Therapeutic Target For Diabetic Nephropathy Research Articles

Novel approaches and therapeutic targets for diabetic nephropathy: Advances and promising strategies

Diabetic nephropathy is a progressive condition characterized by kidney damage and functional decline, primarily attributed to hyperglycemia. Special keywords and probes related to diabetic nephropathy were utilized by Google search engine to obtain relevant information from Google, Google Scholar, PubMed, Science Alert, and Google Scholar databases. This review explores the interconnected mechanisms underlying its pathogenesis. Hyperglycemia initiates glomerular hypertrophy and increased glomerular filtration rate as compensatory responses, but persistent hyperglycemia leads to renal inflammation, oxidative stress, abnormal extracellular matrix (ECM) accumulation, and increased albuminuria. These processes contribute to structural changes, declining glomerular filtration rate, and potential end-stage renal disease (ESRD) progression. Advanced glycation end products (AGEs) and the renin-angiotensin system (RAS) play key roles in hyperglycemic-induced glomerular hypertrophy. Glomerular hyperfiltration, mediated by the renin-angiotensin-aldosterone system (RAAS), impaired tubuloglomerular feedback, and increased capillary filtration coefficient, further contributes to increased glomerular filtration rate. Inflammation and oxidative stress, triggered by hyperglycemia and AGEs, promote kidney damage. Abnormal ECM accumulation, driven by hyperglycemia and the transforming growth factor-beta pathway, leads to structural changes. Hyperglycemia-induced microalbuminuria and proteinuria reflect early signs of kidney damage. Managing diabetic nephropathy poses challenges, but ongoing research offers potential solutions. Novel therapeutic targets, combination therapies, personalized medicine approaches, regenerative medicine, and gene therapy are being explored. Advancements in diagnostics, including targeted therapies and non-invasive tools, show promise in preventing or mitigating the progression of diabetic nephropathy. Understanding these mechanisms is crucial for early detection, glycemic control, blood pressure management, and targeted therapies to slow disease progression. Collaboration among healthcare stakeholders is essential in finding effective solutions for this complex condition. This review therefore highlights the importance of a comprehensive approach to managing diabetic nephropathy and improving patient outcomes.

The emerging role of MALAT1 lncRNA in diabetic nephropathy: based on the review of the literature and bioinformatic analysis

Previous studies have found that the metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) exerts its biological effects on the progression of diabetic nephropathy by sponging microRNAs and affecting the gene transcription of downstream molecules. In this study, the primary emphasis is placed on the functions that MALAT1 plays in relation to the pathophysiology of diabetic nephropathy as well as the processes that underlie these roles. In addition, the usage of this long noncoding RNA as a possible biomarker or therapeutic target for diabetic nephropathy will be discussed.

Weighted gene co-expression network analysis of key targets and interventional mechanism of Milkvetch root in diabetic nephropathy.

This work aimed to explore the key targets and intervention mechanisms of Huangqi (Astragalus membranaceus) in diabetic nephropathy using weighted gene co-expression network analysis (WGCNA). The findings will provide references for identifying critical therapeutic targets for diabetic nephropathy. The GSE1009 dataset was selected from the Gene Expression Omnibus (GEO) database of the National Center for Biotechnology Information (NCBI) for analysis. WGCNA network was constructed to identify differentially expressed genes (DEGs). Gene ontology (GO) and pathway enrichment analysis were performed on the DEGs. There were 752 downregulated DEGs and 1,547 upregulated DEGs in the diabetic nephropathy samples. Genes such as PLCE1, CLIC5, PTPRO, HSPA12A, AIF1, GMDS, and SEMA5A were significantly suppressed in the diabetic nephropathy samples, while genes such as CEP152, LUNAR1, and SLC9A1 were significantly upregulated. The optimal soft threshold for the WGCNA network was determined as 12. Hierarchical clustering analysis was conducted to detect co-expression modules with corresponding color assignments, and a total of 9 modules were identified. Clinical characteristics showed a high correlation with the gray, blue, green, and brown modules of the WGCNA. GO analysis and KEGG pathway enrichment analysis revealed that the blue module DEGs were mainly enriched in immune response, inflammatory response, signal transduction, plasma membrane, extracellular region, cell surface, extracellular matrix, and proteinaceous extracellular matrix. The green module DEGs were mainly enriched in mitochondrial elongation, mitochondrial mutation termination, translation, mitochondrial inner membrane, mitochondrion, ATP biosynthetic process, mitochondrial large ribosomal subunit, mitochondrial intermembrane space, nucleolus, and ribosome. Visualization analysis of the bioactive components of Huangqi showed compounds such as quercetin, resveratrol, 7-O-methylisomucronulatol, and isoquercetin, which had more targets. Differentially expressed genes in diabetic nephropathy were mainly enriched in immune response and inflammatory response. Various components of Huangqi have positive application value in the treatment of diabetic nephropathy and can be considered for clinical promotion.

