Dysregulated lipid metabolism contributes to diabetic nephropathy (DN), but the genetic links remain unclear. This study identified lipid metabolism genes associated with DN risk using summary-data-based Mendelian randomization (SMR). SMR screened 757 lipid metabolism genes by integrating large-scale blood methylation quantitative trait locus (mQTL; n = 1,980), expression QTL (eQTL; n = 31,684), and protein QTL (pQTL; n = 54,219) datasets with FinnGen genome-wide association study (5,042 cases/79,344 controls), followed by validation in GCST005881 (5,908 cases/4,967 controls). Functional enrichment, protein-protein interaction, and mQTL-eQTL integration were performed. Nephroseq data were used to examine tissue-level expression-renal function correlations. External bulk and single-cell transcriptomic datasets were analyzed to assess stage- and cell-type-specific expression. CERS2, MED27, and PLA2G1B were prioritized as DN-associated risk genes. Genetically predicted higher expression of CERS2 (OR = 1.246, p_SMR = 0.027) and MED27 (OR = 1.551, p_SMR = 0.032) increased DN risk. Methylation at cg26058502 (CERS2: OR = 0.604, FDR = 1.61 × 10-23) and cg13628444 (MED27: OR = 0.662, FDR = 3.82 × 10-10) demonstrated negative regulatory effects on gene expression. PLA2G1B was linked to increased risk at methylation (cg16396488: OR = 1.369, p_SMR = 7.82 × 10-4) and protein (OR = 3.057, p_SMR = 0.005) levels. However, in the Nephroseq database, higher expression of all three genes correlated with better kidney function. External bulk transcriptomics showed transient upregulation of CERS2 and MED27 in early DN but not advanced stages. PLA2G1B exhibited no differential expression or association with renal function. Single-cell analysis demonstrated broad detection of CERS2 and MED27 across renal cell types with subset enrichment, whereas PLA2G1B expression was sparse, with no evident disease-associated shifts. These findings indicate discordance between genetically inferred risk effects and observed expression patterns, suggesting complex regulatory mechanisms.

Ferroptotic renal tubular epithelial cells (RTECs) promote renal fibrosis (RF) by inducing epithelial-to-mesenchymal transition (EMT), thereby aggravating diabetic kidney disease (DKD) progression. Calcitriol has been shown to ameliorate ferroptosis in neonatal hypoxic-ischemic encephalopathy but not in DKD. Thus, we hypothesized that calcitriol alleviates RF and mitigates DKD by inhibiting ferroptosis in RTECs and aimed to reveal the underlying molecular mechanism. To test this hypothesis, calcitriol was administered to mice with DKD, whereas calcitriol combined with an inducer of ATF3 or TLR4 was employed in HK-2 cells with simulated DKD. Our latest bioinformatic analysis demonstrated that activating transcription factor 3 (ATF3), toll-like receptor 4 (TLR4), gamma-aminobutyric acid receptor-associated protein-like 1 (GABARAPL1), and indoleamine 2,3-dioxygenase 1 (IDO1) are hub genes related to inflammatory response, ferroptosis, RF, and DKD. Calcitriol and vitamin D receptor (VDR) are closely interrelated with these hub genes, with Jun proto-oncogene (JUN) involved as a key node. Calcitriol effectively alleviated inflammation, ferroptosis, and EMT in RTECs, and ameliorated RF in DKD and simulated DKD. Calcitriol significantly downregulated JUN, ATF3, and TLR4 but did not significantly affect GABARAPL1 expression in DKD and simulated DKD. Upregulation of ATF3 by supplementing ATF3 inducer counteracted the ameliorative effects of calcitriol on inflammation, ferroptosis, EMT, and RF in simulated DKD. However, the amelioration of calcitriol in inflammation, ferroptosis, EMT, and RF in simulated DKD was not significantly impacted by lipopolysaccharides-induced TLR4. Calcitriol alleviates RF and mitigates DKD by inhibiting inflammation and ferroptosis in RTECs in DKD and simulated DKD via the JUN/ATF3 pathway.

