Cardio-reno-vascular protection in type 2 diabetes mellitus: new insights into pharmacotherapeutic management.

INTRODUCTION: From 2008 and following the withdrawal of rosiglitazone, obligatory cardiovascular outcomes trials are performed for glucose lowering drugs introduced to the market to ensure their cardiovascular (CV) safety. Paradoxically, these studies have demonstrated CV safety but also shown additional cardio-reno-vascular protection of some therapeutic agents. Additionally, nonsteroidal mineralocorticoid receptor antagonists (ns-MRA) have emerged as novel drugs for cardio - and renoprotection in type 2 diabetes (T2D) and chronic kidney disease (CKD). In addition to atherosclerotic CV disease, heart failure (HF) and CKD are important clinical problems in T2D leading to poor quality of life and premature death as such cardio-reno-vascular protection is an important clinical issue. AREAS COVERED: We provide new insights into pharmacotherapeutic cardio-reno-vascular protection in T2D based on the new glucose lowering drugs and ns-MRA. PUB MED/CINAHL/Web of Science/Scopus were searched (May 2024). EXPERT OPINION: The conventional glucose lowering approach alone which was implemented for decades is now replaced by the use of disease modifying drugs which lower the rates of CV events, HF decompensation, hospitalization due to HF, slow progression of CKD and all-cause mortality. Indeed, the choice of medications in T2D should be focused on underlying co-morbidities with cardio-reno-vascular protection rather than a gluco-centric approach.

Sanqi oral solution ameliorates renal fibrosis by suppressing fibroblast activation via HIF-1α/PKM2/glycolysis pathway in chronic kidney disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Sanqi oral solution (SQ) is a traditional Chinese patent medicine, widely used to treat chronic kidney diseases (CKD) in the clinic in China. Previous studies have confirmed its anti-renal fibrosis effect, but the specific pharmacological mechanism is still unclear. AIM OF THE STUDY: Focusing on energy metabolism in fibroblasts, the renoprotective mechanism of SQ was investigated in vitro and in vivo. METHODS: Firstly, the fingerprint of SQ was constructed and its elementary chemical composition was analyzed. In the 5/6Nx rats experiment, the efficacy of SQ on the kidney was evaluated by detecting serum and urine biochemical indexes and pathological staining of renal tissues. Lactic acid and pyruvic acid levels in serum and renal tissues were detected. PCNA protein expression in kidney tissue was detected by immunofluorescence assay and Western blot. Expression levels of HIF-1α, PKM2 and HK2 were determined by immunohistochemistry, Western blot or RT-qPCR assay. In addition, the effect of SQ intervention on cell proliferation and glycolysis was evaluated in TGF-ß1-induced NRK-49F cells, and the role of SQ exposure and HIF-1α/PKM2/glycolysis pathway were further investigated by silencing and overexpressing HIF-1α gene in NRK-49F cells. RESULTS: In 5/6 Nx rats, SQ effectively improved renal function and treated renal injury. It reduced the levels of lactic acid and pyruvic acid in kidney homogenates from CKD rats and decreased the expression levels of HIF-1α, PKM2, HK2, α-SMA, vimentin, collagen I and PCNA in kidney tissues. Similar results were observed in vitro. SQ inhibited NRK-49F cell proliferation, glycolysis and the expression levels of HIF-1α, PKM2 induced by TGF-ß1. Furthermore, we established NRK-49F cells transfected with siRNA or pDNA to silence or overexpress the HIF-1α gene. Overexpression of HIF-1α promoted cellular secretion of lactic acid and pyruvic acid in TGF-ß1-induced NRK-49F cells, however, this change was reversed by intervention with SQ or silencing the HIF-1α gene. Overexpression of HIF-1α can further induce increased PKM2 expression, while SQ intervention can reduce PKM2 expression. Moreover, PKM2 expression was also inhibited after silencing HIF-1α gene, and SQ was not effective even when given. CONCLUSION: The mechanism of action of SQ was explored from the perspective of energy metabolism, and it was found to regulate PKM2-activated glycolysis, inhibit fibroblast activation, and further ameliorate renal fibrosis in CKD by targeting HIF-1α.