Panax Notoginseng Saponins Alleviate High Glucose-Induced Glomerular Endothelial Cell Injury by Inhibiting the ET-1/PKC/TGF-β1 Signaling Pathway

This study aimed to investigate the protective effects and underlying mechanisms of Panax notoginseng saponins (PNS) on glomerular endothelial cell (GEC) injury induced by high glucose, which is crucial in the development of diabetic nephropathy. GECs were treated with high glucose alone, PNS alone, or a combination of PNS and overexpression of endothelin-1 (ET-1), a key regulator in endothelial dysfunction. The results showed that high glucose inhibited cell viability, increased reactive oxygen species (ROS) levels, and upregulated the expression of fibronectin (FN), collagen type IV (Col-IV), protein kinase C (PKC), transforming growth factor-beta 1 (TGF-β1), and ET-1. Additionally, high glucose downregulated the expression of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT). PNS treatment significantly protected against high glucose-induced GEC injury by promoting cell viability, reducing ROS generation, downregulating FN, Col-IV, PKC, TGF-β1, and ET-1 expression, and upregulating SOD, GSH-Px, and CAT expression. However, ET-1 overexpression reversed the protective effects of PNS, indicating the involvement of the ET-1/protein kinase C (PKC)/TGF-β1 pathway. In conclusion, PNS demonstrated a protective effect against high glucose-induced GEC injury by inhibiting the ET-1/PKC/TGF-β1 pathway. These findings suggest that PNS may be a potential therapeutic target for diabetic nephropathy by antagonizing ET-1.

Short-chain fatty acids directly exert anti-inflammatory responses in podocytes and tubular epithelial cells exposed to high glucose.

Aims: Gut-microbiome derived short-chain fatty acids exert anti-inflammatory effects and delay progression of kidney disease in diabetic nephropathy. The aim of this study was to examine the impact in vivo and in vitro of short-chain fatty acid treatment on cellular pathways involved in the development of experimental diabetic nephropathy. Methods: To determine the effect of short-chain fatty acids in diabetic nephropathy, we compared wildtype, GPR43-/- and GPR109A-/- mice diabetic mice treated with acetate or butyrate and assessed variables of kidney damage. We also examined the impact of short-chain fatty acid treatment on gene expression in renal tubular cells and podocytes under high glucose conditions. Results: Short-chain fatty acid treatment with acetate or butyrate protected wild-type mice against development of diabetic nephropathy, exhibiting less glomerular hypertrophy, hypercellularity and interstitial fibrosis compared to diabetic controls. Acetate and butyrate treatment did not provide the same degree of protection in diabetic GPR43-/- and GPR109A-/- diabetic mice respectively. Consistent with our in vivo results, expression of pro-inflammatory genes in tubular epithelial cells exposed to high glucose were attenuated by acetate and butyrate treatment. Acetate did not reduce inflammatory or fibrotic responses in glucose stimulated GPR43-/- TECs. Butyrate mediated inhibition of pro-fibrotic gene expression in TECs through GPR109A, and in podocytes via GPR43. Conclusion: SCFAs protect against progression of diabetic nephropathy and diminish podocyte and tubular epithelial injury and interstitial fibrosis via direct, GPR-pathway dependent effects on intrinsic kidney cells. GPR43 and GPR109A are critical to short-chain fatty acid mediated reno-protection and have potential to be harnessed as a therapeutic target in diabetic nephropathy.

Myokines: Novel therapeutic targets for diabetic nephropathy.

