Renal Protective Effects Research Articles

Network pharmacology combined with transcriptomics reveals that formononetin, a biologically component of Astragalus membranaceus (Fisch.) Bunge, inhibits the PI3K/Akt signaling pathway to improve chronic renal failure

Ethnopharmacological relevanceFormononetin (FMN), one of the main isoflavones isolated from Astragalus membranaceus (Fisch.) Bunge, has multiple pharmacological and renal-protective effects. Our previous study suggested FMN as a candidate compound for the treatment of chronic renal failure (CRF). However, the mechanism underlying the repressive effect of FMN on the development of CRF is still unknown. Aims of the studyTo investigate the protective effect of FMN on CRF using in vivo and in vitro models and elucidate the potential underlying mechanism. Materials and methodsAn in vivo model of adenine-induced CRF and an in vitro model of human proximal tubule epithelial cells (HK-2) stimulated with transforming growth factor (TGF)-β1 were used. Serum levels of renal function parameters and inflammatory cytokines were evaluated. Histological analysis was performed to determine the extent of renal injury and fibrosis. Network pharmacology and mRNA sequencing were used to explore the potential mechanism. PPI analysis and molecular docking were used to identify key targets. Polymerase chain reaction and western blotting were used to determine the mechanism underlying the effect of FMN on CRF. ResultsFMN decreased the levels of renal function biochemical markers, including serum creatinine, blood urea nitrogen, and 24 h urine protein content. Treatment with FMN improved renal tubule injury and extracellular matrix (ECM) components, including collagens I and III. In addition, FMN significantly inhibited epithelial-mesenchymal transition (EMT); decreased the expression of fibronectin, N-cadherin, vimentin, α-SMA, and TGF-β1; and restored the expression of E-cadherin. The effect of FMN on renal interstitial fibrosis contributed to decreasing the expression of PI3K, p-Akt, and interleukin (IL) 4, restoring the expression of nitric oxide synthase 3 (NOS3), and reducing the release of inflammatory cytokines (IL-1β, IL-6, and tumor necrosis factor-alpha), both in vivo and in vitro. FMN treatment improved renal function and deposition of ECM components, reduced protein levels of EMT markers in rat kidneys and HK-2 cells, decreased the release of inflammatory cytokines, and inhibited the PI3K/Akt signaling pathway. ConclusionsFMN treatment significantly reduced the release of inflammatory cytokines and inhibited the effects of the PI3K/Akt signaling pathway on the key targets IL-4 and NOS3. Our results suggest FMN therapy as a novel therapeutic strategy for treating CRF.

Mizhuo Guanchangye enema delays the decline of renal function in rats with chronic kidney disease by intervening in the TLR4/MyD88/NF-κB pathway

BackgroundChronic kidney disease (CKD) is a prevalent chronic condition that poses a significant threat to human health. There is a close connection between the gut and kidneys, jointly influencing the onset and progression of CKD through the “gut-kidney axis.” Traditional Chinese medicine has shown potential in CKD treatment, but the specific mechanisms require further investigation.ObjectivesThis study aims to explore the protective effects of Mizhuo Enema (MZGCY) on kidney function in CKD rats by regulating the TLR4/MyD88/NF-κB signaling pathway.MethodsThe researcher employed a CKD rat model, which was divided into four groups: Control, Model, half-dose Mizhuo Guanchangye (1/2 MZGCY), and full-dose Mizhuo Guanchangye (MZGCY). Post enema administration, assessments were conducted on kidney function indicators, which included blood urea nitrogen (BUN), serum creatinine (SCR), and 24-h urinary protein. Additionally, measurements were taken for intestinal toxic substances such as indoxyl sulfate (IS) and lipopolysaccharide (LPS), as well as inflammatory factors interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Examinations of pathological changes in both the intestines and kidneys were also performed. During this process, immunofluorescence was utilized to detect the expression levels of proteins toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), and nuclear factor kappa B (NF-κB) in the intestinal tissues.ResultsIt was found that after enema treatment, the BUN, SCR, and 24-h urinary protein levels in the MZGCY and 1/2 MZGCY groups significantly decreased, indicating notable improvement in kidney function. Compared to the model group, the IS, LPS, IL-6, and TNF-α levels in the MZGCY and 1/2 MZGCY groups were significantly reduced. Immunofluorescence showed a marked decrease in the expression of TLR4, MyD88, and NF-κB proteins in the intestines of the MZGCY group.ConclusionMZGCY significantly reduces the levels of intestinal toxins and inflammatory factors in the serum of CKD rats by interfering with the TLR4/MyD88/NF-κB signaling pathway, thereby improving intestinal and renal pathological changes and delaying CKD progression. This study demonstrates that MZGCY has significant renal protective effects, providing a new potential approach for CKD treatment.

