated that FGF21 intervention increased clotting time, decreased oxidative stress and inflammation, and avoided thrombosis in addition to considerably improving glomerular filtration damage. After 8 weeks of FGF21 treatment, glomerular glycogen deposition, fibrosis, and renin expression decreased in db/db mice. Moreover, there was a notable reduction of creatinine and fasting blood glucose levels. Additionally, the CDK1 gene, a key player in controlling the cell cycle, was discovered through examination of the transcriptome sequencing data. It was also shown that FGF21 dramatically reduces the expression of CDK1, which may help diabetic nephropathy by averting mitotic catastrophe and changing the renal cell cycle.

In short, FGF21 improved the development of diabetic nephropathy in diabetic nephropathy-affected animals by reducing glomerular filtration damage, inflammation, and oxidative stress, inhibiting the formation of thrombus, and controlling the cell cycle through CDK1.

Cardiorenal syndrome (CRS) is an interdependent dysfunction of the heart and kidneys, where failure in one organ precipitates failure in the other. The pathophysiology involves sustained renin-angiotensin-aldosterone-system (RAAS) activation, mitochondrial dysfunction, inflammation, fibrosis, oxidative stress and tissue remodeling, culminating in organ dysfunction. Existing therapies targeting the RAAS, diuretics and other agents have limitations, including diuretic resistance and compensatory sodium reabsorption. Therefore, there is a pressing need for novel druggable targets involved in CRS pathogenesis. This review addresses the challenges of existing treatments and emphasizes the importance of discovering new therapeutic targets. It highlights emerging targets such as Klotho, sex-determining region Y box 9 (SOX9), receptor-interacting protein kinase 3 (RIPK3), β-amino-isobutyric acid (BAIBA), thrombospondin-1 (TSP-1), among others, with their potential roles in CRS.

The glucagon-like peptide-1 receptor agonist (GLP-1RA) is a pharmacological agent utilized for the treatment of diabetes, known for its significant reno protective effects. This study aims to investigate the impact of liraglutide, a representative GLP-1RA medication, on early endothelial dysfunction in diabetic rats and elucidate its underlying mechanisms.

The present study employed a high-fat, high-sugar diet in combination with a single intraperitoneal injection of streptozotocin (STZ) to establish an experimental rat model of diabetes. Subsequently, the therapeutic efficacy of liraglutide on renal injury in this model was evaluated using various doses.

Compared to the DKD rats, the rats treated with Liraglutide exhibited significant reductions in levels of blood glucose (Glu), serum creatinine (Scr), and blood urea nitrogen (BUN) (P < 0.05). Furthermore, there was a dose-dependent decrease in urinary protein levels, including 24-hour urinary protein excretion rate and microalbuminuria (m-ALB), with higher doses demonstrating more pronounced therapeutic effects (P <0.05). In addition, treatment with Liraglutide effectively improved glomerular and interstitial damage, and suppressed the expression of CD31, CD34, and VE-cadherin associated with endothelial cell injury (P < 0.05). Furthermore, Liraglutide administration significantly increased nitric oxide (NO) production (P < 0.05). Moreover, Liraglutide treatment resulted in decreased expression of vascular endothelial growth factor (VEGF), Delta-like ligand-4(Dll4), and Notch2 protein in the Notch2 signaling pathway (P < 0.05).

The findings indicate that Liraglutide has a substantial effect on decreasing urinary protein excretion and improving vascular microinflammation, thus alleviating endothelial dysfunction in diabetic nephropathy. This observed mechanism can be attributed to the inhibition of the Dll4/Notch2 signaling pathway.

