Severe Microvascular Complications Research Articles

Determinants and Stratification of Microvascular Complications of Type 2 Diabetes Mellitus.

Background Diabetes mellitus (DM) is a prevalent metabolic disorder characterized by high blood sugar levels. It is classified into type 1 (T1DM) and type 2 (T2DM), which have different mechanisms and complications. The global prevalence of diabetes, particularly T2DM, has increased significantly in recent decades, leading to a need for standardized data collection of macrovascular and microvascular complications to track disease progression and guide treatment options. This study aims to assess and correlate the prevalence and severity of microvascular complications in patients with T2DM. Methodology This observational, cross-sectional study was conducted at Poonam Multispeciality Hospital in Ahmedabad, India. A total of 4,123 diabetic patients admitted to the hospital were included. Information on sociodemographics and medical history was collected using standardized forms. Fundus photography and fluorescein angiography were performed to assess diabetic retinopathy, and estimated glomerular filtration rate and albumin-to-creatinine ratio were measured to evaluate renal function. Neurological examinations were conducted to score diabetic neuropathy. Chi-square tests were used to determine associations between medical history with diabetic retinopathy and nephropathy, and t-tests were used to compare diabetic neuropathy scores. Kendall's Tau correlation was used to determine correlations between diabetic retinopathy and nephropathy. P-values <0.05 were considered statistically significant. Results The overall prevalence of diabetic retinopathy, nephropathy, and neuropathy was 37.5%. Of the patients included, 47.9% had diabetic nephropathy and 28.9% had diabetic neuropathy. A significant association was observed between the severity of diabetic retinopathy and age, body mass index, duration of diabetes, and hemoglobin A1c (HbA1C) levels. Similarly, significant associations were found between these factors and the severity of diabetic nephropathy. Unpaired t-tests revealed significant differences in diabetic neuropathy examination scores based on the duration of diabetes and Hba1C levels. Moreover, correlation analysis indicated a low, positive correlation between diabetic retinopathy and diabetic nephropathy. Conclusions This study provides insights into the prevalence, severity, and associations of microvascular complications in patients with T2DM, contributing to the understanding and management of these conditions. Additionally, the research revealed a direct association between diabetic retinopathy and different stages of chronic kidney disease determined by the Kidney Disease Improving Global Outcome guidelines.

The roles of gut microbiota and its metabolites in diabetic nephropathy.

Diabetic nephropathy (DN) is a severe microvascular complication of diabetes, which increases the risk of renal failure and causes a high global disease burden. Due to the lack of sustainable treatment, DN has become the primary cause of end-stage renal disease worldwide. Gut microbiota and its metabolites exert critical regulatory functions in maintaining host health and are associated with many pathogenesis of aging-related chronic diseases. Currently, the theory gut-kidney axis has opened a novel angle to understand the relationship between gut microbiota and multiple kidney diseases. In recent years, accumulating evidence has revealed that the gut microbiota and their metabolites play an essential role in the pathophysiologic processes of DN through the gut-kidney axis. In this review, we summarize the current investigations of gut microbiota and microbial metabolites involvement in the progression of DN, and further discuss the potential gut microbiota-targeted therapeutic approaches for DN.

855-P: Evolution of KT-A112, an AAV-Mediated Gene Therapy for the Treatment of Type 1 Diabetes

Type 1 Diabetes (T1D) is a chronic, life-threatening autoimmune disorder characterized by profound insulin deficiency that results from progressive destruction of insulin-producing pancreatic β-cells. For over a century, exogenous insulin delivery was the only option to help T1D patients manage persistent hyperglycemia and reduce the risk of severe microvascular and macrovascular complications. Recent exploratory treatments use complex cell-based therapies requiring long-term immunosuppression. This abstract describes a unique AAV-mediated gene therapy approach to drive skeletal muscle expression of human glucokinase (GcK) and human insulin (INS). One-time IM administration to the quadriceps, gastrocnemius and tibialis anterior muscles of STZ-induced diabetic mice resulted in dose-related increases of pharmacologically active INS at fasting levels (~1 ng/mL) and human C-peptide that decreased fed and fasted blood glucose, lowered HbA1c by &amp;gt;5% at the highest dose, and reduced AUCGlu upon oral glucose challenge. Elevated triglycerides seen in control STZ-treated animals were normalized. No hypoglycemia or other adverse effects were observed through 8 weeks. No immunosuppression was required. Next steps in evaluation of KT-A112 involve a rolling dose-escalation study in STZ-treated NHPs. Disclosure C.Smith: Consultant; Horizon Therapeutics plc, Employee; Kriya Therapeutics. F.Bosch: None. M.Rhodes: None. W.W.Harrington: Consultant; Kriya Therapeutics. M.Stone: None. U.Karadge: None. J.Liu: None. W.J.Quinn: Employee; Kriya Therapeutics. A.Bassiri: None. J.Mallory: Employee; Kriya Therapeutics. V.Jimenez: None.