Fenofibrate and risk of end-stage renal disease: A nationwide cohort study.

AIM: Previous studies have shown that fenofibrate improves outcomes such as albuminuria and estimated glomerular filtration rate decline. We hypothesize that fenofibrate has renoprotective effects and prevents or delays the development of end-stage renal disease. The objective of this study is to investigate the risk of incident end-stage renal disease in relation to fenofibrate treatment in patients who are already taking statins. MATERIALS AND METHODS: We performed a nationwide population-based cohort study using data from the Korea National Health Information Database from 2010 to 2017. Among adults using statins, 413 715 fenofibrate users were compared with 413 715 fenofibrate non-users after 1:1 age, sex and triglyceride matching. The endpoint of this study was incident end-stage renal disease. RESULTS: During a median 3.96-year follow-up, the incidence per 1000 person years of end-stage renal disease was lower in fenofibrate users than in fenofibrate non-users (0.885 vs. 0.960, p < 0.0001). The hazard ratio for end-stage renal disease was lower (0.763, 95% confidence interval 0.710-0.821) in fenofibrate users. This association was significant in patients with hypertension, proteinuria and an estimated glomerular filtration rate <60 mL/min/1.732. CONCLUSIONS: Fenofibrate use in patients taking statins with either hypertension, proteinuria, or decreased estimated glomerular filtration rate is associated with a low risk of incident end-stage renal disease. To confirm the renoprotective effect of fenofibrate in chronic kidney disease, a randomized controlled trial is warranted.

The Renoprotective Mechanisms of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2i)-A Narrative Review.

Chronic kidney disease (CKD) is a noncommunicable condition that has become a major healthcare burden across the globe, often underdiagnosed and associated with low awareness. The main cause that leads to the development of renal impairment is diabetes mellitus and, in contrast to other chronic complications such as retinopathy or neuropathy, it has been suggested that intensive glycemic control is not sufficient in preventing the development of diabetic kidney disease. Nevertheless, a novel class of antidiabetic agents, the sodium-glucose cotransporter-2 inhibitors (SGLT2i), have shown multiple renoprotective properties that range from metabolic and hemodynamic to direct renal effects, with a major impact on reducing the risk of occurrence and progression of CKD. Thus, this review aims to summarize current knowledge regarding the renoprotective mechanisms of SGLT2i and to offer a new perspective on this innovative class of antihyperglycemic drugs with proven pleiotropic beneficial effects that, after decades of no significant progress in the prevention and in delaying the decline of renal function, start a new era in the management of patients with CKD.

The renoprotective potential of montelukast: a scoping review.

Introduction: Kidney damage can result from various factors, leading to structural and functional changes in the kidney. Acute kidney injury (AKI) refers to a sudden decline in kidney function, while chronic kidney disease involves a gradual deterioration lasting more than 3 months. Mechanisms of renal injury include impaired microcirculation, inflammation, and oxidative stress. Cysteinyl-leukotrienes (CysLTs) are inflammatory substances contributing to tissue damage. Montelukast, a leukotriene receptor antagonist, has shown potential renoprotective effects in experimental models of kidney injury. Methods: The authors conducted a scoping review using PubMed, Scopus, and Web of Science databases to identify relevant studies investigating the impact of montelukast on renal diseases. Articles published until 2022 were included and evaluated for quality. Data extraction and analysis were performed based on predetermined inclusion criteria. Results: The scoping review included 30 studies from 8 countries. Montelukast demonstrated therapeutic effects in various experimental models of nephrotoxicity and AKI induced by agents such as cisplatin, lipopolysaccharide, diclofenac, amikacin, Escherichia coli, cyclosporine, methotrexate, cobalt-60 gamma radiation, doxorubicin, and cadmium. Studies involving human subjects with nephrotic syndrome, pyelonephritis, and other renal diseases also reported positive outcomes with montelukast treatment. Montelukast exhibited anti-inflammatory, anti-apoptotic, antioxidant, and neutrophil-inhibiting properties, leading to improved kidney function and histopathological changes. Conclusions: Montelukast shows promise as a renoprotective medication, particularly in early-stage kidney injury. Its ability to mitigate inflammation, oxidative stress, and neutrophil infiltration contributes to its therapeutic effects. Further research is needed to explore the clinical applications and mechanisms underlying the renoprotective action of montelukast.