Bone defects are highly prevalent diseases caused by trauma, tumors, inflammation, congenital malformations and endocrine abnormalities. Ideally effective and side effect free approach to dealing with bone defects remains a clinical conundrum. Klotho is an important protein, which plays an essential role in regulating aging and mineral ion homeostasis. More recently, research revealed the function of Klotho in regulating skeleton development and regeneration. Klotho has been identified in mesenchymal stem cells, osteoblasts, osteocytes and osteoclasts in different skeleton regions. The specific function and regulatory mechanisms of Klotho in long bone and craniofacial bone vary due to their different embryonic development, ossification and cell types, which remain unclear and without conclusion. Moreover, studies have confirmed that Klotho is a multifunctional protein that can inhibit inflammation, resist cancer and regulate the endocrine system, which may further accentuate the potential of Klotho to be the ideal molecule in inducing bone restoration clinically. Besides, as an endogenous protein, Klotho has a promising potential for clinical therapy without side effects. In the current review, we summarized the specific function of Klotho in long bone and craniofacial skeleton from phenotype to cellular alternation and signaling pathway. Moreover, we illustrated the possible future clinical application for Klotho. Further research on Klotho might help to solve the existing clinical difficulties in bone healing and increase the life quality of patients with bone injury and the elderly.

Diabetic nephropathy (DN) is a leading cause of chronic kidney disease (CKD), which is characterized by mesangial matrix expansion that involves dysfunctional mesangial cells (MCs). However, the underlying mechanisms remain unclear. This study aims to delineate the spatiotemporal contribution of adrenergic signalling in diabetic kidney fibrosis to reveal potential therapeutic targets.

A model of diabetic nephropathy was induced by in db/db mice. Gene expression in kidneys was profiled by RNA-seq analyses, western blot and immunostaining. Subcellular-localized fluorescence resonance energy transfer (FRET) biosensors determined adrenergic signalling microdomains in MCs. Effects of oral rolipram, a phosphodiesterase 4 (PDE4) inhibitor, on the model were measured.

Our model exhibited impaired kidney function with elevated expression of adrenergic and fibrotic genes, including Adrb1, PDEs, Acta2 and Tgfβ. RNA-seq analysis revealed that MCs with dysregulated YAP pathway were crucial to the extracellular matrix secretion in kidneys from diabetic nephropathy patients. In cultured MCs, TGF-β promoted profibrotic gene transcription, which was regulated by nuclear-localized β-adrenoceptor signalling. Mechanistically, TGF-β treatment diminished nuclear-specific cAMP signalling in MCs and reduced PKA-dependent phosphorylation of YAP, leading to its activation. In parallel, db/db mouse kidneys showed increased expressions of PDE4B and PDE4D. Treatment with oral rolipram alleviated kidney fibrosis in db/db mice.

Diabetic nephropathy impaired nuclear-localized β1-adrenoceptor-cAMP signalling microdomain through upregulating PDE4 expression, promoting fibrosis in MCs via PKA dephosphorylation-dependent YAP activation. Our results suggest PDE4 inhibition as a promising strategy for alleviating kidney fibrosis in diabetic nephropathy.

Klotho, a key component of the endocrine fibroblast growth factor receptor-fibroblast growth factor axis, is a multi-functional protein that impacts renal electrolyte handling. The physiological significance of Klotho will be highlighted in the regulation of calcium, phosphate, and potassium metabolism.

In this review, we compare several murine models with different renal targeted deletions of Klotho and the insights into the molecular and physiological function that these models offer.

In vivo, Klotho deficiency is associated with severely impaired mineral metabolism, with consequences on growth, longevity and disease development. Additionally, we explore the perspectives of Klotho in renal pathology and vascular events, as well as potential Klotho treatment options.

This comprehensive review emphasizes the use of Klotho to shed light on deciphering the renal molecular in vivo mechanisms in electrolyte handling, as well as novel therapeutic interventions.