With the increasing incidence of diabetic nephropathy (DN), there is an urgent need to find effective DN preventive and therapeutic modalities. It is widely believed that effective exercise is good for health. However, the beneficial role of exercise in kidney disease, especially in DN, and the underlying molecular mechanisms have rarely been reported. Muscle is not only an important motor organ but also an important endocrine organ, secreting a group of proteins called "myokines" into the blood circulation. Circulating myokines then move to various target organs to play different biological roles. In this review, we summarize the currently known myokines and the progress in research relating them to DN and discuss its potential as a therapeutic target for DN.

Bone-kidney axis: A potential therapeutic target for diabetic nephropathy.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). However, its pathogenesis remains unclear, and effective prevention and treatment strategies are lacking. Recently, organ-to-organ communication has become a new focus of studies on pathogenesis. Various organs or tissues (the liver, muscle and adipose tissue) secrete a series of proteins or peptides to regulate the homeostasis of distal organs in an endocrine manner. Bone, an important part of the body, can also secrete bone-derived proteins or peptides that act on distal organs. As an organ with high metabolism, the kidney is responsible for signal and material exchange with other organs at any time through circulation. In this review, we briefly discussed bone composition and changes in bone structure and function in DN and summarized the current status of bone-derived proteins and their role in the progression of DN. We speculated that the "bone-kidney axis" is a potential target for early diagnosis and treatment of DN.

Sestrin2 attenuates renal damage by regulating Hippo pathway in diabetic nephropathy.

Glomerular mesangial cell proliferation and extracellular matrix accumulation contribute to the progression of diabetic nephropathy (DN). As a conserved stress-inducible protein, sestrin2 (Sesn2) plays critical role in the regulation of oxidative stress, inflammation, autophagy, metabolism, and endoplasmic reticulum stress. In this study, we investigated the role of Sesn2 on renal damage in diabetic kidney using transgenic mice overexpressing Sesn2 and the effect of Sesn2 on mesangial cell proliferation and extracellular matrix accumulation in diabetic conditions and the possible molecular mechanisms involved. Sesn2 overexpression improved renal function and decreased glomerular hypertrophy, albuminuria, mesangial expansion, extracellular matrix accumulation, and TGF-β1 expression, as well as oxidative stress in diabetic mice. In vitro experiments, using human mesangial cells (HMCs), revealed that Sesn2 overexpression inhibited high glucose (HG)-induced proliferation, fibronectin and collagen IV production, and ROS generation. Meanwhile, Sesn2 overexpression restored phosphorylation levels of Lats1 and YAP and inhibited TEAD1 expression. Inhibition of Lats1 accelerated HG-induced proliferation and expression of fibronectin and collagen IV. Verteporfin, an inhibitor of YAP, suppressed HG-induced proliferation and expression of fibronectin and collagen IV. However, Sesn2 overexpression reversed Lats1 deficiency-induced Lats1 and YAP phosphorylation, nuclear expression levels of YAP and TEAD1, and proliferation and fibronectin and collagen IV expressions in HMCs exposed to HG. In addition, antioxidant NAC or tempol treatment promoted phosphorylation of Lats1 and YAP and inhibited TEAD1 expression, proliferation, and fibronectin and collagen IV accumulation in HG-treated HMCs. Taken together, Sesn2 overexpression inhibited mesangial cell proliferation and fibrosis via regulating Hippo pathway in diabetic nephropathy. Induction of Sesn2 may be a potential therapeutic target in diabetic nephropathy.

Gandi Capsule Improved Podocyte Lipid Metabolism of Diabetic Nephropathy Mice through SIRT1/AMPK/HNF4A Pathway.