Valsartan Mitigates the Progression of Methotrexate-Induced Acute Kidney Injury in Rats via the Attenuation of Renal Inflammation and Oxidative Stress.

Background: Methotrexate (MTX) is a folic acid antagonist, commonly administered for the treatment of a variety of cancers. However, methotrexate toxicity including bone marrow suppression and hepatic and renal toxicity limits its use. Angiotensin AT1 receptor blockers including Valsartan (Val) possess the ability to ameliorate MTX-induced toxicity through various mechanisms. In this study, we explored the potential reno-protective effects of Val against MTX-induced acute kidney injury in rats. Methods: Twenty-four Wistar rats were randomly segregated into 3 groups. Group 1 served as the control group and received an oral dose of 1mL/kg of normal saline. Group 2 received a single dose of 20 mg/kg of MTX intraperitoneally (IP) for 5 days. Group 3 received a single IP dose of 20 mg/kg of MTX followed by an oral dose of 10 mg/kg of Valsartan for 5 days. At the end of the experiment, the levels of serum kidney biomarkers, inflammatory and oxidative stress markers were accessed. Furthermore, the effect of MTX on kidney tissue histology was examined. Results and discussion: Our results showed that MTX treatment increased the level of serum kidney and inflammatory biomarkers and decreased the level of antioxidants SOD and GSH while increasing the lipid peroxidation contents. Furthermore, MTX treatment caused structural changes to kidney histology. However, the administration of Val significantly prevented these changes. Conclusion: Valsartan possesses nephroprotective potential and might serve as a potential therapeutic strategy against MTX-induced kidney injury.

Renoprotective strategies.

Kidney disease remains a condition with an increasing incidence, high morbidity and mortality associated with cardiovascular events. The incidence of end-stage renal disease is expected to increase. Despite of the technical improvement, dialysis never achieved a full clearance of the blood dialysis. Therefore, the demand for new renoprotective measures has never been greater. Here, we report new strategies for preventing renal damage.

Renoprotective mechanisms of exercise training against acute and chronic renal diseases - A perspective based on experimental studies.

Regular exercise training can lead to several health benefits, reduce mortality risk, and increase life expectancy. On the other hand, a sedentary lifestyle is a known risk factor for chronic diseases and increased mortality. Acute kidney injury (AKI) and chronic kidney disease (CKD) represent a significant global health problem, affecting millions of people worldwide. The progression from AKI to CKD is well-recognized in the literature, and exercise training has emerged as a potential renoprotective strategy. Thus, this article aims to review the main molecular mechanisms underlying the renoprotective actions of exercise training in the context of AKI and CKD, focusing on its antioxidative, anti-inflammatory, anti-apoptotic, anti-fibrotic, and autophagy regulatory effects. For that, bibliographical research was carried out in Medline/PubMed and Scielo databases. Although the pathophysiological mechanisms involved in renal diseases are not fully understood, experimental studies demonstrate that oxidative stress, inflammation, apoptosis, and dysregulation of fibrotic and autophagic processes play central roles in the development of tissue damage. Increasing evidence has suggested that exercise can beneficially modulate these mechanisms, potentially becoming a safe and effective non-pharmacological strategy for kidney health protection and promotion. Thus, the evidence base discussed in this review suggests that an adequate training program emerges as a valuable tool for preserving renal function in experimental animals, mainly through the production of antioxidant enzymes, nitric oxide (NO), irisin, IL-10, and IL-11. Future research can continue to explore these mechanisms to develop specific guidelines for the prescription of exercise training in different populations of patients with kidney diseases.