The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It is produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia and other anomalies. Importantly, it is associated with chronic pathologies (often age-related) that have an inflammatory component. This includes atherosclerosis, diabetes and Alzheimer's disease. Its mode of action in these diseases is not well understood, but it inhibits or regulates multiple major pathways. Klotho has a membrane form and a soluble form (s-Klotho). Cytosolic Klotho is postulated but not well characterized. s-Klotho has endocrine properties that are incompletely elucidated. It binds to the FGF receptor 1c (FGFR1c) that is widely expressed (including endothelial cells). It also attaches to soluble FGF23, and FGF23/Klotho binds to FGFRs. Thus, s-Klotho might be a roaming FGF23 coreceptor, but it has other functions. Notably, Klotho (cell-bound or soluble) counteracts inflammation and appears to mitigate related aging (inflammaging). It inhibits NF-κB and the NLRP3 inflammasome. This inflammasome requires priming by NF-κB and produces active IL-1β, membrane pores and cell death (pyroptosis). In accord, Klotho countered inflammation and cell injury induced by toxins, damage-associated molecular patterns (DAMPs), cytokines, and reactive oxygen species (ROS). s-Klotho also blocks the TGF-β receptor and Wnt ligands, which lessens fibrotic disease. Low Klotho is associated with loss of muscle mass (sarcopenia), as occurs in aging and chronic diseases. s-Klotho counters the inhibitory effects of myostatin and TGF-β on muscle, reduces inflammation, and improves muscle repair following injury. The inhibition of TGF-β and other factors may also be protective in diabetic retinopathy and age-related macular degeneration (AMD). This review examines Klotho functions especially as related to inflammation and potential applications.

Chronic kidney disease presents global health challenges, with hemodialysis as a common treatment. However, non-dialyzable uremic toxins demand further investigation for new therapeutic approaches. Renal tubular cells require scrutiny due to their vulnerability to uremic toxins.

In this study, a systems biology approach utilized transcriptomics data from healthy renal tubular cells exposed to healthy and post-dialysis uremic plasma.

Differential gene expression analysis identified 983 up-regulated genes, including 70 essential proteins in the protein-protein interaction network. Modularity-based clustering revealed six clusters of essential proteins associated with 11 pathological pathways activated in response to non-dialyzable uremic toxins.

Notably, WNT1/11, AGT, FGF4/17/22, LMX1B, GATA4, and CXCL12 emerged as promising targets for further exploration in renal tubular pathology related to non-dialyzable uremic toxins. Understanding the molecular players and pathways linked to renal tubular dysfunction opens avenues for novel therapeutic interventions and improved clinical management of chronic kidney disease and its complications.

Environmental exposure of arsenic impairs the cardiometabolic profile, skeletal muscle health, and neurological function. Such declining tissue health is observed as early as in one's childhood, where the exposure is prevalent, thereby accelerating the effect of time's arrow. Despite the known deleterious effects of arsenic exposure, there is a paucity of specific treatment plans for restoring tissue function in exposed individuals. In this review, we propose to harness the untapped potential of existing regenerative rehabilitation programs, such as stem cell therapeutics with rehabilitation, acellular therapeutics, and artificial intelligence/robotics technologies, to address this critical gap in environmental toxicology. With regenerative rehabilitation techniques showing promise in other injury paradigms, fostering collaboration between these scientific realms offers an effective means of mitigating the detrimental effects of arsenic on tissue function.

Klotho is a membrane protein predominantly expressed in the kidneys, and its discovery was serendipitously made through gene-targeting experiments conducted on mice. Klotho has a favorable role in the regulation of multiple cellular processes, such as aging, oxidative stress, inflammation, and apoptosis. This regulation occurs through the targeting of diverse signaling molecules, cell membrane receptors, and ion channels, achieved by physical contacts or enzymatic activities of Klotho. This review examines the role of Klotho in the epigenetic regulation of molecules associated with diabetes.

Authors conducted a thorough literature search using the PubMed®, Web of Science™, and Scopus®. Relevant articles up to September 2023, published in the English language were considered. We reviewed research databases searching for studies that included keywords klotho, epigenetic, and diabetes.

14 related papers about epigenetic modification of proteins involved in diabetes pathogenesis were selected to be included in this narrative review. In the studies, the kidney was the most investigated organ regarding this correlation. Also, phosphorylation and methylation were the common epigenetic modifications of proteins by Klotho.