Podocyte lipid accumulation is a potential therapeutic target for diabetic nephropathy (DN). This study was aimed at clarifying the mechanism of Gandi capsule (GDC) ameliorating DN by regulating the lipid metabolism of podocytes. Network pharmacology methods were performed to screen the key molecules and potential targets of GDC for constructing the molecular-protein interaction network of GDC and conducting signal pathway enrichment analysis. GDC was predicted to ameliorate DN through SIRT1/AMPK/HNF4A pathway. Our results showed that GDC improved renal function in db/db mice. Besides, GDC exhibited effectiveness in relieving kidney tissue damage and renal lipid accumulation in db/db mice, and same effects were present in GDC-active ingredient baicalin. We further proved the new role of HNF4A in the lipid metabolism of DN mediated by SIRT1 and AMPK signaling pathways. The results suggested decreased expression of SIRT1 and p-AMPKα in the kidney tissue and increased expression of HNF4A of db/db mice compared with the control group. GDC and baicalin could reverse these expression changes. Furthermore, similar expression changes were observed in the murine podocyte cell line (MPC-5) treated with different concentrations of GDC and baicalin. Our research suggested that GDC and its active ingredient baicalin could alleviate the abnormal lipid metabolism in the kidney of db/db mice and might exert renal protection through the SIRT1/AMPK/HNF4A pathway.

Inhibition of the lncRNA MIAT prevents podocyte injury and mitotic catastrophe in diabetic nephropathy

Podocyte damage is strongly associated with the progression of diabetic nephropathy. Mitotic catastrophe plays an essential role in accelerating podocyte loss and detachment from the glomerular basement membrane. In the current study, we observed that the long non-coding RNA (lncRNA) MIAT was noticeably upregulated in the plasma and kidney tissues of patients with diabetic nephropathy, and this upregulation was accompanied by higher albumin/creatinine ratios and serum creatinine levels. By generating CRISPR-Cas9 Miat-knockout (KO) mice in vivo and employing vectors in vitro, we found that the depletion of Miat expression significantly restored slit-diaphragm integrity, attenuated foot process effacement, prevented dedifferentiation, and suppressed mitotic catastrophe in podocytes during hyperglycemia. The mechanistic investigation revealed that Miat increased Sox4 expression and subsequently regulated p53 ubiquitination and acetylation, thereby inhibiting the downstream factors CyclinB/cdc2 by enhancing p21cip1/waf1 activity, and that Miat interacted with Sox4 by sponging miR-130b-3p. Additionally, the inhibition of miR-130b-3p with an antagomir in vivo effectively enhanced glomerular podocyte injury and mitotic dysfunction, eventually exacerbating proteinuria. Based on these findings, MIAT may represent a therapeutic target for diabetic nephropathy.

Excessive Activation of Notch Signaling in Macrophages Promote Kidney Inflammation, Fibrosis, and Necroptosis.

Diabetic nephropathy (DN) is one of the main causes of end-stage renal disease (ESRD). Existing treatments cannot control the progression of diabetic nephropathy very well. In diabetic nephropathy, Many monocytes and macrophages infiltrate kidney tissue. However, the role of these cells in the pathogenesis of diabetic nephropathy has not been fully elucidated. In this study, we analyzed patient kidney biopsy specimens, diabetic nephropathy model animals. Meanwhile, we cocultured cells and found that in diabetic nephropathy, damaged intrinsic renal cells (glomerular mesangial cells and renal tubular epithelial cells) recruited monocytes/macrophages to the area of tissue damage to defend against and clear cell damage. This process often involved the activation of different types of macrophages. Interestingly, the infiltrating macrophages were mainly M1 (CD68+iNOS+) macrophages. In diabetic nephropathy, crosstalk between the Notch pathway and NF-κB signaling in macrophages contributed to the polarization of macrophages. Hyperpolarized macrophages secreted large amounts of inflammatory cytokines and exacerbated the inflammatory response, extracellular matrix secretion, fibrosis, and necroptosis of intrinsic kidney cells. Additionally, macrophage depletion therapy with clodronate liposomes and inhibition of the Notch pathway in macrophages alleviated the pathological changes in kidney cells. This study provides new information regarding diabetic nephropathy-related renal inflammation, the causes of macrophage polarization, and therapeutic targets for diabetic nephropathy.

Integrated bioinformatics analysis reveals novel key biomarkers in diabetic nephropathy.