Gender-Specific Renoprotective Pathways in αMUPA Transgenic Mice Subjected to Acute Kidney Injury.

Acute kidney injury (AKI) is a serious health concern with high morbidity and high mortality worldwide. Recently, sexual dimorphism has become increasingly recognized as a factor influencing the severity of the disease. This study explores the gender-specific renoprotective pathways in αMUPA transgenic mice subjected to AKI. αMUPA transgenic male and female mice were subjected to ischemia-reperfusion (I/R)-AKI in the presence or absence of orchiectomy, oophorectomy, and L-NAME administration. Blood samples and kidneys were harvested 48 h following AKI for the biomarkers of kidney function, renal injury, inflammatory response and intracellular pathway sensing of or responding to AKI. Our findings show differing responses to AKI, where female αMUPA mice were remarkably protected against AKI as compared with males, as was evident by the lower SCr and BUN, normal renal histologically and attenuated expression of NGAL and KIM-1. Moreover, αMUPA females did not show a significant change in the renal inflammatory and fibrotic markers following AKI as compared with wild-type (WT) mice and αMUPA males. Interestingly, oophorectomized females eliminated the observed resistance to renal injury, highlighting the central protective role of estrogen. Correspondingly, orchiectomy in αMUPA males mitigated their sensitivity to renal damage, thereby emphasizing the devastating effects of testosterone. Additionally, treatment with L-NAME proved to have significant deleterious impacts on the renal protective mediators, thereby underscoring the involvement of eNOS. In conclusion, gender-specific differences in the response to AKI in αMUPA mice include multifaceted and keen interactions between the sex hormones and key biochemical mediators (such as estrogen, testosterone and eNOS). These novel findings shed light on the renoprotective pathways and mechanisms, which may pave the way for development of therapeutic interventions.

Evaluation of Effect of Montelukast in the Model of Streptozotocin Induced Diabetic Nephropathy in Rats.

Background: Diabetic nephropathy is a progressive condition and a leading cause of end-stage renal disease. Oxidative stress and inflammation play an important role in its pathogenesis. In pre-clinical studies, Montelukast had shown renoprotective and anti-oxidant properties, hence the study was planned to evaluate the effect of Montelukast in a Streptozotocin (STZ) induced model of diabetic nephropathy. Methods: 40 Wistar rats of either sex were randomly divided into four groups viz. 1. Vehicle control group, 2. Enalapril (5 mg/kg), 3. Montelukast low-dose (10 mg/kg) and 4. High-dose (20 mg/kg) group. On day 1, diabetes was induced using a single dose of STZ (60 mg/kg) intraperitoneally. Diabetes induction was verified based on fasting blood glucose (FBG) levels on day 7 and from day 8 to day 42, rats were given study drugs. FBG, serum creatinine, blood urea nitrogen (BUN) and urine microalbumin levels were assessed pre-study and post-study. Assessments of kidney malondialdehyde (MDA), reduced glutathione (GSH) and renal histopathology were carried out at the end of the study. Results: Montelukast 10 mg/kg group showed significantly lower urine microalbumin levels compared to the vehicle control group (p < 0.05). Montelukast 20 mg/kg group showed significantly lower levels of FBG, serum creatinine, BUN and urine microalbumin compared to the vehicle control group (p < 0.05). In addition, Montelukast 20 mg/kg group also showed better effects on kidney MDA and GSH levels (p < 0.05) and histopathological scores compared to the vehicle control group. Conclusion: Montelukast showed a protective effect in the model of diabetic nephropathy because of its antioxidant effect.