Klotho has a significant role in the maturation of adipocytes and the regulation of systemic glucose metabolism, exhibiting a strong association with the pathogenesis of diabetes. Both epigenetic alterations and the modulation of protein phosphorylation by Klotho play significant roles in the regulation of Klotho expression and the modulation of other molecules implicated in the etiology of diabetes.

Podocyte damage is the major cause of glomerular injury and proteinuria in multiple chronic kidney diseases. Metadherin (MTDH) is involved in podocyte apoptosis and promotes renal tubular injury in mouse models of diabetic nephropathy and renal fibrosis; however, its role in podocyte injury and proteinuria needs further exploration. Here, we show that MTDH was induced in the glomerular podocytes of patients with proteinuric chronic kidney disease and correlated with proteinuria. Podocyte-specific knockout of MTDH in mice reversed proteinuria, attenuated podocyte injury, and prevented glomerulosclerosis after advanced oxidation protein products challenge or adriamycin injury. Furthermore, specific knockout of MTDH in podocytes repressed β-catenin phosphorylation at the Ser675 site and inhibited its downstream target gene transcription. Mechanistically, on the one hand, MTDH increased cAMP and then activated protein kinase A (PKA) to induce β-catenin phosphorylation at the Ser675 site, facilitating the nuclear translocation of MTDH and β-catenin; on the other hand, MTDH induced the deaggregation of pyruvate kinase M2 (PKM2) tetramers and promoted PKM2 monomers to enter the nucleus. This cascade of events leads to the formation of the MTDH/PKM2/β-catenin/CBP/TCF4 transcription complex, thus triggering TCF4-dependent gene transcription. Inhibition of PKA activity by H-89 or blockade of PKM2 deaggregation by TEPP-46 abolished this cascade of events and disrupted transcription complex formation. These results suggest that MTDH induces podocyte injury and proteinuria by assembling the β-catenin-mediated transcription complex by regulating PKA and PKM2 function.

The senescence of renal tubular epithelial cells (RTECs) is crucial in the progression of diabetic kidney disease (DKD). Accumulating evidence suggests a close association between insufficient mitophagy and RTEC senescence. Yeast mitochondrial escape 1-like 1 (YME1L), an inner mitochondrial membrane metalloprotease, maintains mitochondrial integrity. Its functions in DKD remain unclear. Here, we investigated whether YME1L can prevent the progression of DKD by regulating mitophagy and cellular senescence.

We analyzed YME1L expression in renal tubules of DKD patients and mice, explored transcriptomic changes associated with YME1L overexpression in RTECs, and assessed its impact on RTEC senescence and renal dysfunction using an HFD/STZ-induced DKD mouse model. Tubule-specific overexpression of YME1L was achieved through the use of recombinant adeno-associated virus 2/9 (rAAV 2/9). We conducted both in vivo and in vitro experiments to evaluate the effects of YME1L overexpression on mitophagy and mitochondrial function. Furthermore, we performed LC-MS/MS analysis to identify potential protein interactions involving YME1L and elucidate the underlying mechanisms.

Our findings revealed a significant decrease in YME1L expression in the renal tubules of DKD patients and mice. However, tubule-specific overexpression of YME1L significantly alleviated RTEC senescence and renal dysfunction in the HFD/STZ-induced DKD mouse model. Moreover, YME1L overexpression exhibited positive effects on enhancing mitophagy and improving mitochondrial function both in vivo and in vitro. Mechanistically, our LC-MS/MS analysis uncovered a crucial mitophagy receptor, BCL2-like 13 (BCL2L13), as an interacting partner of YME1L. Furthermore, YME1L was found to promote the phosphorylation of BCL2L13, highlighting its role in regulating mitophagy.

This study provides compelling evidence that YME1L plays a critical role in protecting RTECs from cellular senescence and impeding the progression of DKD. Overexpression of YME1L demonstrated significant therapeutic potential by ameliorating both RTEC senescence and renal dysfunction in the DKD mice. Moreover, our findings indicate that YME1L enhances mitophagy and improves mitochondrial function, potentially through its interaction with BCL2L13 and subsequent phosphorylation. These novel insights into the protective mechanisms of YME1L offer a promising strategy for developing therapies targeting DKD.