Preclinical Evidence of Mulberry Leaf Polysaccharides on Diabetic Kidney Disease: a Systematic Review and Meta-Analysis.

Mulberry leaf polysaccharides (MLPs) have a variety of biological activities. Preliminary scattered evidence of preclinical studies have reported their potenzial effects on diabetic kidney disease (DKD). Here, we intended to assess the preclinical evidence of MLPs and explore their potenzial mechanisms on DKD, offering a scientific reference for the therapeutic use of MLPs. The study has been registered under the CRD42022309117 registration number at PROSPERO. Comprehensive search was conducted across eight databases from their establishment till January 2024, and eight studies with 270 animals were included in the meta-analysis. The primary outcome measurements in the MLP group, including serum creatinine (Scr) (P = 0.0005), blood urea nitrogen (BUN) (P = 0.02), 24-hour urinary protein (UP) (P = 0.001), and urinary microalbumin (UAlb) (P < 0.0001), were significantly reduced compared to the control group. Additionally, MLP treatment was significantly correlated with fasting blood glucose (FBG), total cholesterol (TC), protein expression of TGF-β1, CTGF mRNA, and the kidney index (all P values < 0.05) and delayed the progression of local pathological changes in the kidney. Subgroup analysis revealed significant species differences in the efficacy of MLPs. Also, it showed that the dosage of streptozotocin potenzially affected the Scr and UAlb results, while the duration of MLP treatment influenced UAlb results. MLPs may exert potenzial renal protection by delaying renal fibrosis, inhibiting inflammatory reactions, suppressing the growth hormone-insulin-like growth factor-insulin-like growth factor binding protein axis, and regulating the insulin receptor pathway. In summary, MLPs have multifaceted renal protective effects, suggesting their potenzial for treating DKD.

SGLT2 inhibitor, a new bullet in heart failure management

The global health landscape is confronted with substantial challenges stemming from diabetes mellitus and heart failure (HF). The escalating incidence of diabetes mellitus (DM), in correlation with HF, underscores the imperative necessity for efficacious strategies in the realm of prevention and management. The most recent advancements in therapeutic approaches, specifically Sodium-glucose transporter 2 inhibitors (SGLT2i), present a promising prospect for enhancing outcomes and addressing the existing gaps in HF management. This paper aims to elucidate the significance of SGLT2i in the therapeutic management of both reduced and preserved heart failure, with or without the presence of DM. SGLT2i are new heart failure drugs. In trials, SGLT2i improved diastolic dysfunction, reduced oxidative stress, inflammation, fibrosis, and myofilament rigidity. The first SGLT2 inhibitor studies, EMPA-REG OUTCOME, DECLARE-TIMI 58, and CANVAS, showed that Empagliflozin and Canagliflozin reduced HF mortality and rehospitalization in type 2 diabetes mellitus (T2DM) patients. Dapagliflozin reduces HF hospitalizations without impacting T2DM mortality. Canagliflozin avoided creatinine rises, kidney disease deaths, and cardiovascular deaths in the CREDENCE Study. SGLT2i improve health in heart failure with preserved ejection fraction (HFpEF). SGLT2i improved health status statistically in the PRESERVED-HF and EMPEROR-Preserved investigations. SGLT2i became known as a promising therapeutic choice in the treatment of HF. The substantial evidence from prominent large-scale clinical trials has substantiated the cardiovascular and renal protective effects of SGLT2i. Furthermore, the benefits of these medications are relevant for individuals who have been diagnosed with heart failure with reduced ejection fraction (HFrEF), as well as those who are experiencing heart failure with preserved ejection fraction (HFpEF). Keyword: diabetes mellitus, heart failure, management, SGLT2 inhibitor