Inorganic nitrate benefits contrast-induced nephropathy after coronary angiography for acute coronary syndromes: the NITRATE-CIN trial.

BACKGROUND AND AIMS: Contrast-induced nephropathy (CIN), also known as contrast-associated acute kidney injury (CA-AKI) underlies a significant proportion of the morbidity and mortality following coronary angiographic procedures in high-risk patients and remains a significant unmet need. In pre-clinical studies inorganic nitrate, which is chemically reduced in vivo to nitric oxide, is renoprotective but this observation is yet to be translated clinically. In this study, the efficacy of inorganic nitrate in the prevention of CIN in high-risk patients presenting with acute coronary syndromes (ACS) is reported. METHODS: NITRATE-CIN is a double-blind, randomized, single-centre, placebo-controlled trial assessing efficacy of inorganic nitrate in CIN prevention in at-risk patients presenting with ACS. Patients were randomized 1:1 to once daily potassium nitrate (12 mmol) or placebo (potassium chloride) capsules for 5 days. The primary endpoint was CIN (KDIGO criteria). Secondary outcomes included kidney function [estimated glomerular filtration rate (eGFR)] at 3 months, rates of procedural myocardial infarction, and major adverse cardiac events (MACE) at 12 months. This study is registered with ClinicalTrials.gov: NCT03627130. RESULTS: Over 3 years, 640 patients were randomized with a median follow-up of 1.0 years, 319 received inorganic nitrate with 321 received placebo. The mean age of trial participants was 71.0 years, with 73.3% male and 75.2% Caucasian; 45.9% had diabetes, 56.0% had chronic kidney disease (eGFR <60 mL/min) and the mean Mehran score of the population was 10. Inorganic nitrate treatment significantly reduced CIN rates (9.1%) vs. placebo (30.5%, P < .001). This difference persisted after adjustment for baseline creatinine and diabetes status (odds ratio 0.21, 95% confidence interval 0.13-0.34). Secondary outcomes were improved with inorganic nitrate, with lower rates of procedural myocardial infarction (2.7% vs. 12.5%, P = .003), improved 3-month renal function (between-group change in eGFR 5.17, 95% CI 2.94-7.39) and reduced 1-year MACE (9.1% vs. 18.1%, P = .001) vs. placebo. CONCLUSIONS: In patients at risk of renal injury undergoing coronary angiography for ACS, a short (5 day) course of once-daily inorganic nitrate reduced CIN, improved kidney outcomes at 3 months, and MACE events at 1 year compared to placebo.

Plausible prediction of renoprotective effects of sodium-glucose cotransporter-2 inhibitors in patients with chronic kidney diseases.

This narrative review was conducted due to uncertainty in predicting the beneficial impact of sodium-glucose cotransporter-2 (SGLT2) inhibitors on a dip of estimated glomerular filtration rate (eGFR), regardless of albuminuria presence, with the aim of elucidating plausible predictors of kidney function outcome among patients treated with SGLT2 inhibitors. The PubMed and Web of Science databases were searched in May 2023 for relevant articles published in English between 2013 and 2023. A total of 25 full-length scientific publications (comprising 11 large randomized trials and two cohort studies) were included for analysis. The majority of studies demonstrated a limited value of conventional biomarkers, such as initial decline in eGFR, a trajectory of eGFR during SGLT2 inhibitor administration, and urine albumin-to-creatinine ratio (UACR), in prediction of renoprotection. Included studies showed that the tendency to decreased eGFR, UACR, hemoglobin, glycosylated hemoglobin, lipid profile, serum uric acid, inflammatory biomarkers and natriuretic peptides did not predict clinical outcomes in groups without heart failure (HF) treated with SGLT2 inhibitors. In HF groups, biomarkers of inflammation, kidney injury, oxidative stress, mitochondrial dysfunction, ketogenesis, energy metabolism, and adipose tissue dysfunction (adropin and irisin), were detected with the aim of finding potential biomarkers. Biomarkers of adipose tissue dysfunction and inflammation may be promising for predicting SGLT2 inhibitor benefit compared with N-terminal pro-B-type natriuretic peptide and energy metabolism indicators.