The aim of this study was to explore the renoprotective effects of Klotho on podocyte injury mediated by complement activation and autoantibodies in idiopathic membranous nephropathy (IMN).

Rat passive Heymann nephritis (PHN) was induced as an IMN model. Urine protein levels, serum biochemistry, kidney histology, and podocyte marker levels were assessed. In vitro, sublytic podocyte injury was induced by C5b-9. The expression of Klotho, transient receptor potential channel 6 (TRPC6), and cathepsin L (CatL); its substrate synaptopodin; and the intracellular Ca2+ concentration were detected via immunofluorescence. RhoA/ROCK pathway activity was measured by an activity quantitative detection kit, and the protein expression of phosphorylated-LIMK1 (p-LIMK1) and p-cofilin in podocytes was detected via Western blotting. Klotho knockdown and overexpression were performed to evaluate its role in regulating the TRPC6/CatL pathway.

PHN rats exhibited proteinuria, podocyte foot process effacement, decreased Klotho and Synaptopodin levels, and increased TRPC6 and CatL expression. The RhoA/ROCK pathway was activated by the increased phosphorylation of LIMK1 and cofilin. Similar changes were observed in C5b-9-injured podocytes. Klotho knockdown exacerbated podocyte injury, while Klotho overexpression partially ameliorated podocyte injury.

Klotho may protect against podocyte injury in IMN patients by inhibiting the TRPC6/CatL pathway. Klotho is a potential target for reducing proteinuria in IMN patients.

Epithelial-mesenchymal transition (EMT) is an important biological process contributing to kidney fibrosis and chronic kidney disease. This process is characterized by decreased epithelial phenotypes/markers and increased mesenchymal phenotypes/markers. Tubular epithelial cells (TECs) are commonly susceptible to EMT by various stimuli, for example, transforming growth factor-β (TGF-β), cellular communication network factor 2, angiotensin-II, fibroblast growth factor-2, oncostatin M, matrix metalloproteinase-2, tissue plasminogen activator (t-PA), plasmin, interleukin-1β, and reactive oxygen species. Similarly, glomerular podocytes can undergo EMT via these stimuli and by high glucose condition in diabetic kidney disease. EMT of TECs and podocytes leads to tubulointerstitial fibrosis and glomerulosclerosis, respectively. Signaling pathways involved in EMT-mediated kidney fibrosis are diverse and complex. TGF-β1/Smad and Wnt/β-catenin pathways are the major venues triggering EMT in TECs and podocytes. These two pathways thus serve as the major therapeutic targets against EMT-mediated kidney fibrosis. To date, a number of EMT inhibitors have been identified and characterized. As expected, the majority of these EMT inhibitors affect TGF-β1/Smad and Wnt/β-catenin pathways. In addition to kidney fibrosis, these EMT-targeted antifibrotic inhibitors are expected to be effective for treatment against fibrosis in other organs/tissues.

Introduction: The severe cases of COVID-19, a disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), often present with acute kidney injury (AKI). Although old age and preexisting medical conditions have been identified as principal risk factors for COVID-19-associated AKI, the molecular basis behind such a connection remains unknown. In this study, we investigated the pathogenic role of Klotho deficiency in COVID-19-associated AKI and explored the therapeutic potential of Klotho-derived peptide 1 (KP1). Methods: We assessed the susceptibility of Klotho deficient Kl/Kl mice to developing AKI after expression of SARS-CoV-2 N protein. The role of KP1 in ameliorating tubular injury was investigated by using cultured proximal tubular cells (HK-2) in vitro and mouse model of ischemia-reperfusion injury (IRI) in vivo. Results: Renal Klotho expression was markedly downregulated in various chronic kidney disease (CKD) models and in aged mice. Compared to wild-type counterparts, mutant KL/KL mice were susceptible to overexpression of SARS-CoV-2 N protein and developed kidney lesions resembling AKI. In vitro, expression of N protein alone induced HK-2 cells to express markers of tubular injury, cellular senescence, apoptosis and epithelial-mesenchymal transition, whereas both KP1 and Klotho abolished these lesions. Furthermore, KP1 mitigated kidney dysfunction, alleviated tubular injury and inhibited apoptosis in AKI model induced by IRI and N protein. Conclusion: These findings suggest that Klotho deficiency is a key determinant of developing COVID-19-associated AKI. As such, KP1, a small peptide recapitulating Klotho function, could be an effective therapeutic for alleviating AKI in COVID-19 patients.

