In clinical practice, sodium-glucose transporter 2 inhibitor (SGLT2i) reduces the composite renal outcomes in patients with diabetic kidney disease (DKD). However, its effect on regulating renal mitochondria remains unclear. Mitochondrial quality control (MQC) has been identified as a key factor in DKD. Peroxiredoxin3 (Prdx3) serves as a primary antioxidant protein in mitochondria. In this study, we investigated the expression of Prdx3 in patients with DKD, diabetic mice and HK-2 cells exposed to high glucose and explored SGLT2i potential mechanism of action. The results also showed that empagliflozin (Empa) treatment improved proteinuria and ameliorated renal pathological damage. We observed that Empa has an impact on the expression of Prdx3 in diabetic mice and HK-2 cells exposed to high glucose, so does the mitochondrial dynamic proteins and mitophagy-related proteins Mfn2, Drp1, PINK1, Parkin, LC3II, and P62. In vitro experiments after transfected with pcDNA3.1(+)-Prdx3 and siPrdx3 the expression of Mfn2, Drp1, PINK1, Parkin, LC3II, and P62 changed. The expression of PINK1 decreased after the knockdown of Prdx3. Furthermore, the knockdown of PINK1 accelerated the MQC damage and weakened the protective effect of Empa. Because Empa has impacts on Prdx3, which plays a protective role by influencing MQC, we investigated the latent impact of Prdx3 deficiency on renal injury and its molecular mechanism in vivo and in vitro in DKD. Herein, we demonstrate that Empa treatment modulates MQC potentially via Prdx3 through interacting with PINK1.

Mitophagy, the selective removal of damaged mitochondria, plays a critical role in kidney diseases, but its involvement in hypertensive nephropathy (HTN) is not well understood. To address this gap, we investigated mitophagy-related genes in HTN, identifying potential biomarkers for diagnosis and treatment. Transcriptome datasets from the Gene Expression Omnibus database were analyzed, resulting in the identification of seven mitophagy related differentially expressed genes (MR-DEGs), namely PINK1, ULK1, SQSTM1, ATG5, ATG12, MFN2, and UBA52. Further, we explored the correlation between MR-DEGs, immune cells, and inflammatory factors. The identified genes demonstrated a strong correlation with Mast cells, T-cells, TGFβ3, IL13, and CSF3. Machine learning techniques were employed to screen important genes, construct diagnostic models, and evaluate their accuracy. Consensus clustering divided the HTN patients into two mitophagy subgroups, with Subgroup 2 showing higher levels of immune cell infiltration and inflammatory factors. The functions of their proteins primarily involve complement, coagulation, lipids, and vascular smooth muscle contraction. Single-cell RNA sequencing revealed that mitophagy was most significant in proximal tubule cells (PTC) in HTN patients. Pseudotime analysis of PTC confirmed the expression changes observed in the transcriptome. Intercellular communication analysis suggested that mitophagy might regulate PTC's participation in intercellular crosstalk. Notably, specific transcription factors such as HNF4A, PPARA, and STAT3 showed strong correlations with mitophagy-related genes in PTC, indicating their potential role in modulating PTC function and influencing the onset and progression of HTN. This study offers a comprehensive analysis of mitophagy in HTN, enhancing our understanding of the pathogenesis, diagnosis, and treatment of HTN.

Diabetic kidney disease (DKD) is one of the main types of chronic kidney disease, which seriously affects the quality of life of patients. Shen-Qi-Huo-Xue formula (SQHXF), based on the Shen-Qi-Di-Huang decoction, is a traditional Chinese medicine formula for DKD. This study explored the mechanism of action of SQHXF on DKD through analysis of drug components, in vivo and in vitro experiments.

To elucidate the regulatory mechanisms of HIF-1α/HIF-2α homeostasis on ferroptosis and epithelial-mesenchymal transition (EMT) in renal tubular epithelial cells and the mechanism of action of SQHXF against DKD.

The components of SQHXF were analyzed using UPLC-Q Exactive HF/MS. The effects of SQHXF on renal function, urinary proteins, glucose-lipid metabolism, hepatic function, renal tissue hypoxia, ferroptosis and EMT were analyzed following gavage of DKD model mice with different SQHXF doses. The effects of changes in HIF-1α and HIF-2α expression on ferroptosis and EMT, as well as the modulatory effects of SQHXF-containing serum, were assessed in vitro. The potential feedback mechanism of HIFs/ferroptosis/EMT was elucidated using HIF-1α knockdown and a ferroptosis inhibitor.

One-hundred and fifty compounds in SQHXF were tested for bloodstream entry. In vivo study showed that SQHXF was able to reduce creatinine, uric acid, fasting plasma glucose, 24-h urinary protein, low-density lipoprotein cholesterol, and aspartate aminotransferase levels, up-regulate HIF-1α, down-regulate HIF-2α, reduce ferroptosis, and alleviate renal fibrosis and EMT in tubular epithelial cells. HIF-1α/HIF-2α imbalance promoted ferroptosis and EMT in HK-2 cells, which was attenuated by SQHXF-containing serum. HIF-1α knockdown decreased HIF-2α expression and reduced ferroptosis and EMT. Inhibition of ferroptosis reduced EMT but failed to regulate HIF-1α and HIF-2α.

SQHXF alleviated ferroptosis and EMT, improved liver and kidney function, reduced proteinuria, and alleviated renal lesions by maintaining equilibrium between HIF-1α and HIF-2α.

Hyperglycemia-induced inflammation and fibrosis in renal tubular epithelial cells are critical factors driving the progression of diabetic nephropathy (DN). Celastrol, a bioactive compound derived from Tripterygium wilfordii Hook.F, is recognized for its anti-inflammatory and anti-fibrotic properties. This study aimed to investigate the renoprotective effects of celastrol against high glucose (HG)-induced damage in human kidney 2 (HK-2) cells. Briefly, HK-2 cells were exposed to high glucose and treated with celastrol. Cell viability and apoptosis were evaluated using CCK-8 assay kit and flow cytometry, respectively. The pro-inflammatory cytokines, oxidative stress markers, and fibrotic-related proteins were measured using ELISA and immunoblotting. To further confirm the mechanistic actions of celastrol, the PI3K/Akt/NF-κB pathway was examined, and HG-treated cells were co-incubated with the NF-κB inhibitor bortezomib. Our result revealed that celastrol at the moderate concentration of 50 nM mitigated HG-induced toxicity, suggesting an optimal therapeutic window. Celastrol improved cell viability and reduced apoptosis in HG-treated HK-2 cells. It significantly decreased levels of inflammatory cytokines such as IL-6, TNF-α, IL-1β, and MCP-1, while enhancing antioxidant activities of GSH-Px and SOD, and lowering MDA levels, indicating diminished oxidative stress. Mechanistically, these renoprotective effects of celastrol partly attributed via inhibition of the PI3K/Akt/NF-κB signalling pathway, as blocking NF-κB signalling by bortezomib resulted in similar inhibitory effects against inflammation and fibrosis. Collectively, celastrol acts as a renoprotective agent against renal inflammation, oxidative stress, and fibrosis, partly through the inhibition of the PI3K/Akt/NF-κB pathway, offering potential therapeutic benefits against hyperglycemia-induced renal injury in DN.