Diabetic kidney disease (DKD), characterized by progressive renal dysfunction, is a prevalent microvascular complication of diabetes mellitus and a leading cause of end-stage renal disease worldwide. Despite advances in glycemic and blood pressure control, the incidence and prevalence of DKD continue to escalate, posing a growing public health challenge. Extracellular vesicles, particularly exosomes, are nanometer-sized vesicles secreted by diverse cells and have emerged as key regulators of intercellular communication. By transferring molecular cargo—including proteins, lipids, and nucleic acids—they exert pleiotropic effects on cellular homeostasis and participate in both physiological and pathological processes. Accumulating evidence has revealed dynamic alterations in the quantity and composition of urinary exosomes under diabetic conditions, implicating these vesicles in the multifactorial pathogenesis of DKD and highlighting their promise as liquid biopsy biomarkers for DKD. This review provides a comprehensive overview of the landscape of research on exosomes in DKD. We elucidate their roles in molecular pathology, investigate their potential for diagnostic and prognostic biomarker discovery powered by multi-omics and machine learning approaches, and examine their implications for therapeutic applications, including their use as drug delivery vehicles and direct therapeutic agents. Looking forward, we highlight critical research gaps and future directions, emphasizing the need for artificial intelligence (AI)-integrated multi-omics analyses to decipher exosome heterogeneity, large-scale multicenter trials to validate biomarker efficacy, and innovative strategies to overcome barriers in clinical translation, ultimately paving the way for personalized medicine in DKD management.

Introduction: Renal tubulointerstitial inflammation represents an effective indicator for predicting the progression of diabetic kidney disease (DKD). Mitophagy abnormality is 1 of the most important factors involved in tubule injury. However, the exact molecular mechanism underlying mitophagy abnormality- mediated tubulointerstitial inflammation in DKD remains poorly understood. Methods: In this study, a streptozotocin-induced DKD mouse model was established and HK-2 cells treated with high glucose (HG) served as an in vitro model. Tubular mitophagy was regulated through pharmacological urolithin A (UA) administration. The functional effect of the transient receptor potential cation channel, subfamily C, member 6 (TRPC6) was explored using genetic interventions in vivo and in vitro. Results: We found that renal tubulointerstitial inflammation in DKD was closely associated with mitophagy inhibition, which was mediated by disturbance of PINK1/Parkin pathway. Mitophagy activation significantly attenuated tubular injury and tubulointerstitial inflammation. Further, it was found that TRPC6 was markedly increased in DKD and played an essential role in mitophagy inhibition by activating calpain-1. Knockdown of Trpc6 partially reversed mitophagy abnormality and consequently attenuated tubular injury and tubulointerstitial inflammation in vivo and in vitro. Finally, we found that tubular TRPC6mediated mitophagy inhibition was blocked with BAPTA (a specific Ca2 & thorn;chelator) or calpeptin (a specific calpain-1 inhibitor). Conclusion: Our study reveals that TRPC6-calpain-1 axis promotes tubulointerstitial inflammation in DKD by inhibiting mitophagy.