Potential renoprotective effect of SGLT2 inhibitors against contrast-induced AKI in diabetic STEMI patients undergoing primary PCI.

BACKGROUND: It has been demonstrated that there is a significant reduction in the incidence of cardiovascular events, mortality rates, and worsening kidney disease in patients using sodium-glucose cotransporter 2 inhibitors (SGLT2i). However, there is limited information about the effect of SGLT2i on the incidence of contrast-induced acute kidney injury (CI-AKI) in patients undergoing primary percutaneous intervention (pPCI). AIMS: Our research was focused on examining how SGLT2i exposure impacts CI-AKI occurrence in patients with ST-segment elevation myocardial infarction (STEMI) and undergoing pPCI. RESULTS: This retrospective, single-center, case-control study included diabetic patients diagnosed with STEMI who underwent pPCI in a tertiary healthcare center between 2021 and 2022. The study population included SGLT2i users (n = 130) and non-SGLT2i users (n = 165). Inverse probability propensity score weighting and doubly robust estimation were performed to decrease bias and to balance covariate distribution for estimating average treatment for those treated. In a doubly robust inverse probability weighted regression model, in which covariates were balanced, CI-AKI risk was also found to be lower in the SGLT2i-user group (OR: 0.86 [0.76-0.98]; 95% CI; P = 0.028). In addition, ejection fraction, admission creatinine, albumin, and volume of contrast media were found to be independent predictors of CI-AKI in patients presenting with STEMI and undergoing pPCI. CONCLUSION: Our study provides evidence supporting the potential protective effect of SGLT2i against CI-AKI in diabetic patients presenting with STEMI and undergoing pPCI.

Sirtuin 3 is required for the dexmedetomidine-mediated alleviation of inflammation and oxidative stress in nephritis.

INTRODUCTION: Although sirtuin 3 (SIRT3) is known to be involved in dexmedetomidine (DEX)-mediated alleviation of renal ischemia and reperfusion injury, the influence of the association between DEX and SIRT3 on nephritis development remains unclear. In this study, the role of SIRT3 in DEX-mediated amelioration of inflammation and oxidative stress in nephritis as well as the possible underlying mechanism were explored in vivo and in vitro. METHODS: An animal model of glomerulonephritis was generated by injecting mice with interferon-alpha (IFNα)-expressing adenoviruses, and periodic acid-Schiff staining was then used to reveal pathogenicity-related changes in the renal tissue. Additionally, human embryonic kidney cells (HEK293) and renal mesangial cells (RMCs) were treated with IFNα to establish cell models of inflammation in vitro. RESULTS: DEX administration alleviated glomerulonephritis in the animal model and upregulated SIRT3 expression in the renal tissue. SIRT3 knockdown inhibited the renoprotective effects of DEX against nephritis. IFNα induced inflammation, oxidative stress, and apoptosis in the RMCs and HEK293 cells and reduced their growth, as evidenced by the evaluation of cytokine levels (enzyme-linked immunosorbent assay), reactive oxygen species generation, catalase and superoxide dismutase activities, nuclear factor-erythroid factor 2-related factor 2/heme oxygenase-1 signal transduction, apoptotic cell proportion, and cell viability. In addition to promoting SIRT3 expression, DEX inhibited IFNα-induced inflammation, oxidative stress, and apoptosis in these cells and promoted their viability. SIRT3 knockdown partially reversed the beneficial effects of DEX on RMCs and HEK293 cells. CONCLUSIONS: Our results suggest that DEX exhibits renoprotective activity during nephritis progression, protecting renal cells against inflammatory injury by promoting SIRT3 expression.

