• JAK-STAT pathway
• autoimmune diseases
• cancer
• inflammation

• Humans
• Podocytes/pathology
• Diabetic Nephropathies/metabolism
• Mesangial Cells/metabolism
• Endothelial Cells/metabolism
• Kidney Glomerulus/pathology
• Diabetes Mellitus/pathology

• JAK/STAT signaling
• diabetic kidney disease
• etiology
• inhibitor
• treatment strategy

• diabetes
• oxidative stress
• reactive oxygen species

• Humans
• Oxidative Stress/physiology
• Diabetes Mellitus
• Reactive Oxygen Species
• Cardiovascular Diseases
• Cardiovascular System/metabolism
• NADPH Oxidases/metabolism

• Janus kinases (JAK)
• cytokines
• fibroblast
• fibrosis
• inhibitor
• signal transducer and activator of transcription (STAT)

• Animals
• Humans
• Janus Kinases/metabolism
• Signal Transduction/physiology
• STAT Transcription Factors/genetics
• STAT Transcription Factors/metabolism
• Neoplasms/metabolism
• Fibrosis
• Mammals/metabolism

Background: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. This study explored the core genes and pathways associated with DKD to identify potential diagnostic and therapeutic targets.

Methods: We downloaded microarray datasets GSE96804 and GSE104948 from the Gene Expression Omnibus (GEO) database. The dataset includes a total of 53 DKD samples and 41 normal samples. Differentially expressed genes (DEGs) were identified using the R package “limma”. The Metascape database was subjected to Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses to identify the pathway and functional annotations of DEGs. A WGCAN network was constructed, the hub genes in the turquoise module were screened, and the core genes were selected using LASSO regression to construct a diagnostic model that was then validated in an independent dataset. The core genes were verified by in vitro and in vivo experiments.

Results: A total of 430 DEGs were identified in the GSE96804 dataset, including 285 upregulated and 145 downregulated DEGs. WGCNA screened out 128 modeled candidate gene sets. A total of eight genes characteristic of DKD were identified by LASSO regression to build a prediction model. The results showed accuracies of 99.15% in the training set (GSE96804) and 94.44% and 100%, respectively, in the test (GSE104948-GPL22945 and GSE104948-GPL24120). Three core genes (OAS1, SECTM1, and SNW1) with high connectivity were selected among the modeled genes. In vitro and in vivo experiments confirmed the upregulation of these genes.

Conclusion: Bioinformatics analysis combined with experimental validation identified three novel DKD-specific genes. These findings may advance our understanding of the molecular basis of DKD and provide potential therapeutic targets for its clinical management.

Diabetic nephropathy (DN) is a chronic, inflammatory disease affecting millions of diabetic patients worldwide. DN is associated with proteinuria and progressive slowing of glomerular filtration, which often leads to end-stage kidney diseases. Due to the complexity of this metabolic disorder and lack of clarity about its pathogenesis, it is often more difficult to diagnose and treat than other kidney diseases. Recent studies have highlighted that the immune system can inadvertently contribute to DN pathogenesis. Cells involved in innate and adaptive immune responses can target the kidney due to increased expression of immune-related localization factors. Immune cells then activate a pro-inflammatory response involving the release of autocrine and paracrine factors, which further amplify inflammation and damage the kidney. Consequently, strategies to treat DN by targeting the immune responses are currently under study. In light of the steady rise in DN incidence, this timely review summarizes the latest findings about the role of the immune system in the pathogenesis of DN and discusses promising preclinical and clinical therapies.

• Diabetes Mellitus/pathology
• Diabetic Nephropathies/pathology
• Humans
• Immunity
• Inflammation/metabolism
• Kidney/pathology
• Kidney Failure, Chronic/etiology

• National Natural Science Foundation of China

• Cancer
• Cytokine
• Immunity
• JAK
• STAT
• Transcription factor

Signal transducer and activator of transcription (STAT) plays an essential role in the inflammatory reaction and immune response of numerous renal diseases. STATs can transmit the signals of cytokines, chemokines, and growth factors from the cell membrane to the nucleus. In the canonical STAT signaling pathways, upon binding with their cognate receptors, cytokines lead to a caspase of Janus kinases (JAKs) and STATs tyrosine phosphorylation and activation. Besides receptor-associated tyrosine kinases JAKs, receptors with intrinsic tyrosine kinase activities, G-protein coupled receptors, and non-receptor tyrosine kinases can also activate STATs through tyrosine phosphorylation or, alternatively, other post-translational modifications. Activated STATs translocate into the nucleus and mediate the transcription of specific genes, thus mediating the progression of various renal diseases. Non-canonical STAT pathways consist of preassembled receptor complexes, preformed STAT dimers, unphosphorylated STATs (U-STATs), and non-canonical functions including mitochondria modulation, microtubule regulation and heterochromatin stabilization. Most studies targeting STAT signaling pathways have focused on canonical pathways, but research extending into non-canonical STAT pathways would provide novel strategies for treating renal diseases. In this review, we will introduce both canonical and non-canonical STAT pathways and their roles in a variety of renal diseases.