Background Tubulointerstitial fibrosis plays an important role in the progression of diabetic kidney disease (DKD). Sacubitril/valsartan (Sac/Val) exerts a robust beneficial effect in DKD. However, the potential functional effect of Sac/Val on tubulointerstitial fibrosis in DKD is still largely unclear. Methods Streptozotocin-induced diabetic mice were given Sac/Val or Val by intragastric administration once a day for 12 weeks. The renal function, the pathological changes of tubule injury and tubulointerstitial fibrosis, as well as mitochondrial morphology of renal tubules in mice, were evaluated. Genome-wide gene expression analysis was performed to identify the potential mechanisms. Meanwhile, human tubular epithelial cells (HK-2) were cultured in high glucose condition containing LBQ657/valsartan (LBQ/Val). Further, mitochondrial functions and Sirt1/PGC1α pathway of tubular epithelial cells were assessed by Western blot, Real-time-PCR, JC-1, MitoSOX or MitoTracker. Finally, the Sirt1 specific inhibitor, EX527, was used to explore the potential effects of Sirt1 signaling in vivo and in vitro. Results We found that Sac/Val significantly ameliorated the decline of renal function and tubulointerstitial fibrosis in DKD mice. The enrichment analysis of gene expression indicated metabolism as an important modulator in DKD mice with Sac/Val administration, in which mitochondrial homeostasis plays a pivotal role. Then, the decreased expression of Tfam and Cox IV;, as well as changes of mitochondrial function and morphology, demonstrated the disruption of mitochondrial homeostasis under DKD conditions. Interestingly, Sac/Val administration was found to restore mitochondrial homeostasis in DKD mice and in vitro model of HK-2 cells. Further, we demonstrated that Sirt1/PGC1α, a crucial pathway in mitochondrial homeostasis, was activated by Sac/Val both in vivo and in vitro. Finally, the beneficial effects of Sac/Val on mitochondrial homeostasis and tubulointerstitial fibrosis was partially abolished in the presence of Sirt1 specific inhibitor. Conclusions Taken together, we demonstrate that Sac/Val ameliorates tubulointerstitial fibrosis by restoring Sirt1/PGC1α pathway-mediated mitochondrial homeostasis in DKD, providing a theoretical basis for delaying the progression of DKD in clinical practice.

Objective To investigate the effect of nicotinamide adenine dinucleotide-dependent deacetylase 1(Sirt1)on high glucose-induced exosome release from podocytes.Methods Immortalized mouse podocytes MPC5 were divided into six groups:normal glucose group(5.5 mmol/L glucose,group A),high mannitol group(5.5 mmol/L glucose+24.5 mmol/L manni-tol,group B),high glucose group(30.0 mmol/L glucose,group C),high glucose+Sirt1-overexpressed lentivirus transfection group(Sirt1-overexpressed lentivirus transfection+30.0 mmol/L glucose,group D),high glucose+negative lentivirus transfection group(negative lentivirus transfection+30.0 mmol/L glucose,group E),and high glucose+exosome secretion inhibitor group(GW4869+30.0 mmol/L glucose,group F).Western blot was used to analyze the expression levels of Nephrin,Podocin,Sirt1,CD63,CD81,and Alix in each group.Real-time quantitative polymerase chain reaction was used to analyze the expression level of Sirt1 mRNA in D and E group.The morphology of podocyte exosomes was observed by a transmission electron microscope.The particle size and concentration of exosomes were determined by nanoparticle tracking analysis.Results The results of RT-qPCR showed that the relative expression of Sirt1 mRNA was significantly increased in group D compared with that in group E(t= 14.580,P＜0.01).The results of nanoparticle tracking analysis and Western blot showed that the relative expression of Sirt1,Nephrin,and Podocin proteins in podocytes among groups A to C was significantly different(F=49.84-106.40,P＜0.01).Com-pared with group A,group C had significantly increased secretion of podocyte exosomes(t=14.550,P＜0.01)and significantly re-duced expression of Sirt1,Nephrin,and Podocin(t=7.446-15.110,P＜0.01).Compared with group E,group D had significantly reduced release of podocyte exosomes(t=74.610,P＜0.01)and significantly increased relative expression of Sirt1,Nephrin,and Podocin(t=4.657-32.860,P＜0.05).Compared with group C,group F had significantly reduced release of podocyte exosomes(t=16.300,P＜0.05)and significantly increased relative expression of Nephrin and Podocin(t=3.790,8.151,P＜0.01),but showed no significant change in the expression level of Sirt1(P＞0.05).Con-clusion Loss of Sirt1 in high glucose-treated podocytes promotes exosome secretion and podocyte injury.