Murine Malaria Model: Ketoconazole Prevented Malaria while Proguanil and Sulfadoxine/Pyrimethamine Protected against Malaria-associated Anemia and Kidney Damage.

BACKGROUND: The concern about the global spread of resistant malaria has made the researchers not focus only on the treatment of established infections but relatively more on the prevention of the disease. OBJECTIVE: This study evaluates the chemopreventive activity of ketoconazole in a murine malarial model. METHOD: Five out of seven groups of mice were pretreated for five days with proguanil (PRG), sulfadoxine/ pyrimethamine (SP), 10, 20, and 40 mg/kg body weight (b.w) of ketoconazole (KET10, KET20, and KET40), before being infected (on the sixth day) with Plasmodium berghei. Two other groups were infected-not-treated (INT) and not-infected-nor-treated (NINT). At 72 hours postinfection, five out of ten mice in each group were sacrificed to assess parasitemia, chemoprevention, hematologic, hepatic, and renal parameters. The remaining mice were observed for 28 days to determine their mean survival day post-infection (SDPI). RESULTS: All ketoconazole groups, except KET10, demonstrated 100% chemoprevention and significantly higher mean SDPI (p<0.001) in relation to INT (negative control). There was no significant difference in the mean SDPI observed in KET20 in relation to PRG or NINT (healthy control). A dose-related increase (p<0.01) in the mean plasma urea was observed when ketoconazole groups were compared to one another: KET10 versus KET20 (p<0.01) and KET20 versus KET40 (p<0.01). Sulfadoxine/pyrimethamine demonstrated significantly reduced mean plasma urea (p<0.001) and creatinine (p<0.05) in relation to INT and NINT, respectively. While PRG demonstrated significantly higher mean red blood cell (RBC), hemoglobin (HGB), and hematocrit (HCT) in relation to INT. CONCLUSION: Ketoconazole possesses prophylactic antimalarial activity with associated dose-related renal impairment. Sulfadoxine/pyrimethamine demonstrated renoprotective potentials, while PRG prevented malaria-associated anemia.

Ameliorative effect of montelukast against STZ induced diabetic nephropathy: targeting HMGB1, TLR4, NF-κB, NLRP3 inflammasome, and autophagy pathways.

Diabetic nephropathy (DN) is reported as one of the most serious microvascular diabetic complications and the trigger of end-stage renal disease (ESRD), underscoring the concern of any therapeutic intervention directed at ameliorating the development and progression of DN. The current study explored the renoprotective impact of montelukast (Mon) against streptozotocin (STZ)-induced DN in rats compared to a standard anti-hyperglycemic insulin (Ins) treatment. Diabetes was induced by a single dose of STZ (55 mg/kg). Diabetic rats were treated with Mon (10 and 20 mg/kg, oral gavage) for eight weeks. Mon administration for 8 weeks after induction of diabetes conferred significant dose-dependent renoprotection, independent of blood glucose levels (unlike Ins), as evidenced by the improvement in serum creatinine, and blood urea nitrogen (BUN), and ameliorated STZ-induced renal necrotic, inflammatory alterations, and renal fibrosis. Additionally, Mon treatment in diabetic rats significantly restored redox hemostasis as evidenced by malondialdehyde (MDA) and total antioxidant capacity (TAC) levels; significantly reduced the renal expression of high mobility group box (HMGB) 1, toll-like receptor (TLR) 4, nuclear factor kappa B (NF-κB) (in the nucleus), NOD-like receptor family pyrin domain containing (NLRP) 3, and interleukin (IL)-1ß. Moreover, Mon administration ameliorated the dysregulation in autophagy as evidenced by p62 and microtubule-associated protein 1A/1B-light chain 3 (LC3)-II levels. In conclusion, the renoprotective effect of Mon is potentially associated with its modulatory effect on inflammatory cytokines, antioxidant properties, and autophagy.