Models of kidney injury have classically concentrated on glomeruli as the primary site of injury leading to glomerulosclerosis or on tubules as the primary site of injury leading to tubulointerstitial fibrosis. However, current evidence on the mechanisms of progression of chronic kidney disease indicates that a complex interplay between glomeruli and tubules underlies progressive kidney injury. Primary glomerular injury can clearly lead to subsequent tubule injury. For example, damage to the glomerular filtration barrier can expose tubular cells to serum proteins, including complement and cytokines, that would not be present in physiological conditions and can promote the development of tubulointerstitial fibrosis and progressive decline in kidney function. In addition, although less well-studied, increasing evidence suggests that tubule injury, whether primary or secondary, can also promote glomerular damage. This feedback from the tubule to the glomerulus might be mediated by changes in the reabsorptive capacity of the tubule, which can affect the glomerular filtration rate, or by mediators released by injured proximal tubular cells that can induce damage in both podocytes and parietal epithelial cells. Examining the crosstalk between the various compartments of the kidney is important for understanding the mechanisms underlying kidney pathology and identifying potential therapeutic interventions.

Exosomes play a role in cell communication by transporting content between cells. Here, we tested whether renal podocyte-derived exosomes affect the injury of glomerular endothelial cells in lupus nephritis (LN). We found that exosomes containing high levels of high mobility group protein B1 (HMGB1) were released from podocytes in patients with LN, BALB/c mice injected with pristane (which induces lupus-like disease in mice), and cultured human renal glomerular endothelial cells (HRGECs) treated with LN plasma. In vitro, GW4869 (an inhibitor of exosome biogenesis/release) or exosome removal alleviated the injury of HRGECs induced by LN plasma. Additionally, leptomycin B or knockdown of HMGB1 in podocyte-derived exosomes reduced endothelial cell injury and the expression of tripartite motif-containing protein 27 (TRIM27). Knockdown or overexpression of TRIM27 attenuated or promoted the damage of HRGECs treated with LN plasma. In vivo, knockdown of HMGB1 in podocytes ameliorated the injury of glomerular endothelial cells in a mouse model of LN. Furthermore, the injection of podocyte-derived exosomes into mice caused glomerular endothelial cell dysfunction. In conclusion, our study revealed that podocyte-derived exosomes may mediate the injury of glomerular endothelial cells seen in LN.

Growth differentiation factor 15 (GDF-15) is a cytokine involved in regulating homeostasis, and its expression is up-regulated in response to injury, stress, and inflammation. This study explored the role of GDF-15 in diabetic nephropathy (DN), a severe complication of diabetes mellitus, and its potential as a biomarker for disease progression.

As a member of the transforming growth factor-β superfamily, GDF-15 exhibits its renal protective functions primarily through its anti-inflammatory effects and the up-regulation of other renal protective factors. This study evaluated the association between circulating GDF-15 levels and DN progression, examining the underlying mechanisms.

Circulating GDF-15 levels are closely linked to the development and progression of DN. While existing research has yielded some consistent conclusions, a comprehensive understanding of the role of GDF-15 in DN pathogenesis is needed to identify new therapeutic targets and strategies.

GDF-15 has the potential to be a prognostic and diagnostic biomarker for DN. It is crucial to establish appropriate reference ranges and explore their clinical utility in routine practice for validating the role of GDF-15 in DN management. Further interventional studies are required to confirm its clinical value in diagnosing and predicting the progression of DN.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Therefore, understanding the molecular regulatory mechanisms underlying the pathogenesis of DKD is imperative. In this study, we aimed to explore the molecular mechanisms of tubule region endothelial dysfunction in early DKD. Early-stage DKD model was established in 16-week-old female db/db mice for 16 weeks. Body weight, glucose level, and urine albumin-to-creatinine ratio (UACR) were measured. Hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining were performed to evaluate pathological lesions. RNA sequencing data of the kidneys and integrated publicly available single-cell and spatial transcriptome datasets were used to investigate the mechanism of endothelial dysfunction. There was a significant increase in body weight (p = 0.001), glucose levels (p=0.0008), and UACR (p=0.006) in db/db mice compared with db/m mice. H&E and PAS staining showed that vacuolar lesions and protein casts of tubules were the major histopathological changes observed in early-stage DKD mice. The apoptotic pathway in endothelial cells was notably activated in DKD, and Thbs1 was identified as the central gene involved in this apoptotic process. Deconvolution of the cell composition in the RNA sequencing data showed a decrease in the proportion of endothelial cells in the DKD mice. Further analysis of the activity and regulatory network of transcription factors showed that Creb1 was activated in both mouse and human early-stage DKD, suggesting that Creb1 activation may be involved in early kidney injury. The endothelial cell apoptotic pathway is activated in DKD, and the proportion of endothelial cells was reduced in the DKD mice, which is significantly associated with Thbs1. Keywords: Diabetic kidney disease, Endothelial dysfunction, RNA sequencing,Thbs1, Creb1.

The kidneys contribute to the overall health of an organism by maintaining systemic homeostasis. This process involves various biological mechanisms, in which the Krüppel-like factors (KLFs), a family of transcription factors, are essential for regulating development, differentiation, proliferation, and cellular apoptosis. They also play a role in the metabolic regulation of essential nutrients, such as glucose and lipids. The dysregulation of these transcription factors is associated with the development of various pathologies, which can ultimately lead to renal fibrosis, severely compromising kidney function. In this context, the present article provides a comprehensive review of the existing literature, offering an enriching analysis of the findings related to the role of KLFs in nephrology, while also highlighting their potential therapeutic role in the treatment of renal diseases.