Background A significant cause of advanced renal failure is diabetic nephropathy (DKD), with few treatment options available. Calcitriol shows potential in addressing fibrosis related to DKD, though its molecular mechanisms remain poorly understood. This research seeks to pinpoint the crucial genes and pathways influenced by calcitriol within the scope of DKD-related fibrosis. Methods Single-cell gene expression profiling of calcitriol treated DKD rat kidney tissue and screening of fibrosis-associated cell subsets. Mendelian randomization and enrichment analyses (CIBERSORT, GSVA, GSEA, Motif Enrichment) were used to explore gene-immune cell interactions and signaling pathways. Key findings were validated using independent datasets and protein expression data from the Human Protein Atlas. Results Calcitriol treatment reduced proliferative cell populations and highlighted the FoxO signaling pathway's role in DKD. SUMO3 and CD74 were identified as key markers linked to immune infiltration and renal function. These genes were significantly associated with creatinine levels and eGFR, indicating their potential role in DKD progression. Conclusion Our results suggest that calcitriol modulates DKD fibrosis through the FoxO pathway, with SUMO3 and CD74 serving as potential biomarkers for kidney protection. These results provide fresh insights into strategies for treating DKD.

Iron overload is common in cardiovascular disease, it is also the factor that drives ferroptosis. Noncoding RNAs play an important role in heart disease; however, their regulatory role in iron overload-mediated ferroptosis remains much unknown. In our study, the iron overload model in mice was constructed through a high-iron diet, and ammonium iron citrate treatment was used to mimic iron overload in vitro. We found iron overload induced ferroptosis in cardiomyocytes, which was dependent on the high expression of transferrin receptor (TFRC). MiR-31-5p was downregulated during iron overload; it inhibited cardiomyocyte ferroptosis by targeting TFRC. CircPIK3C2A, a highly expressed circRNA in the heart, was upregulated when iron was overloaded. CircPIK3C2A enhanced the expression of TFRC by sponging miR-31-5p and promoted ferroptosis during iron overload. Our results reveal a novel mechanistic insight into noncoding RNA-based ferroptosis and identify the circPIK3C2A/miR-31-5p/TFRC axis as a promising therapeutic target for myocardial damage.

The transcription factor hypoxia-inducible factor-1α (HIF-1α), as a master regulator of adaptive responses to hypoxia, possesses two transcriptional activation domains [TAD, N-terminal (NTAD), and C-terminal (CTAD)]. Although the roles of HIF-1α NTAD in kidney diseases have been recognized, the exact effects of HIF-1α CTAD in kidney diseases are poorly understood. Here, two independent mouse models of hypoxia-induced kidney injury were established using HIF-1α CTAD knockout (HIF-1α CTAD-/-) mice. Furthermore, hexokinase 2 (HK2) and mitophagy pathway are modulated using genetic and pharmacological methods, respectively. We demonstrated that HIF-1α CTAD-/- aggravated kidney injury in two independent mouse models of hypoxia-induced kidney injury, including ischemia/reperfusion-induced kidney injury and unilateral ureteral obstruction-induced nephropathy. Mechanistically, we found that HIF-1α CTAD could transcriptionally regulate HK2 and subsequently ameliorate hypoxia-induced tubule injury. Furthermore, it was found that HK2 deficiency contributed to severe renal injury through mitophagy inhibition, while mitophagy activation using urolithin A could significantly protect against hypoxia-induced kidney injury in HIF-1α C-TAD-/- mice. Our findings suggested that the HIF-1α CTAD-HK2 pathway represents a novel mechanism of kidney response to hypoxia, which provides a promising therapeutic strategy for hypoxia-induced kidney injury.

Podocyte injury is a characteristic feature of diabetic nephropathy (DN). The secretion of exosomes in podocytes increases significantly in DN; however, the precise mechanisms remain poorly understood. Here, we demonstrated that Sirtuin1 (Sirt1) was significantly downregulated in podocytes in DN, which correlated negatively with increased exosome secretion. Similar results were observed in vitro. We found that lysosomal acidification in podocytes following high glucose administration was markedly inhibited, resulting in the decreased lysosomal degradation of multivesicular bodies. Mechanistically, we indicated that loss of Sirt1 contributed to the inhibited lysosomal acidification by decreasing the expression of the A subunit of the lysosomal vacuolar-type H+ ATPase proton pump (ATP6V1A) in podocytes. Overexpression of Sirt1 significantly improved lysosomal acidification with increased expression of ATP6V1A and inhibited exosome secretion. These findings suggest that dysfunctional Sirt1-mediated lysosomal acidification is the exact mechanism of increased secretion of exosomes in podocytes in DN, providing insights into potential therapeutic strategies for preventing DN progression.