The underlying molecular mechanisms of diabetic nephropathy have yet not been investigated clearly. In this investigation, we aimed to identify key genes involved in the pathogenesis and prognosis of diabetic nephropathy. We downloaded next-generation sequencing data set GSE142025 from Gene Expression Omnibus database having 28 diabetic nephropathy samples and nine normal control samples. The differentially expressed genes between diabetic nephropathy and normal control samples were analyzed. Biological function analysis of the differentially expressed genes was enriched by Gene Ontology and REACTOME pathways. Then, we established the protein-protein interaction network, modules, miRNA-differentially expressed gene regulatory network and transcription factor-differentially expressed gene regulatory network. Hub genes were validated by using receiver operating characteristic curve analysis. A total of 549 differentially expressed genes were detected including 275 upregulated and 274 downregulated genes. The biological process analysis of functional enrichment showed that these differentially expressed genes were mainly enriched in cell activation, integral component of plasma membrane, lipid binding, and biological oxidations. Analyzing the protein-protein interaction network, miRNA-differentially expressed gene regulatory network and transcription factor-differentially expressed gene regulatory network, we screened hub genes MDFI, LCK, BTK, IRF4, PRKCB, EGR1, JUN, FOS, ALB, and NR4A1 by the Cytoscape software. The receiver operating characteristic curve analysis confirmed that hub genes were of diagnostic value. Taken above, using integrated bioinformatics analysis, we have identified key genes and pathways in diabetic nephropathy, which could improve our understanding of the cause and underlying molecular events, and these key genes and pathways might be therapeutic targets for diabetic nephropathy.

Pharmacological inhibition of MyD88 suppresses inflammation in tubular epithelial cells and prevents diabetic nephropathy in experimental mice.

Emerging evidence shows that chronic inflammation mediated by toll-like receptors (TLRs) contributes to diabetic nephropathy. Myeloid differentiation primary-response protein-88 (MyD88) is an essential adapter protein of all TLRs except TLR3 in innate immunity. It is unclear whether MyD88 could be a therapeutic target for diabetic nephropathy. Here, we used a new small-molecule MyD88 inhibitor, LM8, to examine the pharmacological inhibition of MyD88 in protecting kidneys from inflammatory injury in diabetes. We showed that MyD88 was significantly activated in the kidney of STZ-induced type 1 diabetic mice in tubular epithelial cells as well as in high glucose-treated rat tubular epithelial cells NRK-52E. In cultured tubular epithelial cells, we show that LM8 (2.5-10 μM) or MyD88 siRNA attenuated high-concentration glucose-induced inflammatory and fibrogenic responses through inhibition of MyD88-TLR4 interaction and downstream NF-κB activation. Treatment with LM8 (5, 10 mg/kg, i.g.) significantly reduced renal inflammation and fibrosis and preserved renal function in both type 1 and type 2 diabetic mice. These renoprotective effects were associated with reduced MyD88-TLR4 complex formation, suppressed NF-κB signaling, and prevention of inflammatory factor expression. Collectively, our results show that hyperglycemia activates MyD88 signaling cascade to induce renal inflammation, fibrosis, and dysfunction. Pharmacological inhibition of MyD88 may be a therapeutic approach to mitigate diabetic nephropathy and the inhibitor LM8 could be a potential candidate for such therapy.

Telmisartan Mitigates High-Glucose-Induced Injury in Renal Glomerular Endothelial Cells (rGECs) and Albuminuria in Diabetes Mice.

Diabetic nephropathy (DN) is a common and severe complication of diabetes, impacting millions of people worldwide. High concentrations of serum glucose-associated injury of renal glomerular endothelial cells (rGECs) are involved in the DN pathogenesis. We found that exposure to high glucose increased the expression of angiotensin II type 1 receptor (AT1R) in human rGECs (hrGECs). To block the increased AT1R level, we used the newly developed antagonist Telmisartan. This study investigated whether Telmisartan possessed a beneficial effect against high-glucose-induced insults in hrGECs and explored the underlying mechanism. Our findings indicate that Telmisartan ameliorated high-glucose-induced mitochondrial dysfunction by increasing mitochondrial membrane potential. Also, Telmisartan attenuated oxidative stress by reducing the levels of two oxidative stress biomarkers 8-hydroxy-2 deoxyguanosine (8-OHDG) and malondialdehyde (MDA). Further, we found that Telmisartan prevented high-glucose-induced expression of NADPH oxidase 2 (NOX-2). Interestingly, exposure to high glucose resulted in the increased endothelial permeability of renal glomerular endothelial cells, which was mitigated by treatment with Telmisartan. Mechanistically, these effects are mediated by the MLCK/MLC-2/occludin signaling pathway. In the leptin-deficient db/db diabetic mouse model, we proved that Telmisartan treatment ameliorated the reduction of occludin and albuminuria. In conclusion, our findings demonstrate that Telmisartan possesses protective effects on high-glucose-induced injury to renal glomerular endothelial cells; its antagonizing of AT1R could be a potential therapeutic target in diabetic nephropathy.