• STAT
• renal diseases
• signal transduction

Janus kinase 2 (JAK2) is activated in diabetic mellitus (DM) conditions and may enhance oxidative stress, apoptosis and fibrosis in many tissues. Whether JAK2 activation is involved in the occurrence of diabetic erectile dysfunction (ED) is unknown.

We performed this study to investigate the effect of JAK2 deficiency on diabetic ED.

Conditional JAK2 gene knockout mice (Cre^+/+‐JAK2^fl/fl) were used, in which JAK2 gene knockout could be induced by tamoxifen. Mice fell into four groups: control, JAK2 knockout (JAK2^−/−), DM, and DM with JAK2^−/−. DM was induced by intraperitoneal injection of streptozotocin. Two months later, JAK2 gene knockout was induced with tamoxifen in Cre^+/+‐JAK2^fl/fl mice. After another 2 months, erectile function was measured by electrical stimulation of the cavernous nerve, and penile tissues were harvested. Ratio of maximal intracavernosal pressure (MIP) to mean arterial blood pressure (MAP), expression and phosphorylation of JAK2, oxidative stress level, NO/Cyclic Guanosine Monophosphate (cGMP) pathway, apoptosis, fibrosis, and transforming growth factor beta 1 (TGF‐β1)/Smad/Collagen IV pathway in corpus cavernosum, were measured.

JAK2 expression was remarkably decreased after induction with tamoxifen. JAK2 was activated in penile tissues of diabetic mice, and JAK2 deficiency could improve the impaired erectile function caused by DM. However, in mice without DM, JAK2 deficiency had no apparent influence on erectile function. Levels of oxidative stress, apoptosis, fibrosis, and TGF‐β1/Smad/Collagen IV pathway were all elevated by DM, whereas JAK2 deficiency lessened these alterations in diabetic mice. Moreover, JAK2 deficiency improved the expression of the down‐regulated NO/cGMP pathway in diabetic mice. In non‐diabetic mice, no apparent changes were found in aforementioned parameters after JAK2 gene knockout.

Our study showed that JAK2 deficiency could improve erectile function in diabetic mice, which might be mediated by reduction in oxidative stress, apoptosis, and fibrosis in corpus cavernosum.

• Janus kinase 2
• apoptosis
• diabetic erectile dysfunction
• fibrosis
• oxidative stress

• SCFA
• STAT3
• complement C5
• diabetic kidney disease
• gut microbiota
• inflammation

The intracellular ROCK signaling pathway is an important modulator of blood pressure and of cardiovascular and renal remodeling when Rho-kinase activity is increased. Besides, in preclinical models of diabetes, ROCK activation has also a role in abnormal glucose metabolism as well as in subsequent vascular and myocardial dysfunction. In humans, there are a few data assessing ROCK activation in patients with type 2 diabetes mellitus (T2D) and no studies assessing upstream/downstream components of the ROCK pathway. We assessed here levels of ROCK activation and some of the RhoA/ROCK cascade molecules in peripheral blood mononuclear cells (PBMCs) in T2D patients under current treatment.

Cross-sectional observational study comparing 28 T2D patients under current antidiabetic treatment with 31 consecutive healthy subjects, matched by age and gender. Circulating levels of malondialdehyde, angiotensin II and inflammatory cytokines IL-6 and IL-8 were determined in all subjects. ROCK activation in PMBCs, upstream and downstream cascade proteins, and levels of the proinflammatory molecules VCAM, ICAM-1 and IL-8 were determined in their PMBCs by Western blot.

Compared to healthy controls, ROCK activation in T2D patients measured by 2 direct ROCK targets in PBMCs was increased by 420 and 570% (p < 0001) and it correlated significantly with serum glucose levels. p38 MAPK phosphorylation (downstream from ROCK) and JAK-2 (upstream from ROCK) were significantly higher in the T2D patients by 580% and 220%, respectively. In T2D patients, significantly increased PBMC levels of the proinflammatory molecules VCAM-1, ICAM-1 and IL-8 were observed compared to control subjects (by 180%, 360% and 260%, respectively). Circulating levels of Ang II and MDA were significantly higher in T2D patients by 29 and 63%, respectively.