Klotho, a 1012 amino acid transmembrane protein, is a potent tumor suppressor in different cancer types. Klotho is composed of two internal repeats KL1 and KL2, and the tumor suppressor activity is primarily attributed to the KL1 domain. Despite its significant role in regulating various cancer-related pathways, the precise mechanism underlying its tumor suppressor activity remains unresolved. In this study, we aimed to identify the sequence responsible for the tumor suppressor function of Klotho and gain insights into its mechanism of action. To accomplish this, we generated expression vectors of truncated KL1 at the C and N-terminal regions and evaluated their ability to inhibit the colony formation of several cancer cell lines. Our findings demonstrated that truncated KL1 1-340 (KL340) effectively inhibited colony formation similar to KL1, while truncated KL1 1-320 (KL320) lost this activity. Furthermore, this correlated with the inhibitory effect of KL1 and KL340 on the Wnt/β-catenin pathway, whereas KL320 had no effect. Transcriptomic analysis of MCF-7 cells expressing the constructs revealed enriched pathways associated with tumor suppressor activity in KL1 and KL340. Interestingly, the α-fold predictor tool highlighted distinct differences in the α and β sheets of the TIM barrel fold of the truncated Klotho constructs, adding to our understanding of their structural variations. In summary, this study identified the 340 N-terminal amino acids as the sequence that possesses Klotho's tumor suppressor activity and reveals a critical role in the 320-340 sequence for this function. It also provides a foundation for the development of Klotho-based therapeutic approaches for cancer treatment.

The increasing recreational use of ecstasy (MDMA) poses significant risks to human health, including reports of fatal renal failure due to its adverse renal effects. While MDMA-induced renal toxicity might result from systemic effects, there is also substantial evidence of direct harm to renal tissues by MDMA or its metabolites. The precise mechanisms underlying renal toxicity remain unclear. This study explored the impact of a single intraperitoneal dose of MDMA (20 mg/kg) on rat kidneys. Serum BUN and creatinine levels were evaluated to assess renal function, while TNF-α and TGF-β protein concentrations were measured using ELISA. mRNA levels of Bax, Bcl-xl, and Bcl-2 were quantified using quantitative RT-PCR. Additionally, apoptosis and histopathological changes in renal tissue were examined. Results showed a transient increase in serum BUN and creatinine in MDMA-treated rats. There were decreases in TNF-α and TGF-β levels in the renal tissue. Both pro-apoptotic Bax and anti-apoptotic Bcl-xl gene expressions were significantly reduced, whereas Bcl-2 expression and apoptosis did not show significant changes. No structural alterations were observed in the renal tissues. Overall, this study suggests that the renal adverse effects of MDMA may be mediated through the disruption of cytokine pathways, with notable reductions in TGF-β possibly linked to decreased TNF-α levels.

Peptides and peptide aptamers have emerged as promising molecules for a wide range of biomedical applications due to their unique properties and versatile functionalities. The screening strategies for identifying peptides and peptide aptamers with desired properties are discussed, including high-throughput screening, display screening technology, and in silico design approaches. The synthesis methods for the efficient production of peptides and peptide aptamers, such as solid-phase peptide synthesis and biosynthesis technology, are described, along with their advantages and limitations. Moreover, various modification techniques are explored to enhance the stability, specificity, and pharmacokinetic properties of peptides and peptide aptamers. This includes chemical modifications, enzymatic modifications, biomodifications, genetic engineering modifications, and physical modifications. Furthermore, the review highlights the diverse biomedical applications of peptides and peptide aptamers, including targeted drug delivery, diagnostics, and therapeutic. This review provides valuable insights into the advancements in screening, synthesis, modification, and biomedical applications of peptides and peptide aptamers. A comprehensive understanding of these aspects will aid researchers in the development of novel peptide-based therapeutics and diagnostic tools for various biomedical challenges.