Perioperative acute kidney injury: The renoprotective effect and mechanism of dexmedetomidine.

Dexmedetomidine (DEX) is a highly selective and potent α2-adrenoceptor (α2-AR) agonist that is widely used as a clinical anesthetic to induce anxiolytic, sedative, and analgesic effects. In recent years, a growing body of evidence has demonstrated that DEX protects against acute kidney injury (AKI) caused by sepsis, drugs, surgery, and ischemia-reperfusion (I/R) in organs or tissues, indicating its potential role in the prevention and treatment of AKI. In this review, we summarized the evidence of the renoprotective effects of DEX on different models of AKI and explored the mechanism. We found that the renoprotective effects of DEX mainly involved antisympathetic effects, reducing inflammatory reactions and oxidative stress, reducing apoptosis, increasing autophagy, reducing ferroptosis, protecting renal tubular epithelial cells (RTECs), and inhibiting renal fibrosis. Thus, the use of DEX is a promising strategy for the management and treatment of perioperative AKI. The aim of this review is to further clarify the renoprotective mechanism of DEX to provide a theoretical basis for its use in basic research in various AKI models, clinical management, and the treatment of perioperative AKI.

Exploring the Cardiovascular Benefits of Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors: Expanding Horizons Beyond Diabetes Management.

Globally, cardiovascular disease (CVD) continues to be the primary cause of morbidity and mortality. The risk of cardiovascular disease is markedly increased in individuals with type 2 diabetes mellitus (T2DM), making managing cardiovascular health a top priority. Initially developed for their glucose-lowering properties, sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as a transformative class of pharmaceuticals with profound cardiovascular benefits that extend far beyond glycemic control. One of the most striking findings is the substantial reduction in major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and cardiovascular mortality, observed in clinical trials evaluating SGLT2 inhibitors. These extraordinary cardioprotective effects are demonstrated by landmark trials such as EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58, which are discussed in detail. In addition, SGLT2 inhibitors have demonstrated positive outcomes in heart failure (HF) with reduced ejection fraction, which has led to their incorporation into HF treatment guidelines. SGLT2 inhibitors offer renoprotection by delaying the progression of diabetic kidney disease, reducing albuminuria, preserving glomerular filtration rates, and their immediate cardiovascular benefits. We investigate the potential mechanisms underlying these renal benefits, focusing on the role of hemodynamic alterations and intraglomerular pressure reduction. In addition, SGLT2 inhibitors have a distinct diuretic effect that can contribute to volume reduction and symptom alleviation in patients with heart failure (HF). This diuretic action, distinct from conventional diuretics, warrants additional research to optimize their use in T2DM and HF patients. The risk of euglycemic diabetic ketoacidosis, genital mycobacterial infections, and bone fractures are also discussed. Understanding these issues is essential for making educated clinical decisions. In conclusion, SGLT2 inhibitors have transcended their initial function as anti-diabetic agents to become essential components of cardiovascular and renal protection strategies in T2DM patients. Their diverse benefits, which include cardioprotection, renoprotection, and the potential for HF management, highlight their potential to transform cardiovascular medicine. Optimizing the use of SGLT2 inhibitors in clinical practice bears the promise of improved cardiovascular outcomes for patients with T2DM and beyond as we navigate this changing landscape.

Clinical trials with reno-vascular end points in patients with diabetes: Changing the scenario over the past 20 years.

Major clinical advances over the last 20 years in the area of diabetic kidney disease (DKD) have been confirmed in large seminal clinical trials. These findings add to the previously identified benefits resulting from intensive glucose and blood pressure control therapies. Furthermore, newer glucose lowering treatments such as SGLT2 inhibitors and GLP-1 agonists appear very promising and are likely to transform the management and outlook of DKD over the next decade. In addition, novel mineralocorticoid receptor antagonists and a recently reported trial with an endothelin receptor blocker also have the potential to change clinical practice.