T2D patients under treatment with glucose-lowering drugs, antihypertensive treatment as well as with statins have significantly increased ROCK activation in their circulating leukocytes along with higher phosphorylation of downstream cascade proteins despite pharmacologic treatment, along with increased plasma angiotensin II and MDA levels. ROCK inhibition might have an additional role in the prevention and treatment of T2D.

• Diabetes
• ERM
• Fasudil
• JAK
• MYPT-1
• Metabolic syndrome
• Metformin
• ROCK
• Rho kinase
• p38 MAPK

• diabetes
• inflammation
• renal disease

• PI07/0870 Instituto de Salud Carlos III
• PI15/00298 Instituto de Salud Carlos III
• PI16/02057 Instituto de Salud Carlos III
• PI16/00024 Instituto de Salud Carlos III
• FI14/00033 Instituto de Salud Carlos III
• CD16/00165 Instituto de Salud Carlos III

• Diabetic nephropathy
• MiR-520h
• NORAD
• TLR4

• Advanced glycation end products
• Diabetic nephropathy
• End-stage renal disease
• Glomerular filtration rate
• Medicinal plants
• Mitogen-activated protein kinases

• Animals
• Diabetic Nephropathies/drug therapy
• Diabetic Nephropathies/metabolism
• Humans
• Hypoglycemic Agents/chemistry
• Hypoglycemic Agents/pharmacology
• NF-kappa B/metabolism
• Phytochemicals/pharmacology
• Phytochemicals/therapeutic use
• Plants, Medicinal/chemistry
• Transcription Factor RelA
• Transforming Growth Factor beta
• p38 Mitogen-Activated Protein Kinases/metabolism

• Abdominal aortic aneurysm
• Klf4
• Phenotype switching
• Pin1
• Smooth muscle
• Ubiquitylation

• cell signaling
• diabetic nephropathy
• inflammation
• podocyte

• Albuminuria/drug therapy
• Albuminuria/pathology
• Animals
• Diabetic Nephropathies/drug therapy
• Diabetic Nephropathies/genetics
• Diabetic Nephropathies/pathology
• Diabetic Nephropathies/urine
• Disease Models, Animal
• Disease Progression
• Fibronectins/metabolism
• Glomerular Basement Membrane/cytology
• Glomerular Basement Membrane/pathology
• Humans
• Janus Kinase 2/antagonists & inhibitors
• Janus Kinase 2/metabolism
• Male
• Mice
• Mice, 129 Strain
• Mice, Transgenic
• Podocytes/metabolism
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• RNA, Messenger/metabolism
• STAT3 Transcription Factor/metabolism
• Signal Transduction/drug effects

• U01 DK076139 NIDDK NIH HHS
• P30 DK089503 NIDDK NIH HHS
• N01DK75000 NIDDK NIH HHS
• U01 DK060994 NIDDK NIH HHS
• P30 DK020572 NIDDK NIH HHS
• P30 DK081943 NIDDK NIH HHS
• R24 DK082841 NIDDK NIH HHS
• R37 DK056731 NIDDK NIH HHS

Reactive oxidative species (ROS) toxicity remains an undisputed cause and link between Alzheimer’s disease (AD) and Type-2 Diabetes Mellitus (T2DM). Patients with both AD and T2DM have damaged, oxidized DNA, RNA, protein and lipid products that can be used as possible disease progression markers. Although the oxidative stress has been anticipated as a main cause in promoting both AD and T2DM, multiple pathways could be involved in ROS production. The focus of this review is to summarize the mechanisms involved in ROS production and their possible association with AD and T2DM pathogenesis and progression. We have also highlighted the role of current treatments that can be linked with reduced oxidative stress and damage in AD and T2DM.

• Alzheimer’s disease
• Anti-diabetic drugs
• Antioxidant treatments
• Oxidative stress
• ROS production
• Type-2 diabetes mellitus

Excessive deposition of extracellular matrix (ECM) in the glomerulus contributed by mesangial cells is the hallmark of diabetic nephropathy, eventually leading to glomerulosclerosis. In this study, we examined the regulatory signals involved in the high glucose (HG)-induced overproduction of ECM in rat mesangial cells (RMCs). We disclosed excessive fibronectin and collagen IV production, tyrosine phosphorylation of signal transducer and activator of transcription 1 and 3 (STAT1/3), and up-regulation of suppressor of cytokine signaling-3 (SOCS-3) expression in HG-treated RMCs. STAT1/STAT3 binding element was essential for SOCS-3 promoter activity stimulated by HG. HG was capable of promoting the specific DNA binding activities to an oligonucleotide probe containing the SOCS-3 sequence. The selective phosphoinositide 3-kinase (PI3K) inhibitor LY294002 and dominant negative p85 vector (DNΔp85) transfection effectively abolished these HG-induced responses. Moreover, HG markedly increased the cyclin kinase inhibitor p27^Kip1 protein expression, which could be inhibited by LY294002 or transfection of DNΔp85. Taken together, these results suggest that HG-induced SOCS-3 upregulation depends upon the presence of STAT-binding element in the SOCS-3 promoter, which is specifically activated by STAT1/3. The PI3K/STAT1/3 signaling pathway mediated HG-triggered ECM accumulation and SOCS-3 upregulation in RMCs.