Background: The association between diabetic nephropathy and arterial elasticity and endothelial function is well established. In this study, we compared the effect of the combination of dulaglutide and dapagliflozin versus DPP-4 inhibitors on the endothelial glycocalyx, arterial stiffness, myocardial function, and albuminuria. Methods: Overall, 60 patients were randomized to combined dulaglutide and dapagliflozin treatment (n = 30) or DPP-4 inhibitors (DPP-4i, n = 30) (ClinicalTrials.gov: NCT06611904). We measured at baseline and 4 and 12 months post-treatment: (i) the perfused boundary region of the sublingual arterial microvessels, (ii) pulse wave velocity (PWV) and central systolic blood pressure (cSBP), (iii) global left ventricular longitudinal strain (GLS), and (iv) urine albumin-to-creatinine ratio (UACR). Results: After twelve months, dual therapy showed greater improvements vs. DPP-4i in PBR (2.10 ± 0.31 to 1.93 ± 0.23 μm vs. 2.11 ± 0.31 to 2.08 ± 0.28 μm, p < 0.001), UACR (326 ± 61 to 142 ± 47 mg/g vs. 345 ± 48 to 306 ± 60 mg/g, p < 0.01), and PWV (11.77 ± 2.37 to 10.7 ± 2.29 m/s vs. 10.64 ± 2.44 to 10.54 ± 2.84 m/s, p < 0.001), while only dual therapy showed improvement in cSBP (130.21 ± 17.23 to 123.36 ± 18.42 mmHg). These effects were independent of glycemic control. Both treatments improved GLS, but the effect of dual therapy was significantly higher compared to DPP-4i (18.19% vs. 6.01%, respectively). Conclusions: Twelve-month treatment with dulaglutide and dapagliflozin showed a greater improvement in arterial stiffness, endothelial function, myocardial function, and albuminuria than DPP-4is. Early initiation of combined therapy as an add-on to metformin should be considered in these patients.

Our previous studies have demonstrated that ubiquitin-specific peptidase 22 (USP22) has the capacity to accelerate renal epithelial-to-mesenchymal transition (EMT) and promote the pathological progression of diabetic tubulointerstitial fibrosis (TIF) by regulating the ubiquitination of Snail1, an EMT transcription factor. Quercetin is a type of flavonol compound widely found in fruits and vegetables that has anti-inflammatory, antioxidant and anti-fibrosis effects. However, whether quercetin promotes the degradation of Snail1 and regulates the pathological progression of TIF by inhibiting USP22 requires further investigation. In this study, we found that quercetin significantly inhibited the expression of USP22 and Snail1 in high glucose (HG)-induced renal tubular epithelial cells (TECs), and reversed the expression of EMT-related proteins and inhibited the overproduction of fibronectin (FN) and Collage Type IV (Collagen IV) induced by high glucose. Additionally, quercetin blocked the deubiquitination of Snail1 mediated by USP22. Further study found that quercetin inhibited the interaction between USP22 and Snail1, thereby reducing the stability of Snail1. Furthermore, quercetin also reduced the protein levels of USP22 and Snail1 in the kidney tissue of diabetic mice and ameliorated renal function, delayed EMT and TIF. In conclusion, quercetin regulates the USP22-Snail1 signal pathway to inhibit the occurrence of EMT both in vitro and in vivo, and ultimately ameliorate the pathological progress of TIF.

Emerging data have revealed that damage to tubular epithelial cell is a driving force in the progression of diabetic kidney disease (DKD). However, the specific mechanisms by which lipotoxicity contributes to the injury of these cells, thereby influencing the development of DKD, are yet to be fully understood. Here, we analyzed the GSE 30529 microarray datasets of human tubulointerstitial tissue samples from the Gene Expression Omnibus database (GEO). Concurrently, we conducted RNA-sequencing on palmitic acid (PA)-treated human renal proximal tubule epithelial cells (HK2 cells). After normalization, the differentially expressed genes (DEGs) were screened by R software and gene ontology (GO) enrichment analysis was conducted, and lysosomal-associated protein transmembrane 5 (LAPTM5) was finally selected. Our findings indicate that the expression of LAPTM5 was obviously increased in DKD patients, and the correlation between LAPTM5, and other clinical parameters of DKD was analyzed using the Spearman correlation analysis. The potential of LAPTM5 as a prognostic biomarker for DKD was further consolidated through receiver operating characteristic (ROC) analysis. To further verify the function of LAPTM5, we established mouse or in vitro systems mimicking DKD. The results showed that a consistent upregulation of LAPTM5, which was also found to be linked with inflammatory mediators within the context of DKD. Additionally, LAPTM5 silencing significantly downregulated mRNA expression of inflammatory factors in PA-treated HK2 cells. These results indicate that LAPTM5 is a potential biomarker and therapeutic treatment target for DKD. This discovery paves the way for future research and development of targeted interventions aimed at mitigating the progression of this prevalent condition.

The association between serum angiopoietin-like 4 (ANGPTL4) levels and the severity of diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus remains unclear.

A total of 1,115 type 2 diabetes mellitus patients were analyzed in this cross-sectional study. DKD index included DKD stages defined by estimated glomerular filtration rate, the albuminuria grades and DKD risk management grades. Serum levels of ANGPTL4 and other biomarkers were detected. Multivariable-adjusted linear and logistic analyses were used to study the association between ANGPTL4 and DKD. The protein levels of ANGPTL4 were assessed in the kidney. Renal tubular cells were stimulated with glucose to study ANGPTL4 expression.

Compared with the participants in the third or fourth quantile of ANGPTL4, those in the first or second quantile of ANGPTL4 were younger, with lower glycated hemoglobin, triglycerides and urinary albumin creatinine ratio (all P < 0.05). There was a negative nonlinear relationship between ANGPTL4 and estimated glomerular filtration rate in type 2 diabetes mellitus patients. One standard deviation increased serum ANGPTL4 levels, the odds ratio of having DKD was 1.40 (95% confidence interval 1.08-1.80). The mediation analysis showed that triglycerides did not mediate the association between ANGPTL4 and DKD. Furthermore, ANGPTL4 could be the strongest among multiple panels of biomarkers in its association of DKD. Compared with mice at 8 weeks-of-age, db/db mice at 18 weeks-of-age had increased ANGPTL4 expression in glomeruli and tubular segments. In vitro, glucose could stimulate ANGPTL4 expression in tubular cells in a dose-dependent manner.

ANGPTL4 could be a potential marker and therapeutic target for DKD treatment.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), and its pathogenesis has not been clarified. Current research suggests that DKD involves multiple cell types and extra-renal factors, and it is particularly important to clarify the pathogenesis and identify new therapeutic targets. Single-cell RNA sequencing (scRNA-seq) technology is high-throughput sequencing of the transcriptomes of individual cells at the single-cell level, which is an effective technology for exploring the development of diseases by comparing genetic information, reflecting the differences in genetic information between cells, and identifying different cell subpopulations. Accumulating evidence supports the role of scRNA-seq in revealing the pathogenesis of diabetes and strengthening our understanding of the molecular mechanisms of DKD. We reviewed the scRNA-seq data this time. Then, we analyzed and discussed the applications of scRNA-seq technology in DKD research, including annotation of cell types, identification of novel cell types (or subtypes), identification of intercellular communication, analysis of cell differentiation trajectories, gene expression detection, and analysis of gene regulatory networks, and lastly, we explored the future perspectives of scRNA-seq technology in DKD research.