Cervical cancer (CC) seriously affects women's health. Therefore, elucidation of the exact mechanisms and identification of novel therapeutic targets are urgently needed. In this study, we identified FAM83F, which was highly expressed in CC cells and tissues, as a potential target. Our clinical data revealed that FAM83F protein expression was markedly elevated in CC tissues and was positively correlated with poor prognosis. Moreover, we observed that FAM83F knockdown significantly inhibited cell proliferation, induced apoptosis, and suppressed glycolysis in CC cells, while its overexpression displayed opposite effects. Mechanistically, FAM83F regulated CC cell growth and glycolysis by the modulation of Wnt/β-catenin pathway. The enhancing effects of FAM83F overexpression on CC cell proliferation and glycolysis could be impaired by the Wnt/β-catenin inhibitor XAV939. Moreover, we found that c-Myc bound to the FAM83F promoter and activated the transcription of FAM83F. Notably, knockdown of FAM83F impaired the enhancement of cell proliferation and glycolysis induced by ectopic c-Myc. Consistent with in vitro findings, results from a xenograft mouse model confirmed the promoting role of FAM83F. In summary, our study demonstrated that FAM83F promoted CC growth and glycolysis through regulating the Wnt/β-catenin pathway, suggesting that FAM83F may be a potential molecular target for CC treatment. Schematic summary of c-Myc-activated FAM83F transcription to promote cervical cancer growth and glycolysis by targeting the Wnt/β-catenin signal pathway.

Podocytes, the key component of the glomerular filtration barrier (GFB), are gradually lost during the progression of diabetic kidney disease (DKD), severely compromising kidney functionality. The molecular mechanisms regulating the survival of podocytes in DKD are incompletely understood. Here, we show that membrane-associated guanylate kinase inverted 2 (MAGI2) is specifically expressed in renal podocytes, and promotes podocyte survival in DKD. We found that MAGI2 expression was downregulated in podocytes cultured with high-glucose in vitro, and in kidneys of db/db mice as well as DKD patients. Conversely, we found enforced expression of MAGI2 via AAV transduction protected podocytes from apoptosis, with concomitant improvement of renal functions. Mechanistically, we found that MAGI2 deficiency induced by high glucose levels activates TGF-β signaling to decrease the expression of anti-apoptotic proteins. These results indicate that MAGI2 protects podocytes from cell death, and can be harnessed therapeutically to improve renal function in diabetic kidney disease.

Podocyte injury is a hallmark of glomerular disease and one of the leading causes of chronic kidney disease (CKD). Peroxisome proliferator-activated receptor α (PPARα) plays a key role in podocyte fatty acid oxidation (FAO). However, the underlying regulatory mechanisms remain unresolved. Trim63 is an E3 ubiquitin ligase that has been shown to inhibit PPARα activity; however, its role in fatty acid metabolism in the kidney has not been elucidated to date. In this study, we investigated the effects of overexpression and knockdown of Trim63 in Adriamycin (ADR)-induced nephropathy and diabetic nephropathy models and a podocyte cell line. In both rodents and human patients with proteinuric CKD, Trim63 was upregulated, particularly in the podocytes of injured glomeruli. In the ADR-induced nephropathy model, ectopic Trim63 application aggravated FAO deficiency and mitochondrial dysfunction and triggered intense lipid deposition, podocyte injury, and proteinuria. Notably, Trim63 inhibition alleviated FAO deficiency and mitochondrial dysfunction, and markedly restored podocyte injury and renal fibrosis in ADR-induced and diabetic nephropathy (DN) models. Additionally, Trim63 was observed to mediate PPARα ubiquitination and degradation, leading to podocyte injury. We demonstrate the pathological role of Trim63, which was previously unrecognized in kidney tissue, in FAO deficiency and podocyte injury. Targeting Trim63 may represent a viable therapeutic strategy for podocyte injury and proteinuria.