Integrative multi-omics and network pharmacology reveal the mechanisms of Fangji Huangqi Decoction in treating IgA nephropathy

Ethnopharmacological relevanceFangji Huangqi Decoction (FJHQD), a classical Chinese herbal formulation, has demonstrated significant clinical efficacy in the treatment of IgA nephropathy (IgAN), although its mechanisms remain poorly understood. Aim of the studyThis study aims to investigate the renal protective mechanisms of FJHQD using an integrated approach that combines transcriptomics, proteomics, and network pharmacology. MethodsRenal glomerular structure changes were assessed via hematoxylin and eosin (H&E) and Masson staining. IgA expression in the glomeruli was quantified using immunofluorescence. Furthermore, the potential mechanisms underlying the effects of FJHQD were explored through a combined strategy of network pharmacology, transcriptomics, and proteomics. The expression of signaling pathway-related proteins was detected using Western blot. ResultsFJHQD inhibited mesangial cell proliferation and renal interstitial fibrosis, and significantly reduced excessive IgA deposition in the glomerular mesangium. Network pharmacology identified 113 important active components and 8 common active components in FJHQD, with quercetin, isorhamnetin, jaranol, and kaempferol having the highest number of target interactions. Integration of network pharmacology with multi-omics approaches revealed that 44 active components regulated numerous immune and inflammatory signaling pathways through 17 hub targets. These pathways include the Calcium signaling pathway, cAMP signaling pathway, Ras signaling pathway, MAPK signaling pathway, and PI3K-AKT signaling pathway. Subsequent in vivo experiments demonstrated that FJHQD effectively regulates the identified pathways in IgAN mice. Ultimately, molecular docking results further validated the reliability of the network pharmacology combined with multi-omics analyses. ConclusionThe findings suggest that FJHQD exerts a renal protective effect, potentially through modulation of the Calcium signaling pathway, cAMP signaling pathway, Ras signaling pathway, MAPK signaling pathway, and PI3K-AKT signaling pathway. These insights offer valuable support for the clinical use of FJHQD and open new avenues for exploring the active compounds and molecular mechanisms of Traditional Chinese Medicines (TCMs).

Impact of ADA Guidelines and Medication Shortage on GLP-1 Receptor Agonists Prescribing Trends in the UK: A Time-Series Analysis with Country-Specific Insights

Background: Several GLP-1 receptor agonists (GLP-1 RAs) are used to treat type 2 diabetes (T2DM). Their cardio- and renal-protective effects and their association with substantial weight loss have been evident and progressively expanded their role in the American Diabetes Association (ADA) guidelines, which are endorsed by the European Association for the Study of Diabetes (EASD). The increased demand led to a global shortage. Methods: We utilized a repeated cross-sectional design, drawing data from national prescribing databases, to analyze six GLP-1 RAs: Dulaglutide, Exenatide, Liraglutide, Lixisenatide, Semaglutide, and Tirzepatide. AutoRegressive Integrated Moving Average (ARIMA) models with exogenous variables were applied to assess the trends over time and in different regions. Results: The prescription rates significantly differ between regions. Wales shows the highest prescribing rate for most GLP-1 RAs. The ARIMA models indicated a significant increase in their prescribing rates after the release of the 2022 ADA guidelines (e.g., Dulaglutide: Post-ADA effect of 15.22, 95% CI: [12.97, 17.47]). Following the GLP-1 RA shortages in July 2023, the prescribing rates, particularly for Semaglutide, increased (Shortage effect: 74.36, 95% CI: [71.92, 76.80]). Model diagnostics, including the Akaike Information Criterion (AIC) and Durbin–Watson statistics, confirmed the robustness of these trends. Conclusions: Informed decisions should be made by considering the prescribing trends before and after important events such as the issuing of new guidelines or safety alerts.