The maintenance of corneal transparency and normal vision is dependent on preservation of epithelial and endothelial cell layer homeostases. Different types of corneal injury can induce swelling and losses in transparency. Fuchs endothelial corneal dystrophy (FECD) is one type of injury that is commonly treated with rho-associated coiled-coil-containing protein kinase (ROCK) inhibitors. While their clinical benefit is apparent, certain aspects of their mechanism of action require clarification. Specifically, although topical eye drops containing ROCK inhibitors have been employed to treat corneal endothelial dysfunction-associated corneal edema, it remains unclear whether interactions between both corneal epithelial and endothelial cell contribute to mitigating clinical signs that compromise normal vision. To address this question, we first review the intricate ROCK signaling pathways and their role in modulating a variety of functions that are related to the maintenance of corneal transparency and normal vision. We also review the results of ongoing clinical trials employing current FDA-approved ROCK inhibitors, highlighting the prominent role of Y-27632 in the treatment of a variety of ocular conditions, particularly FECD, and its promising results in reversing losses in normal vision through facilitating cell proliferation and suppressing apoptosis. This review shows that the ROCK inhibitor clinical benefit is affected by their interactions between the epithelium and the endothelium. This realization makes it likely that ROCK inhibitors will be approved for use in a clinical setting to treat FECD.

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.

Diabetic nephropathy (DN) is a severe diabetic complication disorder. Circular RNAs (circRNAs) actively participate in DN pathogenesis. In this report, we sought to define a new mechanism of circ_0003928 in regulating high glucose (HG)-induced HK-2 cells.

To construct a DN cell model, we treated HK-2 cells with HG. Cell viability and apoptosis were detected by CCK-8 and flow cytometry, respectively. The inflammatory cytokines were quantified by ELISA. Protein analysis was performed by immunoblotting, and mRNA expression was detected by quantitative PCR. The circ_0003928/miR-31-5p and miR-31-5p/MAPK6 relationships were validated by RNA pull-down and luciferase assays.

HG promoted HK-2 cell apoptosis, fibrosis and oxidative stress. Circ_0003928 and MAPK6 levels were enhanced and miR-31-5p level was decreased in HK-2 cells after HG treatment. Circ_0003928 disruption promoted cell growth and inhibited apoptosis, inflammatory response, fibrosis and oxidative stress in HG-induced HK-2 cells. Circ_0003928 targeted miR-31-5p, and MAPK6 was a target of miR-31-5p. Circ_0003928 regulated MAPK6 expression through miR-31-5p. The functions of circ_0003928 disruption in HG-induced HK-2 cells were reversed by miR-31-5p downregulation or MAPK6 upregulation.

Circ_0003928 exerts regulatory impacts on HG-induced apoptosis, inflammation, fibrosis and oxidative stress in human HK-2 cells by the miR-31-5p/MAPK6 axis.

Diabetic kidney disease (DKD) is a major complication of diabetes mellitus (DM), affecting over one-third of type 1 and nearly half of type 2 diabetes patients. As the leading cause of end-stage renal disease (ESRD) globally, DKD develops through a complex interplay of chronic hyperglycemia, oxidative stress, and inflammation. Early detection is crucial, with diagnosis based on persistent albuminuria and reduced estimated glomerular filtration rate (eGFR). Treatment strategies emphasize comprehensive management, including glycemic control, blood pressure regulation, and the use of nephroprotective agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), sodium-glucose cotransporter-2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists. Ongoing research explores novel therapies targeting molecular pathways and non-coding RNAs. Preventive measures focus on rigorous control of hyperglycemia and hypertension, aiming to mitigate disease progression. Despite therapeutic advances, DKD remains a leading cause of ESRD, highlighting the need for continued research to identify new biomarkers and innovative treatments.

In this editorial, we comment on the article by Wu et al published "MicroRNA-630 alleviates inflammatory reactions in rats with diabetic kidney disease by targeting toll-like receptor 4". Diabetic kidney disease (DKD) stands as a significant complication occurring from diabetes mellitus, which contributes substantially to the morbidity and mortality rates worldwide. Renal tubular epithelial cell da-mage, often accompanied by inflammatory responses and mesenchymal trans-differentiation, plays a pivotal role in the progression of DKD. Despite extensive research, the intricate molecular mechanisms underlying these processes remain to be determined. Wu et al remarkable work identifies microRNA-630 (miR-630) as an emerging potential regulator of cell migration, apoptosis, and autophagy, prompting investigation into its association with DKD pathogenesis. This study endeavors to elucidate the impact of miR-630 on TEC injury and the inflammatory response in DKD rats. The role of miR-630 in human DKD will be of interest for future studies.

Studies have shown that Averrhoa carambola L. possesses therapeutic potential for diabetes and related complications. However, the specific beneficial effects and molecular mechanisms of 2-dodecyl-6-meth-oxycyclohexa-2,5-diene-1,4-dione (DMDD) isolated from Averrhoa carambola L. on diabetic nephropathy (DN) require further investigation.

80 C57BL/6 J male mice were subjected to a 1-week adaptive feeding, followed by a high-fat diet and intraperitoneal injection of 100 mg/kg streptozotocin (STZ) to construct an in vivo DN model. Additionally, human renal proximal tubular epithelial cells (HK-2) induced by high glucose (HG) were used as an in vitro DN model. The expression levels of epithelial-mesenchymal transition (EMT), endoplasmic reticulum stress (ERS), and autophagy-related proteins in renal tubular cells were detected by Western Blot, flow cytometry, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA) staining. Transcriptome analysis revealed was conducted to elucidate the specific mechanism of by which DMDD mitigates DN by inhibiting ERS and autophagy. HK-2 cells were transfected with IRE1α overexpression lentivirus to reveal the role of IRE1α overexpression in HG-induced HK-2.

The experimental data showed that DMDD significantly reduced blood glucose levels and improved renal pathological alterations in DN mice. Additionally, DMDD inhibited the calcium (Ca2+) pathway, manifested by decreased autophagosome formation and downregulation of LC3II/I, Beclin-1, and ATG5 expression. Moreover, in HG-induced HK-2 cells, DMDD suppressed the overexpression of GRP78, CHOP, LC3II/I, Beclin1, and ATG5. Notably, IRE1α overexpression significantly increased autophagy incidence; however, DMDD treatment subsequently reduced the expression of LC3II/I, Beclin1, and ATG5.

DMDD effectively inhibits excessive ERS and autophagy, thereby reducing renal cell apoptosis through the IRE1α pathway and Ca 2+ pathway.

Diabetic kidney disease (DKD) is becoming the most leading cause of end-stage renal disease (ESRD). Podocyte injury plays a critical role in DKD progression. Notably, mitochondrial dysfunction is crucial for podocyte injury. MicroRNAs (miRNAs) involves in various kidney diseases. Herein, we discovered miR-29b was induced in the urine of 126 patients with DKD (stage I and II), and negatively correlated with kidney function and podocyte homeostasis. Mechanically, miR-29b targeted peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a co-activator of transcription factors regulating mitochondrial biogenesis and energy metabolism. In vitro, ectopic miR-29b downregulated PGC-1α and promoted podocyte injury, while inhibition of miR-29b alleviated podocyte injury. Consistently, inhibition of miR-29b mitigated podocyte injury and preserved kidney function in ADR nephropathy and db/db mice, and overexpression of miR-29b accelerated disease. Knockout miR-29b specifically in podocyte inhibited mitochondrial dysfunction and podocyte injury. These results revealed miR-29b plays a crucial role in mitochondrial dysfunction through targeted inhibition on PGC-1α, leading to podocyte injury and DKD progression. Importantly, miR-29b could serve as a novel biomarker of podocyte injury and assists to early diagnose DKD.