ADAM metallopeptidase domain 10 knockdown enables podocytes to resist high glucose stimulation by inhibiting pyroptosis via MAPK pathway.

Diabetic nephropathy (DN) is a common severe microvascular complication of diabetes mellitus, and podocyte damage occurs in the early stages of DN. The urine of patients with various types of glomerular disease presents increased levels of ADAM metallopeptidase domain 10 (ADAM10). The present study aimed to explore the role of ADAM10 in podocyte damage. Therefore, the expression of ADAM10 in high glucose (HG)-stimulated podocytes was measured by reverse transcription-qPCR and western blot. Moreover, the effects of ADAM10 knockdown on podocyte inflammation and apoptosis were determined by ELISA, western blot and TUNEL assay after confirming the efficacy of cell transfection. Subsequently, the effects of ADAM10 knockdown on the MAPK pathway and pyroptosis were assessed by western blot. Through performing the aforementioned experiments, the role of the MAPK pathway in the regulatory effects of ADAM10 was then investigated by pretreating podocytes with pathway agonists. ADAM10 expression was upregulated in HG-stimulated podocytes, while ADAM10 knockdown suppressed inflammation, apoptosis and pyroptosis of HG-stimulated podocytes and inhibited the activation of the MAPK signaling pathway. However, when podocytes were pretreated with pathway agonists (LM22B-10 or p79350), the aforementioned effects of ADAM10 knockdown were suppressed. The present study demonstrated that ADAM10 knockdown suppressed the inflammation, apoptosis and pyroptosis of HG-stimulated podocytes by blocking the MAPK signaling pathway.

Youth-Onset Type 2 Diabetes: Burden of Complications and Socioeconomic Cost

With the rise in prevalence of youth-onset type 2 diabetes (T2DM), it is imperative to understand the clinical burden of the disease and the socioeconomic burden this disease imposes. We review the most recent data on youth-onset T2DM, including its pathophysiology, complications, and treatment. We also review existing data to determine the socioeconomic burden of youth-onset T2DM. The incidence of youth-onset T2DM is rising, and significantly accelerated following the COVID-19 pandemic. Youth with T2DM are more frequently from families of racial/ethnic minorities and lower socioeconomic status. Youth-onset T2DM has more rapid disease progression compared to adult-onset type 2 diabetes. It results in earlier and more severe microvascular and macrovascular complications compared to both adult-onset T2DM and youth-onset type 1 diabetes (T1DM). While there is a lack of data describing the socioeconomic cost of youth-onset T2DM, based on extrapolation from analyses of the burden of T2DM in adults and T1DM in youth, we propose that youth-onset T2DM has higher direct and indirect costs than adult-onset T2DM. Youth-onset T2DM presents a significant clinical and socioeconomic burden due to its aggressive presentation and earlier appearance of complications. Additional research is needed regarding the cost of illness in this population.

Associations between the polymorphisms of main components in PI3K/Akt pathway and risk of diabetic kidney disease: A meta-analysis.