Evaluation of the Renal Protective Effects of Cyperus at Varying Concentrations in a Rat Model of Kidney Disorders

Cyperus plants are frequently utilized around the globe to cure a range of human ailments, including as stomach and intestinal issues, as well as for their diuretic, digestant, and lactodepurant properties. Cyperus is a very promising genus in the Cyperaceae family that is used for health supplementation. So current study aims to improving kidney health using different concentrations of (Cyperus) plant in kidney disorders rats. The experiment was conducted at an animal house. all rats were provided with a standard diet for a duration of one week. Subsequently, the rats were segregated into five groups, each consisting of 6 rats. The first group, serving as the control negative (n=6) and labeled as C-ve, were exclusively fed the basal diet for a duration of 28 days. Thirty rats were administered gentamicin to induce renal problems. The experimental groups were administered different concentrations of Cyperus (5%, 7%, and 15%). The findings indicated that group 5, consisting of rats with renal disorders that were fed with 15% Cyperus powder, had the highest blood glucose levels. Conversely, there were no significant variations seen in HDL levels among group 3 &amp; group 4. While results found that Cyperus significantly reduced in urea and uric acid in kidney disorders rats. The results suggested to use Cyperus powder for kidney disorders rats.

Elucidating the complex interplay between chronic kidney disease and hypertension.

Chronic kidney disease (CKD) and hypertension share a complex relationship, each exacerbating the progression of the other. CKD contributes to hypertension by decreasing renal function, leading to fluid retention and increased plasma volume, whereas hypertension exacerbates CKD by increasing glomerular pressure and causing renal damage. This review examines the intertwined nature of CKD and hypertension, exploring the factors driving hypertension in CKD and how hypertension accelerates CKD progression. It discusses the role of the renin-angiotensin system and inflammatory cytokines in this relationship, as well as the potential of blood pressure management to slow renal decline. While studies suggest that meticulous blood pressure control can help attenuate CKD progression, optimal management strategies remain unclear and require further investigation. This review also evaluates the evidence surrounding strict antihypertensive therapy in patients with CKD, considering both diabetic and non-diabetic cases. It recommends blood pressure targets based on CKD stage and presence of diabetes, emphasizing the importance of individualized treatment approaches. Renin-angiotensin system inhibitors are highlighted as a key pharmacological intervention due to their renal protective effects, particularly in patients with CKD with proteinuria. However, evidence regarding their efficacy in patients with CKD but without proteinuria is inconclusive. This review underscores the need for comprehensive approaches to effectively address the intertwined nature of CKD and hypertension and calls for further research to optimize clinical management strategies in this complex interplay.

Rutin loaded bilosomes for enhancing the oral activity and nephroprotective effects of rutin in potassium dichromate induced acute nephrotoxicity in rats

Rutin, a flavone glycoside, has shown to have a significant beneficial kidney protection effect in drug-induced nephropathy. However, its poor solubility and low oral bioavailability have limited its pharmacological applications. This study aimed at formulating rutin-loaded bilosomes to enhance the renal protective effect of rutin for oral application. Rutin-loaded bilosomes were developed using thin-film hydration technique. The prepared formulations were characterized by entrapment efficiency percentage (EE%), vesicular size (VS) and zeta potential (ZP) measurement. The developed formula exhibited moderate EE%, ranging from 20.02 ± 2.85 to 48.57 ± 3.57%, suitable VS results that ranged from 502.1 ± 36 to 665.1 ± 45 nm and high ZP values (≤ -41.4 ± 7.27 mV). Transmission electron microscopy revealed the spherical shape of the developed bilosomes. The in-vitro release study revealed prolonged release of rutin from bilosomes, relative to free drug. F2, prepared using the molar ratio span 60: cholesterol: sodium cholate 1:1:0.5, was selected for further investigations as it showed the highest EE%, smallest VS, optimum ZP, and persistent release profile. In-vivo studies were performed on drug-induced nephropathy in rats. Acute renal failure was induced using a single dose of potassium dichromate (PDC; 15 mg/kg; i.p). The selected formulation, F2, alleviated kidney dysfunction, oxidative stress and inflammation via decreasing MDA, TNF-α and TGF-β and increasing GSH. In addition, F2 promoted Akt/PI3K activation against PDC-induced acute renal failure. Histopathology results came in accordance with in-vivo results. Thus, bilosomes could be considered a potential delivery system for enhancing the oral delivery and kidney protection activity of rutin.