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease worldwide. Recent researches have shown that circular RNAs (circRNAs) could affect the progress of DN, but the mechanism is still indistinct. In this work, we explored the roles of hsa_circ_0008360 in DN.

The levels of hsa_circ_0008360, microRNA-346 (miR-346) and Winglesstype family member 2B (WNT2B) were indicated by quantitative real-time polymerase chain reaction (qRT-PCR) in DN tissues and HK2 cells. Meanwhile, the protein level of WNT2B was quantified by Western blot analysis. Besides, the function of cells was examined by Cell Counting Kit-8 (CCK8) assay, flow cytometry assay, western blot, and ELISA kit. Furthermore, the interplay between miR-346 and hsa_circ_0008360 or WNT2B was detected by dual-luciferase reporter assay.

The levels of hsa_circ_0008360 and WNT2B were increased, and the miR-346 level was decreased in the serum of DN patients and HG-treated HK2 cells. For functional analysis, hsa_circ_0008360 deficiency promoted cell viability, inhibits cell apoptosis, inflammatory response, and the synthesis of related fibrotic proteins in HG-treated HK2 cells. Moreover, overexpression of miR-346 induced the proliferation and inhibit apoptosis of HG-induced HK2 cells by inhibiting WNT2B expression. In mechanism, hsa_circ_0008360 acted as a miR-346 sponge to regulate the level of WNT2B.

Hsa_circ_0008360 can regulate miR-346/WNT2B axis in HG-induced HK2 cells, providing an underlying targeted therapy for DN patients.

Diabetic nephropathy, a common and severe complication of diabetes, is the leading cause of end-stage renal disease, ultimately leading to renal failure and significantly affecting the prognosis and lives of diabetics worldwide. However, the complexity of its developmental mechanisms makes treating diabetic nephropathy a challenging task, necessitating the search for improved therapeutic targets. Intercellular communication underlies the direct and indirect influence and interaction among various cells within a tissue. Recently, studies have shown that beyond traditional communication methods, tunnel nanotubes, exosomes, filopodial tip vesicles, and the fibrogenic niche can influence pathophysiological changes in diabetic nephropathy by disrupting intercellular communication. Therefore, this paper aims to review the varied roles of intercellular communication in diabetic nephropathy, focusing on recent advances in this area.

In the human body, the vascular system plays an indispensable role in maintaining homeostasis by supplying oxygen and nutrients to cells and organs and facilitating the removal of metabolic waste and toxins. Blood vessels-the key constituents of the vascular system-are composed of a layer of endothelial cells on their luminal surface. In most organs, tightly packed endothelial cells serve as a barrier separating blood and lymph from surrounding tissues. Intriguingly, endothelial cells in some tissues and organs (e.g., choroid plexus, liver sinusoids, small intestines, and kidney glomerulus) form transcellular pores called fenestrations that facilitate molecular and ionic transport across the vasculature and mediate immune responses through leukocyte transmigration. However, the development and unique functions of endothelial cell fenestrations across organs are yet to be fully uncovered. This review article provides an overview of fenestrated endothelial cells in multiple organs. We describe their development and organ-specific roles, with expanded discussions on their contributions to glomerular health and disease. We extend these discussions to highlight the dynamic changes in endothelial cell fenestrations in diabetic nephropathy, focal segmental glomerulosclerosis, Alport syndrome, and preeclampsia, and how these unique cellular features could be targeted for therapeutic development. Finally, we discuss emerging technologies for in vitro modeling of biological systems, and their relevance for advancing the current understanding of endothelial cell fenestrations in health and disease.

Cell deaths maintain the normal function of tissues and organs. In pathological conditions, the abnormal activation or disruption of cell death often leads to pathophysiological effects. Diabetic kidney disease (DKD), a significant microvascular complication of diabetes, is linked to high mortality and morbidity rates, imposing a substantial burden on global healthcare systems and economies. Loss and detachment of podocytes are key pathological changes in the progression of DKD. This review explores the potential mechanisms of apoptosis, necrosis, autophagy, pyroptosis, ferroptosis, cuproptosis, and podoptosis in podocytes, focusing on how different cell death modes contribute to the progression of DKD. It recognizes the limitations of current research and presents the latest basic and clinical research studies targeting podocyte death pathways in DKD. Lastly, it focuses on the future of targeting podocyte cell death to treat DKD, with the intention of inspiring further research and the development of therapeutic strategies.

Obesity-induced kidney injury contributes to the development of diabetic nephropathy (DN). Here, we identified the functions of ubiquitin-specific peptidase 19 (USP19) in HK-2 cells exposed to a combination of high glucose (HG) and free fatty acid (FFA) and determined its association with TGF-beta-activated kinase 1 (TAK1).

HK-2 cells were exposed to a combination of HG and FFA. USP19 mRNA expression was detected by quantitative RT-PCR (qRT-PCR), and protein analysis was performed by immunoblotting (IB). Cell growth was assessed by Cell Counting Kit-8 (CCK-8) viability and 5-ethynyl-2'-deoxyuridine (EdU) proliferation assays. Cell cycle distribution and apoptosis were detected by flow cytometry. The USP19/TAK1 interaction and ubiquitinated TAK1 levels were assayed by coimmunoprecipitation (Co-IP) assays and IB.

In HG+FFA-challenged HK-2 cells, USP19 was highly expressed. USP19 knockdown attenuated HG+FFA-triggered growth inhibition and apoptosis promotion in HK-2 cells. Moreover, USP19 knockdown alleviated HG+FFA-mediated PTEN-induced putative kinase 1 (PINK1)/Parkin pathway inactivation and increased mitochondrial reactive oxygen species (ROS) generation in HK-2 cells. Mechanistically, USP19 stabilized the TAK1 protein through deubiquitination. Importantly, increased TAK1 expression reversed the USP19 knockdown-mediated phenotypic changes and PINK1/Parkin pathway activation in HG+FFA-challenged HK-2 cells.

The findings revealed that USP19 plays a crucial role in promoting HK-2 cell dysfunction induced by combined stimulation with HG and FFAs by stabilizing TAK1, providing a potential therapeutic strategy for combating DN.

Diabetic kidney disease (DKD), one of the microvascular complications in patients with diabetes mellitus, is a common cause of end-stage renal disease. Cellular senescence is believed to be an essential participant in the pathogenesis of DKD. Although there is evidence that Alpiniae oxyphyllae fructus (AOF) can ameliorate DKD progression and organismal senescence, its ability to ameliorate renal cellular senescence in DKD as well as active components and molecular mechanisms remain to be explored.