Diabetic kidney disease (DKD) is a severe microvascular complication frequently associated with type 1 and type 2 diabetes mellitus. The objective of this work was to evaluate the relevance of PI3K/Akt pathway polymorphisms and DKD susceptibility by a meta-analysis. Case-control studies related to the relationship between PI3K/Akt pathway polymorphisms and DKD risk were searched from Pubmed, Embase, Cochrane Library, SINOMED, CNKI, and Wanfang databases. Statistical analysis and heterogeneity test were conducted by Review Manager 5.4. Totally, 52 eligible studies were enrolled, including seven single nucleotide polymorphisms (SNPs) for four genes in the PI3K/AKT pathway (GNB3: rs5443; eNOS: rs1799983, rs869109213, rs2070744; IL-6: rs1800795, rs1800796; TNFα: rs1800629). The "M" allele of eNOS rs1799983 was related to the increased risk of DKD under random effects model, especially in Asian population (Overall:M vs. W: I2 = 75%, OR=1.29, 95%CI 1.07-1.56; MM + WM vs. WW: I2 = 75%, OR=1.50, 95%CI 1.21-1.86). The "M" allele of eNOS rs869109213 was implicated with higher prevalence of DKD under random effects model, especially in Asian population (Overall:M vs. W: I2 = 63%, OR=1.43, 95%CI 1.22-1.68; MM + WM vs. WW: I2 = 50%, OR=1.36, 95%CI 1.16-1.58; MM vs. WM + WW: I2 = 59%, OR=2.20, 95%CI 1.41-3.43). The "M" allele of eNOS rs2070744 was implicated with higher prevalence of DKD under random effects model, especially in Indian population (Overall: M vs. W: I2 = 47%, OR=1.35, 95%CI 1.15-1.59; MM + WM vs. WW: I2 = 45%, OR=1.32, 95%CI 1.07-1.62; MM vs. WM + WW: I2 = 65%, OR=2.29, 95%CI 1.39-3.77). The "M" allele of IL-6 rs1800796 was predominately associated with higher DKD risks under random effects model, especially in Asian population (Overall: M versus W: I2 = 23%, OR=1.49, 95%CI 1.21-1.84; MM + WM vs. WW: I2 = 1%, OR=1.43, 95%CI 1.15-1.77; MM + WM vs. WW: I2 = 71%, OR=2.77, 95%CI 1.09-7.06). This meta-analysis indicated that polymorphisms in the PI3K/Akt pathway in eNOS rs1799983, rs869109213, rs2070744, and IL-6 rs1800796 were related to the increased risk of DKD.

A review of the hybrid description of diabetes mellitus

Elevated blood sugar levels, which are either brought on by inadequate insulin synthesis by the pancreas or byincorrect insulin usage by the body, characterize diabetes mellitus, a chronic metabolic disease. Diabetes mellituscan cause renal failure, and those with the condition are at least 10 times more likely to have to amputate a foot dueto diabetes than those without it. High blood sugar levels are thought to contribute to kidney and heart problems.A rapid rate of beta cell malfunction and sequences resulting from an absolute lack of insulin hormone secretionmay be used to describe type 1 diabetes mellitus. Type 1 diabetes mellitus often manifests itself in young patients,although it may also affect adults. Diabetic neuropathy, one of the most severe microvascular complications ofdiabetes mellitus, is characterized by a metabolic-vascular disorder that compromises the structure and functionof peripheral somatic or autonomic nerves without inducing inflammation. Dehydration brought on by osmoticdiuresis, which impacts hyperviscosity and a hypercoagulable condition, and elevated blood glucose levels aretypical symptoms of a hyperosmolar hyperglycemic state. People with type 1 diabetes are 12 times more likelythan those with type 2 diabetes to develop diabetic nephropathy.

Fisetin Ameliorates Diabetic Nephropathy-Induced Podocyte Injury by Modulating Nrf2/HO-1/GPX4 Signaling Pathway.

Diabetic nephropathy (DN) is one of the most severe microvascular complications of diabetes and has become the leading cause of end-stage renal disease formation. The pathogenesis of diabetic nephropathy is very complex and is still not fully understood. Fisetin is a flavonoid polyphenolic compound that is widely found in different fruits, vegetables, and medicinal plants. Many studies have indicated that it has a variety of pharmacological activities. In this study, we investigated the mechanism of action of fisetin in the protection of DN-induced podocyte injury both in vivo and in vitro. Results showed that fisetin could reduce high glucose (HG)-induced podocyte injury and streptozotocin (STZ)-induced diabetic nephropathy in mice. According to the histopathological staining results, fisetin ameliorated DN-induced glomerular injury in a dose-dependent manner. Western blot and immunofluorescence results showed that fisetin effectively promoted the expression of podocyte functional integrity marker proteins and inhibited the expression of podocyte injury marker proteins. In addition, according to the Western blot and RT-qPCR results, fisetin activates the nuclear translocation of Nrf2 to exert antioxidative stress ability and affects the expression of downstream antioxidant enzymes HO-1, GPX4, and other ferroptosis-related markers, thereby protecting against HG-induced podocyte ferroptosis and oxidative stress injury in DN mice. In summary, this study demonstrated that fisetin could enhance the antioxidative stress capacity of DN mice by promoting the activation of the Nrf2/HO-1/GPX4 signaling pathway in renal tissues, and attenuated HG-induced podocytes injury and STZ-induced DN in mice.