Diabetic kidney disease (DKD) is characterized by the abnormal deposition of oxidized low-density lipoprotein (ox-LDL), which contributes to podocyte damage. Klotho, an aging suppressor that plays a critical role in protecting podocytes in DKD, is mainly expressed in kidney tubular epithelium and secreted in the blood. However, it has not been established whether Klotho can alleviate podocyte injury by inhibiting renal ox-LDL deposition, and the potential molecular mechanisms require further investigation.

We conducted a comprehensive analysis of serum and kidney biopsy samples obtained from patients diagnosed with DKD. Additionally, to explore the underlying mechanism of Klotho in the deposition of ox-LDL in the kidneys, we employed a mouse model of DKD with the Klotho genotype induced by streptozotocin (STZ). Furthermore, we conducted meticulous in vitro experiments on podocytes to gain further insights into the specific role of Klotho in the deposition of ox-LDL within the kidney.

Our groundbreaking study unveiled the remarkable ability of the soluble form of Klotho to effectively inhibit high glucose-induced ox-LDL deposition in podocytes affected by DKD. Subsequent investigations elucidated that Klotho achieved this inhibition by reducing the expression of the insulin/insulin-like growth factor 1 receptor (IGF-1R), consequently leading to a decrease in the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1) and an enhancement of mitochondrial function. Ultimately, this series of events culminated in a significant reduction in the expression of the oxidized low-density lipoprotein receptor (OLR1), thereby resulting in a notable decrease in renal ox-LDL deposition in DKD.

Our findings suggested that Klotho had the potential to mitigate podocyte injury and reduced high glucose-induced ox-LDL deposition in glomerulus by modulating the IGF-1R/RAC1/OLR1 signaling. These results provided valuable insights that could inform the development of novel strategies for diagnosing and treating DKD.

Kidney disease is highly prevalent and affects approximately 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 because of 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 AKI, CKD, 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.

Renal fibrosis is a common pathological feature of chronic kidney disease (CKD) with various etiologies, which seriously affects the structure and function of the kidney. Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily and plays a critical role in regulating the genes related to xenobiotic and endobiotic metabolism in mammals. Previous studies show that PXR is expressed in the kidney and has protective effect against acute kidney injury (AKI). In this study, we investigated the role of PXR in CKD. Adenine diet-induced CKD (AD) model was established in wild-type and PXR humanized (hPXR) mice, respectively, which were treated with pregnenolone-16α-carbonitrile (PCN, 50 mg/kg, twice a week for 4 weeks) or rifampicin (RIF, 10 mg·kg-1·d-1, for 4 weeks). We showed that both PCN and RIF, which activated mouse and human PXR, respectively, improved renal function and attenuated renal fibrosis in the two types of AD mice. In addition, PCN treatment also alleviated renal fibrosis in unilateral ureter obstruction (UUO) mice. On the contrary, PXR gene deficiency exacerbated renal dysfunction and fibrosis in both adenine- and UUO-induced CKD mice. We found that PCN treatment suppressed the expression of the profibrotic Wnt7a and β-catenin in AD mice and in cultured mouse renal tubular epithelial cells treated with TGFβ1 in vitro. We demonstrated that PXR was colocalized and interacted with p53 in the nuclei of tubular epithelial cells. Overexpression of p53 increased the expression of Wnt7a, β-catenin and its downstream gene fibronectin. We further revealed that p53 bound to the promoter of Wnt7a gene to increase its transcription and β-catenin activation, leading to increased expression of the downstream profibrotic genes, which was inhibited by PXR. Taken together, PXR activation alleviates renal fibrosis in mice via interacting with p53 and inhibiting the Wnt7a/β-catenin signaling pathway.