Angiotensin Receptor-Neprilysin Inhibitor for Chronic Kidney Disease: Strategies for Renal Protection.

Chronic kidney disease (CKD) and hypertension are significant global health challenges that often coexist and aggravate each other. Renin-angiotensin system (RAS) inhibitors are important to the management of these conditions; however, their efficacy for advanced CKD remains uncertain. Angiotensin receptor-neprilysin inhibitor (ARNI) have superior efficacy for heart failure (HF) management, as evidenced by landmark trials such as the PARADIGM-HF and PARAGON-HF, thus leading to its endorsement by various guidelines. Although direct evidence supporting the renal-protective effects of ARNI is lacking, post hoc analyses have suggested its potential to mitigate the decline of the estimated glomerular filtration rate and renal events, particularly in patients with HF with a relatively preserved ejection fraction. Mechanistically, ARNI augments the glomerular filtration rate by dilating glomerular arterioles, relaxing mesangial cells, and improving renal medullary blood flow, thereby mitigating interstitial fibrosis progression. ARNI also effectively addresses non-dipper hypertension, particularly in salt-sensitive individuals, thereby reducing the cardiovascular risk. Uncertainties regarding the efficacy and safety of ARNI for advanced renal failure (estimated glomerular filtration rate &lt;30 mL/min) exist. Excessive hypotension associated with ARNI use may exacerbate the renal function decline, especially in older patients with comorbid HF with a reduced ejection fraction. Hence, vigilant blood pressure monitoring is essential to optimizing the renal benefits of ARNI and minimizing adverse effects. Evidence supporting the renal benefits of ARNI continues to evolve; therefore, ARNI could mitigate renal dysfunction in select patient populations. Further research should be performed to clarify the efficacy of ARNI for advanced renal failure and refine its therapeutic application for patients with concurrent HF and renal dysfunction.

12467 Ethical Challenges During Medication Scarcity

Abstract Disclosure: K. Seetharaman: None. R. Alvi: None. V. Roth: None. J. Maheswaran: None. Ethical considerations while rationing GLP-1 RA during medication scarcity crisis: The prevalence of type 2 diabetes and obesity have risen over the past decade. Type 2 diabetes affects nearly 29 million Americans, and one in 3 Americans are obese. Prompt treatment of type 2 diabetes can result in prevention and progression of several diabetes related complications. In the past 3 decades, advancements in scientific research has led to invention of newer therapeutic agents such as the glucagon like peptide-1 receptor agonist (GLP-1 RA) for management of type 2 diabetes and these medications have shown to provide cardiovascular benefit and renal protective effects. More recently, with increasing benefits of GLP-1 RA in treating obesity even in the absence of diabetes, the prescription rates of GLP-1 RA has increased sharply leading to acute medication scarcity and the resultant crisis has created a chaos in health care having multi-faceted repercussions.We present a short movie enacting 2 clinical scenarios with doctor and patients to initiate discussions on how to ration GLP-1 receptor agonists during times of medication scarcity crisis and the bioethical aspects to consider while making such decisions. We further include discussions by enacting pharmacy care coordinator, bioethicist, critique and defense discussion. Bioethics involved in medication scarcity crisis:https://hu-my.sharepoint.com/:v:/g/personal/kseetharaman_hsph_harvard_edu/EZIHpFRCgb5AsoKLk898TgUBsdp8JNjdAGQ6vOIpZIP1Qg?e=TkxRhz We hope our enacting of various scenarios has given you all valuable ethical perspectives to consider while rationing during times of medicine scarcity.