Emerging Role of Ferroptosis in Diabetic Kidney Disease: Molecular Mechanisms and Therapeutic Opportunities.

Diabetic kidney disease (DKD) is one of the most common and severe microvascular complications of diabetes mellitus (DM), and has become the leading cause of end-stage renal disease (ESRD) worldwide. Although the exact pathogenic mechanism of DKD is still unclear, programmed cell death has been demonstrated to participate in the occurrence and development of diabetic kidney injury, including ferroptosis. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has been identified to play a vital role in the development and therapeutic responses of a variety of kidney diseases, such as acute kidney injury (AKI), renal cell carcinoma and DKD. In the past two years, ferroptosis has been well investigated in DKD patients and animal models, but the specific mechanisms and therapeutic effects have not been fully revealed. Herein, we reviewed the regulatory mechanisms of ferroptosis, summarized the recent findings associated with the involvement of ferroptosis in DKD, and discussed the potential of ferroptosis as a promising target for DKD treatment, thereby providing a valuable reference for basic study and clinical therapy of DKD.

A Review of the Hybrid Description of Diabetes Mellitus

Elevated blood sugar levels, which are either brought on by inadequate insulin synthesis by the pancreas or by incorrect insulin usage by the body, characterize diabetes mellitus, a chronic metabolic disease. Diabetes mellitus can cause renal failure, and those with the condition are at least 10 times more likely to have to amputate a foot due to diabetes than those without it. High blood sugar levels are thought to contribute to kidney and heart problems. A rapid rate of beta cell malfunction and sequences resulting from an absolute lack of insulin hormone secretion may be used to describe type 1 diabetes mellitus. Type 1 diabetes mellitus often manifests itself in young patients, although it may also affect adults. Diabetic neuropathy, one of the most severe microvascular complications of diabetes mellitus, is characterized by a metabolic-vascular disorder that compromises the structure and function of peripheral somatic or autonomic nerves without inducing inflammation. Dehydration brought on by osmotic diuresis, which impacts hyperviscosity and a hypercoagulable condition, and elevated blood glucose levels are typical symptoms of a hyperosmolar hyperglycemic state. People with type 1 diabetes are 12 times more likely than those with type 2 diabetes to develop diabetic nephropathy.

Feasibility, comparability and outcomes of three acquainted facial island flaps for periorbital defects reconstruction.

Severe coloboma of ocular malignant neoplasms post-resection poses a reconstructive challenge to surgeons. To compare the practicability, manipulability and outcomes of temporal (myocutaneous) flaps (TFs), forehead (supratrochlear artery/supraorbital artery) flaps (FFs) and buccal (facial artery) flaps (BFs) for periorbital defects reconstruction, a retrospective case series was conducted and evaluated between March 2014 and March 2021. Patient demographics and clinical parameters including age, gender, pathological diagnosis, operative methods, flap selection, operation time, aesthetic satisfaction and follow-up period were collected. The differences in complications were compared and assessed of the three flaps, including flap survival, venous congestion and donor site healing. Totally, 68 patients who underwent periorbital reconstructive operations because of common ocular malignant tumours were reviewed in this study. As for aesthetic satisfaction, a score more than "moderately dissatisfied" was obtained in 21 patients with TFs (95.5%), and of which the scores in FFs group were 12 cases (60%) and 16 cases with BFs reconstruction (61.5%) (P< .05). Severe microvascular complications underwent re-exploration operation occurred in one patient with FFs (1.5%) (P> .05). Notable flap necrosis was observed in two patients with BFs repair (2.9%) and in one case with FFs repair (1.5%), with no statistical difference between the three flap selections (P> .05). Moderate venous congestion occurred in one patient with TFs (1.5%), which was fully meliorated non-surgically. The three familiar facial island flaps are considered as minor trauma and time-saving process for reconstructing the extensive periorbital defects with comparable ranks of complications.

The role and mechanism of gut microbiota-derived short-chain fatty in the prevention and treatment of diabetic kidney disease.