Coronary atherosclerosis-induced myocardial ischemia leads to cardiomyocyte apoptosis. The regulatory mechanisms for cardiomyocyte apoptosis have not been fully understood. Circular RNAs are non-coding RNAs which play important roles in heart function maintenance and progression of heart diseases by regulating gene transcription and protein translation. Here, we reported a conserved cardiac circular RNA, which is generated from the second exon of LRP6 and named circLRP62-2 . CircLRP62-2 can protect cardiomyocyte from hypoxia-induced apoptosis. The expression of circLRP62-2 in cardiomyocytes was down-regulated under hypoxia, while forced expression of circLRP62-2 inhibited cell apoptosis. Normally, circLRP62-2 was mainly localized in the nucleus. Under hypoxia, circLRP62-2 is associated with heterogeneous nuclear ribonucleoprotein M (hnRNPM) to be translocated into the cytoplasm. It recruited hnRNPM to fibroblast growth factor 9 (FGF9) mRNA to enhance the expression of FGF9 protein, promoting hypoxia-adaption and viability of cardiomyocytes. In summary, this study uncovers a new inhibitor of apoptosis and reveals a novel anti-apoptotic pathway composed of circLRP62-2 , hnRNPM, and FGF9, which may provide therapeutic targets for coronary heart disease and ischemic myocardial injury.

Kawasaki disease (KD) is an acute self-limiting vasculitis with coronary complications, usually occurring in children. The incidence of KD in children is increasing year by year, mainly in East Asian countries, but relatively stably in Europe and America. Although studies on KD have been reported, the pathogenesis of KD is unknown. With the development of high-throughput sequencing technology, growing number of regulatory noncoding RNAs (ncRNAs) including microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA) have been identified to involved in KD. However, the role of ncRNAs in KD has not been comprehensively elucidated. Therefore, it is significative to study the regulatory role of ncRNA in KD, which might help to uncover new and effective therapeutic strategies for KD. In this review, we summarize recent studies on ncRNA in KD from the perspectives of immune disorders, inflammatory disorders, and endothelial dysfunction, and highlight the potential of ncRNAs as therapeutic targets for KD.

Podocyte injury is a characteristic pathological hallmark of diabetic nephropathy (DN). However, the exact mechanism of podocyte injury in DN is incompletely understood. This study was conducted using db/db mice and immortalized mouse podocytes. High-throughput sequencing was used to identify the differentially expressed long noncoding RNAs in kidney of db/db mice. The lentiviral shRNA directed against long non -coding RNA small nucleolar RNA host gene 5 (SNHG5) or microRNA-26a-5p (miR-26a-5p) agomir was used to treat db/db mice to regulate the SNHG5/miR-26a-5p pathway. Here, we found that the expression of transient receptor potential canonical type 6 (TRPC6) was significantly increased in injured podocytes under the condition of DN, which was associated with markedly decreased miR-26a-5p. We determined that miR-26a-5p overexpression ameliorated podocyte injury in DN via binding to 30-UTR of Trpc6, as evidenced by the markedly reduced activity of luciferase reporters by miR-26a-5p mimic. Then, the upregulated SNHG5 in podocytes and kidney in DN was identified, and it was proved to sponge to miR-26a-5p directly using luciferase activity, RNA immunoprecipitation, and RNA pull-down assay. Knockdown of SNHG5 attenuated podocyte injury in vitro, accompanied by an increased expression of miR-26a-5p and decreased expression of TRPC6, demonstrating that SNHG5 promoted podocyte injury by controlling the miR-26a-5p/TRPC6 pathway. Moreover, knockdown of SNHG5 protects against podocyte injury and progression of DN in vivo. In conclusion, SNHG5 promotes podocyte injury via the miR-26a-5p/TRPC6 pathway in DN. Our findings provide novel insights into the pathophysiology of podocyte injury and a potential new therapeutic strategy for DN.