• extracellular matrix
• high glucose
• mesangial cell
• phosphoinositide 3-kinase
• signal transduction

The antidiabetic properties and anti-inflammatory effects of Danzhi Jiangtang Capsules (DJC) have been demonstrated in clinical and laboratory experiments. In this study, we explored whether DJC can ameliorate advanced glycation end products- (AGEs-) mediated cell injury and the precise mechanisms of DJC in treating diabetic nephropathy (DN). Western blot analysis was employed to assess the expressions of iNOS, COX2, and SOCS and the phosphorylation of JAK2, STAT1, and STAT3 in glomerular mesangial cells (GMCs) after treatment with DJC. TNF-α, IL-6, and MCP-1 were determined using double-antibody sandwich ELISA. ROS and NADPH oxidase activity were measured by DCFH-DA assay and lucigenin-enhanced chemiluminescence, respectively. DJC significantly reversed the AGEs-induced expression of COX2 and iNOS. Moreover, DJC inhibited the AGEs-induced JAK2-STAT1/STAT3 activation, resulting in the inhibition of inflammatory cytokines such as IL-6, MCP-1, and TNF-α in a concentration-dependent manner. The ability of DJC to suppress STAT activation was also verified by the observation that DJC significantly increased the SOCS3 protein level. DJC reversed the AGEs-induced accumulation of ROS and NADPH oxidase activity, thus confirming that DJC possesses antioxidant activity. The results suggest that the anti-inflammatory effects of DJC in GMCs may be due to its ability to suppress the JAK2-STAT1/STAT3 cascades and reduce ROS production.

• JAK2
• autophagy
• lysosome
• podocyte

• Diabetic nephropathy (DN)
• Extracellular matrix (ECM)
• High glucose
• Hydrogen sulfide (H(2)S)
• Hyperglycemia

• Animals
• Diabetic Nephropathies/drug therapy
• Diabetic Nephropathies/metabolism
• Humans
• Hydrogen Sulfide/pharmacology
• Hydrogen Sulfide/therapeutic use
• Kidney/drug effects
• Kidney/metabolism
• Oxidative Stress/drug effects
• Renin-Angiotensin System/drug effects
• Signal Transduction/drug effects
• Transforming Growth Factor beta1/metabolism

• TGF-β
• fibrosis
• obstructive nephropathy

• Diabetic nephropathy
• Hyperglycemia
• Oxidative stress responsive signaling cascade
• Pharmacotherapeitics

• cell signaling
• diabetes mellitus
• diabetic nephropathy
• oxidative stress

• Angiotensin receptor blocker
• Coronary arterioles
• Type 2 diabetes mellitus
• Vascular remodeling

• diabetic nephropathy
• glomerular mesangial cell
• podocyte
• renal fibrosis
• signalling pathway

• Diabetic Nephropathies/metabolism
• Diabetic Nephropathies/pathology
• Diabetic Nephropathies/prevention & control
• Humans
• Inflammation
• Oxidative Stress
• Signal Transduction

Diabetes mellitus entails significant health problems worldwide. The pathogenesis of diabetes is multifactorial, resulting from interactions of both genetic and environmental factors that trigger a complex network of pathophysiological events, with metabolic and hemodynamic alterations. In this context, inflammation has emerged as a key pathophysiology mechanism. New pathogenic pathways will provide targets for prevention or future treatments. This review will focus on the implications of inflammation in diabetes mellitus, with special attention to inflammatory cytokines.