Diabetic kidney disease (DKD), an emerging global health issue, is one of the most severe microvascular complications derived from diabetes and a primary pathology contributing to end-stage renal disease. The currently available treatment provides only symptomatic relief and has failed to delay the progression of DKD into chronic kidney disease. Recently, multiple studies have proposed a strong link between intestinal dysbiosis and the occurrence of DKD. The gut microbiota-derived short-chain fatty acids (SCFAs) capable of regulating inflammation, oxidative stress, fibrosis, and energy metabolism have been considered versatile players in the prevention and treatment of DKD. However, the underlying molecular mechanism of the intervention of the gut microbiota-kidney axis in the development of DKD still remains to be explored. This review provides insight into the contributory role of gut microbiota-derived SCFAs in DKD.

Plasmacytoma Variant Translocation 1 (PVT1) Gene as a Potential Novel Target for the Treatment of Diabetic Nephropathy.

Introduction: Diabetic nephropathy (DN), a severe microvascular complication in patients with diabetes, is clinically characterized by progressive decline in glomerular filtration rate (GFR). DN is the most common cause of end-stage renal disease (ESRD), and has a consistently high mortality rate. Despite the fact that the prevalence of DN is increasing worldwide, the molecular mechanism underlying the pathogenesis of DN is not fully understood. Previous studies indicated PVT1 as a key determinant of ESRD as well as a mediator of extracellular matrix (ECM) accumulation in vitro. More investigations into the role of PVT1 in DN development are needed. Objectives: To study the effect of PVT1 silencing on progression of DN in diabetic male C57BL/6 mice at early, intermediate and relatively advanced ages. Methods: Diabetic mice were treated with either scramble-siRNA (DM + siRNA (scramble)) or PVT1-siRNA (DM + siRNA (PVT1)), whereas the control mice were normal mice without siRNA injection (Control). Blood, urine and kidney were collected at the age of 9 (young), 16 (middle-aged) or 24 (old) weeks old. Kidney function, histology and molecular gene expression were evaluated. Results: Our findings showed that silencing of PVT1 reduced kidney hypertrophy, proteinuria (UAE, UACR, UPE, UPCR), serum creatinine, serum TGF-β1, serum insulin decline, glomerular and mesangial areas, and increased creatinine clearance in diabetic mice to levels closer to the age-matched controls. Also, silencing of PVT1 markedly suppressed the upregulation of PAI-1, TGF-β1, FN1, COL4A1, and downregulation of BMP7. Conclusion: Silencing of PVT1 ameliorates DN in terms of kidney function and histology in diabetic mice. The renoprotection is attributed to the reduction in ECM accumulation, TGF-β1 elevation and insulin decline. PVT1 is suggested to play an important role in ECM accumulation which makes it a possible target for the treatment of DN.

Therapeutic efficacy of dapagliflozin on diabetic kidney disease in rats

AimDiabetic kidney disease (DKD) is one of the severe microvascular complications of type 2 diabetes mellitus (T2DM), which eventually leads to irreversible renal damage and develops into end-stage renal disease (ESRD). Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a new class of antidiabetic drugs that act on the kidney to reduce glucose reabsorption. Increasing evidence confirms that dapagliflozin exerts a protective effect on DKD, but the mechanisms have not been reported. The aims of this study were to observe the therapeutic efficacy of dapagliflozin on DKD and investigate the possible immunological mechanism. Materials and methodsT2DM was modeled by a high-sugar and high-fat diet combined with STZ. Then, rats were treated with 10 mg/kg dapagliflozin for 8 weeks. The protective efficacy of dapagliflozin was evaluated by observing body weight, blood glucose, blood serum creatinine, blood urea nitrogen, 24-h urine protein, renal histology and ultrastructure, and oxidative stress levels. The immunological mechanisms were monitored by measuring the levels of TLR2/Myd88/NF-κB by immunohistochemical staining, RT-qPCR and Western blotting. ResultsAfter treatment with dapagliflozin, renal damage was greatly improved. The levels of blood glucose, renal function and proteinuria were significantly decreased, and renal pathological and ultrastructural damage was obviously extenuated, possibly due to the reduction in inflammation and the levels of oxidative stress. ConclusionsDapagliflozin has therapeutic potential for DKD. This effect was possibly mediated by inhibiting inflammation and oxidative stress levels.