Recent therapeutic targets in diabetic nephropathy.

The prevalence of diabetes mellitus has been increased dramatically which in turn leads to complications including cardiovascular diseases, diabetic kidney disease, and substantially end-stage renal disease. We reviewed articles discussing the pathophysiology of diabetic nephropathy with new agents that may be useful in the management of the disease. We used PubMed, Scopus, Google Scholar and the Open-access searching engines. The recent recommendations primarily depend on glycaemic and blood pressure control and the use of standard renin-angiotensin system blockade. Currently, the use of agents with nephroprotective effects beyond the hyperglycaemic lowering effect has been evidenced clinically. In his review, the pathophysiology, clinical manifestations, and lines of treatment of diabetic nephropathy are discussed. In addition, a focus on the clinical role and nephroprotective effects of the emerging therapeutic class, dipeptidyl peptidase IV (DPP-4) inhibitors, is addressed in detail.

Hyperpolarized pyruvate to measure the influence of PKM2 activation on glucose metabolism in the healthy kidney.

The purpose of the current study was to investigate if hyperpolarized [1-13 C]pyruvate can inform us on the metabolic consequences for the kidney glucose metabolism upon treatment with the pyruvate kinase M2 (PKM2) activator TEPP-46, which has shown promise as a novel therapeutic target for diabetic nephropathy. A healthy male Wistar rat model was employed to study the conversion of [1-13 C]pyruvate to [1-13 C]lactate in the kidney 2 and 4 h after treatment with TEPP-46. All rats were scanned with hyperpolarized [1-13 C]pyruvate kidney MR and vital parameters and blood samples were taken after scanning. The PKM2 activator TEPP-46 increases the glycolytic activity in the kidneys, leading to an increased lactate production, as seen by hyperpolarized pyruvate-to-lactate conversion. The results are supported by an increase in blood lactate, a decreased blood glucose level and an increased pyruvate kinase (PK) activity. The metabolic changes observed in both kidneys following treatment with TEPP-46 are largely independent of renal function and could as such represent a new and extremely sensitive metabolic readout for future drugs targeting PKM2. These results warrant further studies in disease models to evaluate if [1-13 C]pyruvate-to-[1-13 C]lactate conversion can predict treatment outcome.

MO630SNOGO-B IS AN IMPORTANT CONTRIBUTOR TO GLOMERULAR ENDOTHELIAL CELL STABILITY AND VASCULAR REMODELLING INTERVENING ON VEGFA/VEGFR2 SIGNALLING

Abstract Background and Aims Nogo-B is an endoplasmic reticulum protein present as a full length and circulating soluble isoform (sNogo-B) corresponding to the first ∼200aa of the N-terminus. Nogo-B is expressed in glomerular endothelial cells (GECs) and is downregulated in the diabetic glomeruli; its repletion, ameliorates diabetic glomerulopathy. However, the precise biological role of Nogo-B and its soluble form in GEC is not well understood. We hypothesise that sNogo-B could modulate VEGFA/VEGFR2 signalling, and vascular remodelling resulting in improved GECs health and vascular remodelling (vessel repair/new vessel formation). We predict that this effect may be mediated by changes in VEGFA/VEGFR2 signalling; a critical signalling pathway which regulates blood vessel function in physiology and disease. Method For this experiment we used human conditionally immortalised GECs. Cells were used after differentiation at 37°. GECs were infected with adenovirus vector expressing sNogo-B or identical vector lacking sNogo-B cDNA (control vector). Cells were serum starved (4 hours, FBS 2%) and exposed to VEGFA (50 ng/ml) for 5’ 10’ 15’ min and VEGFR2 phosphorylation assessed with western immunoblotting. Results VEGFA-Mediated VEGFR2 phosphorylation was upregulated in wild-type GECs after 15 min VEGFA incubation (P<0.05) n=4. sNogo-B overexpression upregulated the sNogo-B protein level in the supernatant by 10 fold and prevented VEGFA/VEGFR2 phosphorylation in human immortalized glomerular endothelial cells(P<0.05). Conclusion sNogo-B prevents the VEGFA mediated VEGFR2 phosphorylation in GECs. Upregulation of VEGFA/VEGFR2 signalling has been implicated in diabetic glomerulopathy. sNogo-B inhibition of VEGFA/VEGFR2 signalling opens new investigations looking at the potential role of sNogo-B as therapeutic target in diabetic nephropathy.