Renal protective effect of Isaria felina mycelium powder on diet and STZ-induced diabetes mice and the identification of major chemical constituents

Type 2 diabetes is a group of metabolic diseases mainly characterized by chronic hyperglycemia. Diabetic kidney disease is the most common microvascular complication of diabetes.The aim of this study was to investigate the therapeutic effect of Isaria felina mycelium powder (IFMP) on diet and streptozotocin (STZ)-induced diabetic mouse model. And we analyze the main chemical constituents of Isaria felina mycelium powder.The main chemical constituents of the alcohol-soluble IFMP were prepared and identified by high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS). The fasting blood glucose and renal index of the mouse model was determined. Serum levels of triglyceride (TG), total cholesterol (TC), serum creatinine (Scr) and blood urea nitrogen (BUN) were detected. The levels of CD2AP and nephrin proteins in the kidney were detected by ELISA kits.A total of 32 compounds were identified, including nucleosides (16 types), amino acids (13 types), sterols (one type) and glycosides (two types). The experimental results showed that compared with the diabetes model group, IFMP reduced fasting blood glucose, food intake and water intake. Biochemical analysis indicated that IFMP reduced the serum levels of TG, TC, BUN and Scr, and increased the levels of CD2AP and nephrin proteins in the kidneys.Therefore, IFMP has the potential to treat diabetes and prevent kidney damage induced by hyperglycemia.

Obtusifolin inhibits podocyte apoptosis by inactivating NF-κB signaling in acute kidney injury.

Acute kidney injury (AKI) is a common clinical condition and is associated with unacceptable morbidity and mortality. Obtusifolin is an anthraquinone extracted from the seeds of Cassia obtusifolia with anti-inflammatory properties. This study focused on the role and mechanism of obtusifolin in AKI. The mouse podocyte cell line MPC5 was exposed to lipopolysaccharide (LPS) to establish a cell model of AKI. The viability of MPC5 cells treated with obtusifolin and/or LPS was detected by 3-(4, 5-Dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide assay. Cell apoptosis was analyzed by flow cytometry. The levels of podocyte injury- and apoptosis-related proteins as well as the nuclear factor-kappaB (NF-κB) signaling pathway was examined using western blotting analysis. The renal protective effects of obtusifolin were determined using an LPS-induced mouse model of AKI. Serum creatinine and blood urea nitrogen levels were measured. Hematoxylin-eosin staining of kidney sections was performed to evaluate renal histology. We found that MPC5 cells treated with LPS showed suppressed cell viability (p < 0.01) and increased cell apoptosis (p < 0.001). LPS reduced the protein expression of Bcl-2, nephrin, and synaptopodin as well as increased the protein levels of Bax and Cleaved Caspase-3 in podocytes in a concentration-dependent manner (p < 0.01). In addition, 10μg/ml LPS-repressed cell viability was rescued by obtusifolin in a concentration-dependent manner (p < 0.01). Moreover, LPS-induced increase in MPC5 cell apoptosis was reversed by obtusifolin treatment (p < 0.01). Obtusifolin administration ameliorated LPS-induced kidney injury and reduced blood urea nitrogen and serum creatinine levels in mice (p < 0.001). Additionally, obtusifolin inhibited LPS-induced activation of NF-κB signaling in vitro and in vivo (p < 0.01). Overall, obtusifolin was effective in protecting renal function against LPS-induced AKI via inactivation of NF-κB signaling, which suggested that obtusifolin may act as a valuable agent for AKI therapy.

New drugs on the horizon for acute kidney injury.

Acute kidney injury (AKI) is a frequent and serious complication in critically ill patients. Currently, no effective therapy to prevent or treat AKI is available. This review highlights recently published developments on pharmacological treatments that aim to prevent AKI or to alleviate the severity of AKI in critical ill patients. Studies on pharmacological interventions aimed to improve hemodynamics, renal perfusion, to mediate inflammation-associated renal damage and to reduce oxidative stress are presented, including several observational studies and randomized trials focused on the potential renal protective effects in relevant patient populations. Different existing and novel compounds are being investigated for the effects on renal endpoints and several show potential to prevent or alleviate the occurrence of AKI. It is now acknowledged that different underlying pathophysiological processes are relevant in the development of AKI. Recognition of these sub-endotypes of AKI and knowledge of the therapeutic target of different compounds is of paramount importance to select the right patient for the right treatment at the right time. The discovery of reno-protective therapies is hampered by the timely detection and recognition of the overriding mechanism of AKI. Nevertheless, several compounds are under investigation, which hold promise for a future treatment.