Mechanisms of Chinese Herbal Medicines for Diabetic Nephropathy Fibrosis Treatment

Diabetic nephropathy (DN) is a severe microvascular complication of diabetes mellitus that is one of the main causes of end-stage renal disease, causing considerable health problems as well as significant financial burden worldwide. The pathological features of DN include loss of normal nephrons, massive fibroblast and myofibroblast hyperplasia, accumulation of extracellular matrix proteins, thickening of the basement membrane, and tubulointerstitial fibrosis. Renal fibrosis is a final and critical pathological change in DN. Although progress has been made in understanding the pathogenesis of DN fibrosis, current conventional treatment strategies may not be completely effective in preventing the disease’s progression. Traditionally, Chinese herbal medicines (CHMs) composed of natural ingredients have been used for symptomatic relief of DN. Increasing numbers of studies have confirmed that CHMs can exert a renoprotective effect in DN, and antifibrosis has been identified as a key mechanism. In this review, we summarize the antifibrotic efficacy of CHM preparations, single herbal medicines, and their bioactive compounds based on their effects on diminishing the inflammatory response and oxidative stress, regulating transforming growth factor, preventing epithelial-mesenchymal transition, and modulating microRNAs. We intend to provide patients of DN with therapeutic interventions that are complementary to existing options.

Associations of microvascular complications with all-cause death in patients with diabetes and COVID-19: The CORONADO, ABCD COVID-19 UK national audit and AMERICADO study groups.

AimTo provide a detailled analysis of the microvascular burden in patients with diabetes hopitalized for COVD‐19.Materials and MethodsWe analysed data from the French CORONADO initiative and the UK Association of British Clinical Diabetologists (ABCD) COVID‐19 audit, two nationwide multicentre studies, and the AMERICADO, a multicentre study conducted in New York area. We assessed the association between risk of all‐cause death during hospital stay and the following microvascular complications in patients with diabetes hospitalized for COVID‐19: diabetic retinopathy and/or diabetic kidney disease and/or history of diabetic foot ulcer.ResultsAmong 2951 CORONADO, 3387 ABCD COVID‐19 audit and 9327 AMERICADO participants, microvascular diabetic complications status was ascertained for 1314 (44.5%), 1809 (53.4%) and 7367 (79.0%) patients, respectively: 1010, 1059 and 1800, respectively, had ≥1 severe microvascular complication(s) and 304, 750 and 5567, respectively, were free of any complications. The patients with isolated diabetic kidney disease had an increased risk of all‐cause death during hospital stay: odds ratio [OR] 2.53 (95% confidence interval [CI] 1.66‐3.83), OR 1.24 (95% CI 1.00‐1.56) and OR 1.66 (95% CI 1.40‐1.95) in the CORONADO, the ABCD COVID‐19 national audit and the AMERICADO studies, respectively. After adjustment for age, sex, hypertension and cardiovascular disease (CVD), compared to those without microvascular complications, patients with microvascular complications had an increased risk of all‐cause death during hospital stay in the CORONADO, the ABCD COVID‐19 diabetes national audit and the AMERICADO studies: adjusted OR (adjOR) 2.57 (95% CI 1.69‐3.92), adjOR 1.22 (95% CI 1.00‐1.52) and adjOR 1.33 (95% CI 1.15‐1.53), respectively. In meta‐analysis of the three studies, compared to patients free of complications, those with microvascular complications had an unadjusted OR for all‐cause death during hospital stay of 2.05 (95% CI 1.42‐2.97), which decreased to 1.62 (95% CI 1.19‐2.119) after adjustment for age and sex, and to 1.50 (1.12‐2.02) after hypertension and CVD were further added to the model.ConclusionMicrovascular burden is associated with an increased risk of death in patients hospitalized for COVID‐19.

Emerging roles of Sodium-glucose cotransporter 2 inhibitors in Diabetic kidney disease

Diabetic kidney disease (DKD), a severe microvascular complication of diabetes mellitus, is the primary cause of end stage renal disease (ESRD). Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of novel anti-diabetic drugs for DKD, which have the potential to prevent renal function from failing. The involved mechanisms have garnered considerable attention. Besides hypoglycemic effect, it seems that various glucose-independent nephroprotective mechanisms also have a role. Among them, improvement in tubuloglomerular feedback is considered as the main reason, followed by reduced intraglomerular pressure and fluid load. In addition, reduced blood pressure, anti-inflammatory effects, nutrient deprivation signaling as well as improved endothelial function are also important. In the future, clinical trials and mechanistic studies might further complement the current knowledge on SGLT2 inhibitors and facilitate to translate these agents to clinical use. Here, we review these mechanisms of SGLT2 inhibitors with an emphasis on kidney protective effects.