This study aimed to investigate the role of AOF in the treatment of cellular senescence in DKD and to explore its active components and potential molecular mechanisms.

The pharmacological efficacy of AOF in ameliorating cellular senescence in DKD was assessed by establishing DKD mouse models and HK-2 cells under high glucose stress. UHPLC-QTOF-MS was used to screen the active compounds in AOF, which were used in conjunction with network pharmacology to predict the molecular mechanism of AOF in the treatment of cellular senescence in DKD.

In vivo experiments showed that AOF reduced GLU, mAlb, Scr, BUN, MDA, SOD levels, and ameliorated renal pathological damage and renal cell senescence in DKD mice. In vitro experiments showed that AOF-containing serum improved the decline in HK-2 cell viability and alleviated cellular senescence under high glucose intervention. The results of the UHPLC-QTOF-MS screened 26 active compounds of AOF. The network pharmacological analyses revealed that Cubebin, 2',6'-dihydroxy-4'-methoxydihydrochalcone, Chalcone base + 3O,1Prenyl, Batatasin IV, and Lucidenolactone were the five core compounds and TP53, SRC, STAT3, PIK3CA, and AKT1 are the five core targets of AOF in the treatment of DKD. Molecular docking simulation results showed that the five core compounds had good binding ability to the five core targets. Western blot validated the network pharmacological prediction results and showed that AOF and AOF-containing serum down-regulate the expression of TP53, and phosphorylation of SRC, STAT3, PIK3CA, and AKT.

Our study shows that AOF may delay the development of cellular senescence in DKD by down-regulating the levels of TP53, and phosphorylation of SRC, STAT3, PIK3CA, and AKT.

Diabetic nephropathy (DN) is a major microvascular complication of diabetes and has become the leading cause of end-stage renal disease worldwide. A considerable number of DN patients have experienced irreversible end-stage renal disease progression due to the inability to diagnose the disease early. Therefore, reliable biomarkers that are helpful for early diagnosis and treatment are identified. The migration of immune cells to the kidney is considered to be a key step in the progression of DN-related vascular injury. Therefore, finding markers in this process may be more helpful for the early diagnosis and progression prediction of DN.

The gene chip data were retrieved from the GEO database using the search term ' diabetic nephropathy '. The ' limma ' software package was used to identify differentially expressed genes (DEGs) between DN and control samples. Gene set enrichment analysis (GSEA) was performed on genes obtained from the molecular characteristic database (MSigDB. The R package 'WGCNA' was used to identify gene modules associated with tubulointerstitial injury in DN, and it was crossed with immune-related DEGs to identify target genes. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on differentially expressed genes using the 'ClusterProfiler' software package in R. Three methods, least absolute shrinkage and selection operator (LASSO), support vector machine recursive feature elimination (SVM-RFE) and random forest (RF), were used to select immune-related biomarkers for diagnosis. We retrieved the tubulointerstitial dataset from the Nephroseq database to construct an external validation dataset. Unsupervised clustering analysis of the expression levels of immune-related biomarkers was performed using the 'ConsensusClusterPlus 'R software package. The urine of patients who visited Dongzhimen Hospital of Beijing University of Chinese Medicine from September 2021 to March 2023 was collected, and Elisa was used to detect the mRNA expression level of immune-related biomarkers in urine. Pearson correlation analysis was used to detect the effect of immune-related biomarker expression on renal function in DN patients.

Four microarray datasets from the GEO database are included in the analysis : GSE30122, GSE47185, GSE99340 and GSE104954. These datasets included 63 DN patients and 55 healthy controls. A total of 9415 genes were detected in the data set. We found 153 differentially expressed immune-related genes, of which 112 genes were up-regulated, 41 genes were down-regulated, and 119 overlapping genes were identified. GO analysis showed that they were involved in various biological processes including leukocyte-mediated immunity. KEGG analysis showed that these target genes were mainly involved in the formation of phagosomes in Staphylococcus aureus infection. Among these 119 overlapping genes, machine learning results identified AGR2, CCR2, CEBPD, CISH, CX3CR1, DEFB1 and FSTL1 as potential tubulointerstitial immune-related biomarkers. External validation suggested that the above markers showed diagnostic efficacy in distinguishing DN patients from healthy controls. Clinical studies have shown that the expression of AGR2, CX3CR1 and FSTL1 in urine samples of DN patients is negatively correlated with GFR, the expression of CX3CR1 and FSTL1 in urine samples of DN is positively correlated with serum creatinine, while the expression of DEFB1 in urine samples of DN is negatively correlated with serum creatinine. In addition, the expression of CX3CR1 in DN urine samples was positively correlated with proteinuria, while the expression of DEFB1 in DN urine samples was negatively correlated with proteinuria. Finally, according to the level of proteinuria, DN patients were divided into nephrotic proteinuria group (n = 24) and subrenal proteinuria group. There were significant differences in urinary AGR2, CCR2 and DEFB1 between the two groups by unpaired t test (P < 0.05).

Our study provides new insights into the role of immune-related biomarkers in DN tubulointerstitial injury and provides potential targets for early diagnosis and treatment of DN patients. Seven different genes ( AGR2, CCR2, CEBPD, CISH, CX3CR1, DEFB1, FSTL1 ), as promising sensitive biomarkers, may affect the progression of DN by regulating immune inflammatory response. However, further comprehensive studies are needed to fully understand their exact molecular mechanisms and functional pathways in DN.

Diabetic kidney disease is one of the most severe chronic microvascular complications of diabetes and a primary cause of end-stage renal disease. Clinical studies have shown that renal inflammation is a key factor determining kidney damage during diabetes. With the development of immunological technology, many studies have shown that diabetic nephropathy is an immune complex disease, and that most patients have immune dysfunction. However, the immune response associated with diabetic nephropathy and autoimmune kidney disease, or caused by ischemia or infection with acute renal injury, is different, and has a com-plicated pathological mechanism. In this review, we discuss the pathogenesis of diabetic nephropathy in immune disorders and the intervention mechanism, to provide guidance and advice for early intervention and treatment of diabetic nephropathy.