• Diabetes
• Diabetic nephropathy
• Diabetic kidney disease
• Inflammation
• Cytokines
• Oxidative stress

• Angiotensin II
• Cardiac fibroblast
• High glucose

• JAK-STAT pathway
• angiotensin II
• angiotensinogen
• hypertension
• kidney
• renin-angiotensin system

• Diabetic nephropathy
• IL-6 blockade
• Regulatory T cells
• Streptozotocin
• TGF-β1
• Th17 cells

Decrease in endogenous hydrogen sulfide (H₂S) was reported to participate in the pathogenesis of diabetic nephropathy (DN). This study is aimed at exploring the relationship between the abnormalities in H₂S metabolism, hyperglycemia-induced oxidative stress and the activation of intrarenal renin-angiotensin system (RAS). Cultured renal mesangial cells (MCs) and streptozotocin (STZ) induced diabetic rats were used for the studies. The expressions of angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin II (Ang II) type I receptor (AT1), transforming growth factor-β1 (TGF-β1) and collagen IV were measured by real time PCR and Western blot. Reactive oxygen species (ROS) production was assessed by fluorescent probe assays. Cell proliferation was analyzed by 5'-bromo-2'-deoxyuridine incorporation assay. Ang II concentration was measured by an enzyme immunoassay. AGT, ACE and AT1 receptor mRNA levels and Ang II concentration were increased in high glucose (HG) -treated MCs, the cell proliferation rate and the production of TGF-β1 and of collagen IV productions were also increased. The NADPH oxidase inhibitor diphenylenechloride iodonium (DPI) was able to reverse the HG-induced RAS activation and the changes in cell proliferation and collagen synthesis. Supplementation of H₂S attenuated HG-induced elevations in ROS and RAS activation. Blockade on H₂S biosynthesis from cystathione-γ-lyase (CSE) by DL-propargylglycine (PPG) resulted in effects similar to that of HG treatment. In STZ-induced diabetic rats, the changes in RAS were also reversed by H₂S supplementation without affecting blood glucose concentration. These data suggested that the decrease in H₂S under hyperglycemic condition leads to an imbalance between oxidative and reductive species. The increased oxidative species results in intrarenal RAS activation, which, in turn, contributes to the pathogenesis of renal dysfunction.

• Acetophenones/pharmacology
• Angiotensin II Type 1 Receptor Blockers/pharmacology
• Angiotensinogen/genetics
• Angiotensinogen/metabolism
• Animals
• Blood Glucose/metabolism
• Cell Proliferation/drug effects
• Cells, Cultured
• Collagen Type IV/metabolism
• Cystathionine beta-Synthase/genetics
• Cystathionine beta-Synthase/metabolism
• Cystathionine gamma-Lyase/genetics
• Cystathionine gamma-Lyase/metabolism
• Diabetes Mellitus, Experimental/enzymology
• Diabetes Mellitus, Experimental/genetics
• Diabetes Mellitus, Experimental/pathology
• Glucose/pharmacology
• Hydrogen Sulfide/pharmacology
• Hyperglycemia/enzymology
• Hyperglycemia/genetics
• Hyperglycemia/metabolism
• Hyperglycemia/pathology
• Kidney/drug effects
• Kidney/pathology
• Losartan/pharmacology
• Mesangial Cells/drug effects
• Mesangial Cells/metabolism
• Mesangial Cells/pathology
• NADPH Oxidases/metabolism
• Onium Compounds/pharmacology
• Peptidyl-Dipeptidase A/genetics
• Peptidyl-Dipeptidase A/metabolism
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Rats
• Reactive Oxygen Species/metabolism
• Receptor, Angiotensin, Type 1/genetics
• Receptor, Angiotensin, Type 1/metabolism
• Renin-Angiotensin System/drug effects
• Transforming Growth Factor beta1/metabolism

Intra bone marrow-bone marrow transplantation (IBM- BMT) + thymus transplantation (TT) has been shown to reduce the incidence of graft versus host disease (GVHD) and restore donor-derived T cell function. In addition, an increase in insulin sensitivity occurred in db/db mice after IBM-BMT+TT treatment. Heme oxygenase (HO)-1 is a stress inducible enzyme which exert antioxidant, antiapoptotic, and immune-modulating properties. We examined whether IBM-BMT+TT could modulate the expression of HO-1 in the kidneys of db/db mice. Six-week-old db/db mice with blood glucose levels higher than 250 mg/dl were treated with IBM-BMT+TT. Six weeks later, the db/db mice showed decreased body weight, blood glucose levels and insulin, and increased plasma adiponectin levels. The upregulation of HO-1 was associated with significantly (p<0.05) increased levels of peNOS and pAKT, but decreased levels of iNOS in the kidneys of db/db mice. Plasma creatinine levels also decreased (p<0.05), and the expression of type IV collagen was improved. Thus IBM-BMT+TT unregulated the expression of HO-1, peNOS and pAKT, while decreasing iNOS levels in the kidney of db/db mice. This was associated with an improvement in renal function.

• HO-1
• IBM-BMT+TT
• antioxidant
• diabetic nephropathy.