Isorhapontigenin ameliorates high glucose-induced podocyte and vascular endothelial cell injuries via mitigating oxidative stress and autophagy through the AMPK/Nrf2 pathway.

Diabetic nephropathy (DN) is a severe microvascular complication of diabetes mellitus and a primary reason for end-stage renal disease (ESRD). Isorhapontigenin (ISO), a natural derivative of stilbene, has significant anti-inflammatory and antioxidant effects. Nevertheless, its impact on DN remains elusive. Human vascular endothelial cells (HUVECs) and podocytes were damaged by high glucose (HG). Cell viability and apoptosis were testified by the cell counting kit-8 (CCK-8) assay and flow cytometry, respectively. The mRNA profiles of antioxidant factors HO-1, NQO1, and Prx1 were monitored by real-time quantitative polymerase chain reaction (RT-qPCR). Western blotting (WB) was implemented to verify the expression of apoptosis-related proteins (Bax, Bad, and Bcl-XL), antioxidant factors (HO-1, NQO1, and Prx1), autophagy-related proteins (Beclin-1, ATG5, p62), podocalyxin (podocin, nephrin, and synaptopodin) and the AMPK/Nrf2 pathway. The levels of oxidative stress-related markers MDA, SOD and CAT were assessed with the corresponding kits. Compound C (CC), an inhibitor of AMPK, was deployed to probe the effects of modulating the AMPK/Nrf2 pathway on ISO in oxidative stress and autophagy in HUVECs and podocytes. Streptozotocin (STZ) was injected intraperitoneally into mice to establish an animal model of diabetes mellitus and to clarify the impact of ISO on the renal parameters such as serum creatinine, urea nitrogen and urinary protein in diabetic mice. ISO notably facilitated cell proliferation, impeded apoptosis, elevated the expression of antioxidant-related factors, alleviated HG-induced oxidative stress and activated autophagy in HUVECs and podocytes. ISO activated the AMPK/Nrf2 pathway. Attenuating AMPK diminished the protective effect of ISO on HUVECs and podocytes, curbed cell proliferation, intensified apoptosis and oxidative stress, and dampened autophagy. In-vivo experiments also displayed that ISO reduced histopathological damage, lowered serum creatinine, urea nitrogen and urinary ACR levels, and eased kidney damage in DN mice. ISO attenuates HG-induced oxidative stress and activates autophagy by motivating the AMPK/Nrf2 pathway, exerting a protective effect on HUVECs and podocytes and reducing renal injury in DN mice.

Krill Oil Turns Off TGF-β1 Profibrotic Signaling in the Prevention of Diabetic Nephropathy.

Diabetic nephropathy (DN), a severe microvascular complication of diabetes mellitus (DM), results in high mortality due to the lack of effective interventions. The current study investigated the preventive effect of krill oil (KO) on DN using a type 2 DM mouse model induced by streptozotocin and high-fat diet for 24 weeks. The diabetic mice developed albuminuria, mesangial matrix accumulation, glomerular hypertrophy, and fibrosis formation, with an increase in renal proinflammatory, oxidative and profibrotic gene expression. KO significantly prevented these effects but did not improve hyperglycemia and glucose intolerance. In high-glucose-treated mesangial cells (MCs), KO preferably modulated TGF-β1 signaling as revealed by RNA-sequencing. In TGF-β1-treated MCs, KO abolished SMAD2/3 phosphorylation and nuclear translocation and activated Smad7 gene expression. The action of KO on the SMADs was confirmed in the diabetic kidneys. Therefore, KO may prevent DN predominantly by suppressing the TGF-β1 signaling pathway.

Glomerular cell cross talk in diabetic kidney diseases.

Diabetic kidney disease (DKD) is a severe microvascular complication of diabetes mellitus. It is the leading inducement of end‐stage renal disease (ESRD), and its global incidence has been increasing at an alarming rate. The strict control of blood pressure and blood glucose can delay the progression of DKD, but intensive treatment is challenging to maintain. Studies to date have failed to find a complete cure. The glomerulus's alterations and injuries play a pivotal role in the initiation and development of DKD. A wealth of data indicates that the interdependent relationship between resident cells in the glomerulus will provide clues to the mechanism of DKD and new ways for therapeutic intervention. This review summarizes the significant findings of glomerular cell cross talk in DKD, focusing on cellular signaling pathways, regulators, and potential novel avenues for treating progressive DKD.