Objective Many studies have reported that microRNAs (miRs) are involved in the regulation of doxorubicin (DOX)-induced cardiotoxicity. MiR-194-5p has been reported significantly upregulated in patients with myocardial infarction; however, its role in myocardial diseases is still unclear. Various stimuluses can trigger the endoplasmic reticulum (ER) stress and it may activate the apoptosis signals eventually. This study aims to explore the regulatory role of miR-194-5p in DOX-induced ER stress and cardiomyocyte apoptosis. Methods H9c2 was treated with 2 μM DOX to induce apoptosis, which is to stimulate the DOX-induced cardiotoxicity model. The expression of miR-194-5p was detected by quantitative real-time PCR (qRT-PCR); the interaction between miR-194-5p and P21-activated kinase 2 (PAK2) was tested by dual luciferase reporter assay; terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and caspase-3/7 activity were used to assess apoptosis; trypan blue staining was applied to measure cell death; Western blotting was performed to detect protein expressions; and ER-related factors splicing X-box binding protein 1 (XBP1s) was detected by polyacrylamide gel electrophoresis and immunofluorescence to verify the activation of ER stress. Results MiR-194-5p was upregulated in cardiomyocytes and mouse heart tissue with DOX treatment, while the protein level of PAK2 was downregulated. PAK2 was predicted as the target of miR-194-5p; hence, dual luciferase reporter assay indicated that miR-194-5p directly interacted with PAK2 and inhibited its expression. TUNEL assay, caspase-3/7 activity test, and trypan blue stain results showed that either inhibition of miR-194-5p or overexpression of PAK2 reduced DOX-induced cardiomyocyte apoptosis. Silencing of miR-194-5p also improved DOX-induced cardiac dysfunction. In addition, DOX could induce ER stress in H9c2, which led to XBP1 and caspase-12 activation. The expression level of XBP1s with DOX treatment increased first then decreased. Overexpression of XBP1s suppressed DOX-induced caspase-3/7 activity elevation as well as the expression of cleaved caspase-12, which protected cardiomyocyte from apoptosis. Additionally, the activation of XBP1s was regulated by miR-194-5p and PAK2. Conclusion Our findings revealed that silencing miR-194-5p could alleviate DOX-induced cardiotoxicity via PAK2 and XBP1s in vitro and in vivo. Thus, the novel miR-194-5p/PAK2/XBP1s axis might be the potential prevention/treatment targets for cancer patients receiving DOX treatment.

目的:探究环状RNA Lrp6(circLrp6)对过氧化氢(H2O2)诱导的H9c2心肌细胞凋亡的影响.方法:通过Sanger测序和RNase R酶切验证circLrp6的环状结构;细胞荧光原位杂交分析circLrp6的亚细胞定位;通过RT-qPCR检测H2O2处理的H9c2细胞和缺血再灌注损伤的小鼠心脏组织中circLrp6的差异表达水平;采用TUNEL染色检测circLrp6是否影响H2O2诱导的心肌细胞凋亡水平;通过生物信息学的方法预测与circLrp6相互结合的下游靶点及其结合位点.结果:circLrp6具有环状结构,定位于细胞核,它在H2O2处理后的H9c2心肌细胞和缺血再灌注的心脏组织中表达水平下调(P<0.05),过表达circLrp6对H2O2处理的心肌细胞具有保护作用,表现为TUNEL染色阳性率下降(P<0.05).另外,circLrp6具有结合miRNA和蛋白质的潜能.结论:circLrp6对H2O2诱导的心肌细胞凋亡具有抑制作用.