Hyperglycemia is a potent risk factor for the development and progression of diabetes-induced nephropathy. Dendropanoxide (DPx) is a natural compound isolated from Dendropanax morbifera (Araliaceae) that exerts various biological effects. However, the role of DPx in hyperglycemia-induced renal tubular cell injury remains unclear. The present study explored the protective mechanism of DPx on high glucose (HG)-induced cytotoxicity in kidney tubular epithelial NRK-52E cells. The cells were cultured with normal glucose (5.6 mM), HG (30 mM), HG + metformin (10 µM), or HG + DPx (10 µM) for 48 h, and cell cycle and apoptosis were analyzed. Malondialdehyde (MDA), advanced glycation end products (AGEs), and reactive oxygen species (ROS) were measured. Protein-based nephrotoxicity biomarkers were measured in both the culture media and cell lysates. MDA and AGEs were significantly increased in NRK-52E cells cultured with HG, and these levels were markedly reduced by pretreatment with DPx or metformin. DPx significantly reduced the levels of kidney injury molecule-1 (KIM-1), pyruvate kinase M2 (PKM2), selenium-binding protein 1 (SBP1), or neutrophil gelatinase-associated lipocalin (NGAL) in NRK-52E cells cultured under HG conditions. Furthermore, treatment with DPx significantly increased antioxidant enzyme activity. DPx protects against HG-induced renal tubular cell damage, which may be mediated by its ability to inhibit oxidative stress through the protein kinase B/mammalian target of the rapamycin (AKT/mTOR) signaling pathway. These findings suggest that DPx can be used as a new drug for the treatment of high glucose-induced diabetic nephropathy.

Epigenetic alterations, especially DNA methylation, have been shown to play a role in the pathogenesis of diabetes mellitus (DM) and its complications, including diabetic kidney disease (DKD). Spleen tyrosine kinase (Syk) is known to be involved in immune and inflammatory disorders. We, therefore, investigated the possible involvement of Syk promoter methylation in DKD, and the mechanisms underlying this process. Kidney tissues were obtained from renal biopsies of patients with early and advanced DKD. A diabetic mouse model (ApoE-/- DM) was generated from ApoE knockout (ApoE-/-) mice using a high-fat and high-glucose diet combined with low-dose streptozocin intraperitoneal injection. We also established an in vitro model using HK2 cells. A marked elevation in the expression levels of Syk, PKCβ, and P66shc in renal tubules was observed in patients with DKD. In ApoE-/- DM mice, Syk expression and the binding of Sp1 to the Syk gene promoter were both increased in the kidney. In addition, the promoter region of the Syk gene exhibited hypomethylation. Syk inhibitor (R788) intervention improved renal function and alleviated pathologic changes in ApoE-/- DM mice. Moreover, R788 intervention alleviated oxidative stress and apoptosis and downregulated the expression of PKCβ/P66shc signaling pathway proteins. In HK2 cells, oxLDL combined with high-glucose stimulation upregulated Sp1 expression in the nucleus (compared with control and oxLDL groups), and this was accompanied by an increase in the binding of Sp1 to the Syk gene promoter. SP1 silencing downregulated the expression of Syk and inhibited the production of reactive oxygen species and cell apoptosis. Finally, PKC agonist intervention reversed the oxidative stress and apoptosis induced by Syk inhibitor (R406). In DKD, hypomethylation at the Syk gene promoter was accompanied by an increase in Sp1 binding at the promoter. As a consequence of this enhanced Sp1 binding, Syk gene expression was upregulated. Syk inhibitors could attenuate DKD-associated oxidative stress and apoptosis via downregulation of PKCβ/P66shc signaling pathway proteins. Together, our results identify Syk as a promising target for intervention in DKD.

Diabetic kidney disease (DKD) is a long-term and serious complication of diabetes that affects millions of people worldwide. It is characterized by proteinuria, glomerular damage, and renal fibrosis, leading to end-stage renal disease, and the pathogenesis is complex and involves multiple cellular and molecular mechanisms. Among three kinds of intraglomerular cells including podocytes, glomerular endothelial cells (GECs) and mesangial cells (MCs), the alterations in one cell type can produce changes in the others. The cell-to-cell crosstalk plays a crucial role in maintaining the glomerular filtration barrier (GFB) and homeostasis. In this review, we summarized the recent advances in understanding the pathological changes and interactions of these three types of cells in DKD and then focused on the signaling pathways and factors that mediate the crosstalk, such as angiopoietins, vascular endothelial growth factors, transforming growth factor-β, Krüppel-like factors, retinoic acid receptor response protein 1 and exosomes, etc. Furthermore, we also simply introduce the application of the latest technologies in studying cell interactions within glomerular cells and new promising mediators for cell crosstalk in DKD. In conclusion, this review provides a comprehensive and updated overview of the glomerular crosstalk in DKD and highlights its importance for the development of novel intervention approaches.

Diabetes mellitus and its complications are a known public health problem nowadays. Diabetic nephropathy is one of the main complications and the result of multiple mechanisms, including: activation of the renin-angiotensin-aldosterone system, formation of advanced glycation end products and chronic inflammation that led to glomerular and tubulo-interstitial damage producing mesangial expansion and glomerulosclerosis, which finally results in chronic kidney disease. Early detection of diabetic nephropathy is essential for adequate intervention to stop, or at least slow down its progression. Multiple markers have been described, not only the classic ones such as serum creatinine, urea, and albuminuria, but at this point also novel biomarkers such as neutrophil gelatinase-associated lipocalin, tumor necrosis factor 1 receptor and monocyte chemoattractant protein-1, among others. The aim of this article was to provide an update review of the role of biomarkers in the diagnosis of diabetic nephropathy.

Metabolic reprogramming to glycolysis is closely associated with the development of chronic kidney disease (CKD). Although it has been reported that phosphofructokinase 1 (PFK) is a rate-limiting enzyme in glycolysis, the role of the platelet isoform of PFK (PFKP) in kidney fibrosis initiation and progression is as yet poorly understood. Here, we investigated whether PFKP could mediate the progression of kidney interstitial fibrosis by regulating glycolysis in proximal tubular epithelial cells (PTECs). We induced PFKP overexpression or knockdown in renal tubules via an adeno-associated virus (AAV) vector in the kidneys of mice following unilateral ureteral occlusion. Our results show that the dilated tubules, the area of interstitial fibrosis, and renal glycolysis were promoted by proximal tubule-specific overexpression of PFKP, and repressed by knockdown of PFKP. Furthermore, knockdown of PFKP expression restrained, while PFKP overexpression promoted TGF-β1-induced glycolysis in the human PTECs line. Mechanistically, Chip-qPCR revealed that TGF-β1 recruited the small mothers against decapentaplegic (SMAD) family member 3-SP1 complex to the PFKP promoter to enhance its expression. Treatment of mice with isorhamnetin notably ameliorated PTEC-elevated glycolysis and kidney fibrosis. Hence, our results suggest that PFKP mediates the progression of kidney interstitial fibrosis by regulating glycolysis in PTECs.