MRC2 Promotes Proliferation and Inhibits Apoptosis of Diabetic Nephropathy.

Diabetic nephropathy (DN) is an important microvascular complication of diabetes and is the main cause of end-stage renal disease. Type 2 mannose receptor C (MRC2) is a member of the mannose receptor protein family, which has been confirmed to have the ability to promote the cell migration signaling pathway and invasion. By complementary DNA chip screening and analysis, we found that the expression of MRC2 was upregulated in the kidneys of mice with diabetic nephropathy. However, the role of MRC2 in diabetic nephropathy is still unclear. This work studied the effect of MRC2 on diabetic nephropathy. After verifying the results of the chip by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, we used small interfering RNAs (siRNAs) to knock down the expression of MRC2 in mouse mesangial cells (MMCs) and analyzed the level of cell proliferation and apoptosis using western blotting, Cell Counting Kit-8, and flow cytometry. The results showed that the MRC2 knockdown inhibited MMC proliferation and induced cell apoptosis. These results suggest that MRC2 may be a molecular marker and a therapeutic target for diabetic nephropathy.

Determining the influence of high glucose on exosomal lncRNAs, mRNAs, circRNAs and miRNAs derived from human renal tubular epithelial cells

Diabetic nephropathy is a lethal disease that can lead to chronic kidney disease and end-stage kidney disease. Exosomes, which are nanosized extracellular vesicles, are closely involved in intercellular communication. Most importantly, exosomes play critical roles in disease occurrence and development. However, the function of exosomes in diabetic nephropathy progression has not been fully elucidated. In the present study, we determined the expression profiles and differences of lncRNAs, mRNAs, circRNAs and miRNAs in exosomes derived from human renal tubular epithelial cells with or without high glucose (HG) treatment. A total of 169 lncRNAs, 885 mRNAs, 3 circRNAs and 152 miRNAs were differentially expressed in exosomes secreted by HG-challenged HK-2 cells (HG group) compared with controls (NC group). The functions of differentially expressed mRNAs, mRNAs colocalized or coexpressed with differentially expressed lncRNAs (DElncRNAs), potential target genes of miRNAs and source genes of circRNAs were investigated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis.According to these differentially expressed RNAs, we established an integrated circRNA-lncRNA-miRNA-mRNA regulatory network. In conclusion, our study suggested that exosomal lncRNAs, mRNAs, circRNAs and miRNAs participate in the progression of diabetic nephropathy and may be possible biomarkers and therapeutic targets in diabetic nephropathy.

MicroRNAs as Regulators of Immune and Inflammatory Responses: Potential Therapeutic Targets in Diabetic Nephropathy.

Diabetic nephropathy (DN) is the principal cause of end-stage renal disease and results in high morbidity and mortality in patients, causing a large socioeconomic burden. Multiple factors, such as metabolic abnormalities, inflammation, immunoregulation and genetic predisposition, contribute to the pathogenesis of DN, but the exact mechanism is unclear, and the therapeutic strategies are not satisfactory. Accordingly, there is an unmet need for new therapeutic targets and strategies for DN. MicroRNAs (miRNAs) act as major epigenetic mechanisms that regulate gene expression and provide novel insights into our understanding of the molecular and signaling pathways that are associated with various diseases, including DN. Studies in the past decade have shown that different miRNAs affect the progression of DN by modulating different aspects of immune and inflammatory responses. Therefore, in this review, we summarized the pivotal roles of miRNAs in inflammatory and immune processes, with an integrative comprehension of the detailed signaling network. Additionally, we discussed the possibilities and significance of these miRNAs as therapeutic targets in the treatment of DN. This review will facilitate the identification of new therapeutic targets and novel strategies that can be translated into clinical applications for DN treatment.