Objective:To investigate the protective effect and potential mechanisms of microRNA-26a-5p (miR-26a-5p) on podocyte injury in diabetic kidney disease (DKD).Methods:(1) In vivo experiment: Four-week-old db/db mice were divided into db/db group, db/db+agomir-NC group and db/db+miR-26a-5p agomir group according to random number table method, with 10 mice in each group, and 10 db/m mice of the same week-old were set as normal control group. At the age of 10 weeks, pathological changes were observed through light and electron microscopy. Kidney weight/body weight (KW/BW), urinary albumin to creatinine ratio (ACR), fasting blood glucose (FBG) and other biochemical indicators were also detected. The position and expression of miR-26a-5p in kidney tissue were determined through fluorescence in situ hybridization and quantitative real-time PCR, while the expressions of transient receptor potential cation channel-6 (TRPC6) and Nephrin in kidney tissue were determined by Western blotting and immunohistochemistry. (2) In vitro experiment: The immortalized mouse podocytes (MPC5) were divided into 5 groups: normal glucose group, high mannitol group, high glucose group, high glucose+miR-26a-5p mimic group, and high glucose+mimic-NC group. The expressions of miR-26a-5p, TRPC6 and Nephrin were detected. Luciferase reporter assay was conducted to research the relationship of miR-26a-5p and TRPC6. Results:(1) In vivo experiment: Compared with db/m group, db/db mice exhibited lower KW/BW and disrupted conditions of ACR, FBG, total cholesterol, triglycerides and low density lipoprotein cholesterol (all P<0.01). Increased glomeruli volume, more extracellular matrix deposition, thicker basement membrane and more foot process fusion were observed by light and electron microscope. Increased expression of TRPC6 protein as well as decreased expression of Nephrin protein and miR-26a-5p were detected in kidney tissues of db/db mice ( P<0.05). Compared with db/db+agomir-NC group, db/db mice transfected by miR-26a-5p agomir exhibited less albuminuria, with less protein expression of TRPC6 and more Nephrin in kidney tissue (all P<0.05). (2) In vitro experiment: Compared with normal glucose group, high glucose-treated podocytes exhibited increased expression of TRPC6 ( P<0.05), as well as decreased expression of Nephrin ( P<0.05) and miR-26a-5p ( P<0.01). Compared with high glucose+mimic-NC group, lower expression of TRPC6 and higher expression of Nephrin were detected in podocytes transfected by miR-26a-5p mimic (both P<0.05). Luciferase reporter assay confirmed that miR-26a-5p could regulate the expression of TRPC6 precisely. Conclusions:The expression of miR-26a-5p in podocytes is down-regulated in the context of high glucose and miR-26a-5p protects podocytes from injury via inhibiting the expression of TRPC6 in DKD.

Circular RNAs (circRNAs) are covalently closed single-stranded RNAs with regulatory activity and regarded as new types of therapeutic targets in diseases such as cancers. By means of RNA-Seq technology, numerous cardiac circRNAs were discovered. Although some candidates were detected to involve in heart disease in murine model, relative low sequence conservation and expression level of their human homologs might result in an insignificant, even distinct effect in the human heart. Therefore, the therapeutic significance of circRNAs should be more strictly considered. It is also necessary to discuss which circRNA is suitable for being applied in heart disease treatment. Here, we are willing to introduce a ~ 1830 nt circular transcript generated from single exon of sodium/calcium exchanger 1 (ncx1) gene (also called solute carrier family 8 member A1, slc8a1), usually named circNCX1 or circSLC8A1, which is gradually coming into our view. circNCX1 is one of the most cardiac-enriched circRNAs. It is widely existent in vertebrate and relatively conserved, indicating its indispensability during the evolution of species. Indeed, circNCX1 was shown to involve in heart development by some expression analysis. It was further revealed that the dysregulation of circNCX1 is one of the key pathogeneses of heart diseases including ischemic cardiac injury and hypertrophic cardiomyopathy. To make the significance of circNCX1 in the heart clear, we comprehensively dissected circNCX1 in the aspects of its parental gene structure, conservation, biogenesis and expression profiles, function, molecular mechanisms, and clinical application in this review. New medicine or therapeutic schedules based on circNCX1 are expected in the future.