Diabetic kidney disease is a common complication of diabetes and remains the primary cause of end-stage kidney disease in the general population. Schisandrin B (Sch B) is an active ingredient in Schisandra chinensis. Our study illustrates that Sch B can mitigate renal tubular cell (RTC) epithelial-mesenchymal transition (EMT) and mitochondrial dysfunction in db/db mice, accompanied by the downregulation of TGF-β1 and the upregulation of PGC-1α. Similarly, Sch B demonstrated a protective effect by reducing the expression of TGF-β1, α-SMA, fibronectin, and Col I, meanwhile enhancing the expression of E-cadherin in human RTCs (HK2 cells) stimulated with high glucose. Moreover, under high glucose conditions, Sch B effectively increased mitochondrial membrane potential, lowered ROS production, and increased the ATP content in HK2 cells, accompanied by the upregulation of PGC-1α, TFAM, MFN1, and MFN2. Mechanistically, the RNA-seq results showed a significant increase in KCP mRNA levels in HK2 cells treated with Sch B in a high glucose culture. The influence of Sch B on KCP mRNA levels was confirmed by real-time PCR in high glucose-treated HK2 cells. Depletion of the KCP gene reversed the impact of Sch B on TGF-β1 and PGC-1α in HK2 cells with high glucose level exposure, whereas overexpression of the KCP gene blocked EMT and mitochondrial dysfunction. Furthermore, the PI3K/Akt pathway was inhibited and the AMPK pathway was activated in HK2 cells exposed to a high concentration of glucose after the Sch B treatment. Treatment with the PI3K/Akt pathway agonist insulin and the AMPK pathway antagonist compound C attenuated the Sch B-induced KCP expression in HK2 cells exposed to a high level of glucose. Finally, molecular autodock experiments illustrated that Sch B could bind to Akt and AMPK. In summary, our findings suggested that Sch B could alleviate RTC EMT and mitochondrial dysfunction by upregulating KCP via inhibiting the Akt pathway and activating the AMPK pathway in DKD.

Diabetic kidney disease (DKD) is a severe microvascular complication of diabetes and is a chronic progressive condition. It is also a common cause of end-stage renal disease (ESRD), which is characterized by proteinuria or a progressive decline in the glomerular filtration rate. Due to their dependence on high-energy and aerobic metabolism, renal tubules are more susceptible to the metabolic disturbances associated with DKD, leading to inflammation and fibrosis. Consequently, tubular injury has become a recent research focus, and significant advancements have been made in studying the role of extracellular vesicles in DKD-associated tubular injury. This review aimed to elucidate the mechanisms and potential applications of different types of extracellular vesicles in tubular injury in DKD to provide new insights for the prevention and treatment of DKD.

Diabetic nephropathy (DN), a chronic progressive kidney disease, is the most prevalent microvascular complication associated with diabetes which causes the end-stage renal disease. Glomerular endothelial cells (GECs) are one of the inherent cells of the glomerulus and are particularly susceptible to be damaged by glucose, lipids and inflammatory factors. Numerous studies indicated that GECs injury was a critical pathological event in the early stages of DN. Previous studies have shown that podocyte pyroptosis occurred through the classical caspase-1 pathway, leading to kidney injury. However, the occurrence of pyroptosis in GECs and the underlying mechanism remain unclear. In this study, we investigated the pyroptosis of GECs during DN and its underlying mechanism. Upon stimulation with high glucose (HG), we observed the upregulation of GSDMD and cleaved N-terminus, disruption of cell membrane integrity, and an increase in IL-18 inflammatory cytokines. Also, we found that the expression of caspase-11, GSDMD and GSDMD-N were increased in C57BL/6J mice induced by STZ combined with high sugar and fat. In addition, the pathological results of kidney showed a significant thickening of the glomerular basement membrane, abnormal increasement of extracellular matrix and hyperplasia with blurred boundaries of glomerulus. Furthermore, interfering the expression of GSDMD improved the pathological degree of kidney. These findings indicated that the pyroptosis of GECs during DN was facilitated by the non-classical pathway of caspase-11/GSDMD, ultimately leading to GECs injury and further aggravating the progression of DN. This work highlights the potential of GSDMD as a therapeutic target for the treatment of DN.

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes and a leading cause of end-stage renal disease worldwide. Autophagy plays an important role in maintaining cellular homeostasis in renal physiology. In DKD, the accumulation of advanced glycation end products induces decreased renal autophagy-related protein expression and transcription factor EB (TFEB) nuclear transfer, leading to impaired autophagy and lysosomal function and blockage of autophagic flux. This accelerates renal resident cell injury and apoptosis, mediates macrophage infiltration and phenotypic changes, ultimately leading to aggravated proteinuria and fibrosis in DKD. Natural polyphenols show promise in treating DKD by regulating autophagy and promoting nuclear transfer of TFEB and lysosomal repair. This review summarizes the characteristics of autophagy in DKD, and the potential application and mechanisms of some known natural polyphenols as autophagy regulators in DKD, with the goal of contributing to a deeper understanding of natural polyphenol mechanisms in the treatment of DKD and promoting the development of their applications. Finally, we point out the limitations of polyphenols in current DKD research and provide an outlook for their future research.

When sodium-glucose cotransporter-2 (SGLT2) inhibitors were first introduced a decade ago, no one expected them to have substantial effects beyond their known glucose-lowering effects, until the emergence of evidence of their robust renal and cardiovascular benefits showing that they could attenuate progression of kidney disease, irrespective of diabetes, as well as prevent the development of acute kidney injury. Still, the precise and elaborate mechanisms underlying the major organ protection of SGLT2 inhibitors remain unclear. SGLT2 inhibitors inhibit the reabsorption of sodium and glucose in the proximal tubule of the kidney and then recovers tubuloglomerular feedback, whereby SGLT2 inhibitors reduce glomerular hyperfiltration. This simple demonstration of their beneficial effects has perplexed experts in seeking more plausible and as yet undisclosed explanations for the whole effects of SGLT2 inhibitors, including metabolism reprogramming and the modulation of hypoxia, inflammation, and oxidative stress. Given that the renal benefits of SGLT2 inhibitors in patients with kidney disease but without diabetes were comparable to those seen in patients with diabetes, it may be reasonable to keep the emphasis on their hemodynamic actions. In this context, the aim of the present review is to provide a comprehensive overview of renal hemodynamics in individuals with diabetes who are treated with SGLT2 inhibitors, with a focus on natriuresis associated with the regulation of tubuloglomerular feedback and potential aquaresis. Throughout the discussion of alterations in renal sodium and water transports, particular attention will be given to the potential enhancement of adenosine and its receptors following SGLT2 inhibition.

Diabetic nephropathy (DN) is one of the most common complications of diabetes, and its main manifestations are progressive proteinuria and abnormal renal function, which eventually develops end stage renal disease (ESRD). The pathogenesis of DN is complex and involves many signaling pathways and molecules, including metabolic disorders, genetic factors, oxidative stress, inflammation, and microcirculatory abnormalities strategies. With the development of medical experimental techniques, such as single-cell transcriptome sequencing and single-cell proteomics, the pathological alterations caused by kidney cell interactions have attracted more and more attention. Here, we reviewed the characteristics and related mechanisms of crosstalk among kidney cells podocytes, endothelial cells, mesangial cells, pericytes, and immune cells during the development and progression of DN and highlighted its potential therapeutic effects.