Assessment of renal pathophysiological processes and protective effect of quercetin on contrast-induced acute kidney injury in type 1 diabetic mice using diffusion tensor imaging

ABSTRACT Purpose: To investigate the renal pathophysiological processes and protective effect of quercetin on contrast-induced acute kidney injury (CI–AKI) in mice with type 1 diabetic mellitus(DM) using diffusion tensor imaging(DTI). Methods: Mice with DM were divided into two groups. In the diabetic + contrast medium(DCA) group, the changes of the mice kidneys were monitored at 1, 24, 48, and 72 h after the injection of iodixanol(4gI/kg). The mice in the diabetic + contrast medium + quercetin(DCA + QE) group were orally given different concentrations of quercetin for seven days before injection of iodixanol. In vitro experiments, renal tubular epithelial (HK-2) cells exposed to high glucose conditions were treated with various quercetin concentrations before treatment with iodixanol(250 mgI/mL). Results: DTI-derived mean diffusivity(MD) and fractional anisotropy(FA) values can be used to evaluate CI-AKI effectively. Quercetin significantly increased the expression of Sirt 1 and reduced oxidative stress by increasing Nrf 2/HO-1/SOD1. The antiapoptotic effect of quercetin on CI-AKI was revealed by decreasing proteins level and by reducing the number of apoptosis-positive cells. In addition, flow cytometry indicated quercetin-mediated inhibition of M1 macrophage polarization in the CI-AKI. Conclusions: DTI will be an effective noninvasive tool in diagnosing CI-AKI. Quercetin attenuates CI-AKI on the basis of DM through anti-oxidative stress, apoptosis, and inflammation.

Renal Protective Effect of Umbelliferone on Acute Kidney Injury in Rats via Alteration of HO-1/Nrf2 and NF-κB Signaling Pathway.

Acute kidney injury (AKI), formerly known as acute renal failure, refers to a sudden and often reversible decline in kidney function. Inflammatory reaction and oxidative stress play a crucial role in the expansion of renal disease. In this experimental study, we scrutinized the renal protective effect of umbelliferone against gentamicin induced renal injury in the rats and explore the mechanism. Wistar rats were used in this study and Gentamicin was used for the induction the AKI in the rats and rats were received the oral administration of umbelliferone. The body weight, organ weight, renal, oxidative stress, cytokines, inflammatory parameters were estimated. The mRNA expression caspase-3, Bax, Bcl-2, TNF-α, IL-1β, IL-6, IL-10, HO-1, and Nrf2 were estimated. Umbelliferone remarkably improved the body weight and altered the absolute and relative weight of hepatic and renal tissue. Umbelliferone significantly suppressed the level of BUN, Scr, magnesium, calcium, phosphorus, sodium, and potassium along with altered the level of oxidative stress parameters like CAT, SOD, GSH, LPO, and GPx. Umbelliferone altered the level of cytokines viz., TNF-α, Il-1β, IL-6, IL-10; inflammatory parameters like PGE2, COX-2, TGF-β, NF-κB, respectively. Umbelliferone significantly altered the mRNA expression of caspase-3, Bax, Bcl-2, TNF-α, IL-1β, IL-6, IL-10, HO-1, and Nrf2. The result showed the renal protective effect of umbelliferone against gentamycin induced renal disease via alteration of HO-1/Nrf2 and NF-κB Signaling Pathway.

Renal protective effects of helix B surface polypeptide in rats with puromycin aminonucleoside nephropathy

Background Recent studies have reported that helix B surface polypeptide (HBSP), an erythropoietin derivative, exhibits strong tissue protective effects, independent of erythropoietic effects, in a renal ischemia-reperfusion (IR) injury model. Meanwhile, the transforming growth factor-β (TGF-β) superfamily member glial cell line-derived neurotrophic factor (GDNF) demonstrated protective effect on podocytes in vitro. Using a rat puromycin aminonucleoside nephropathy (PAN) model, this study observed the renal protective effect of HBSP and investigated its renal protective effect on podocytes and mechanism related to GDNF. Methods Rats nephropathy model was induced by injection of 60 mg/kg of PAN via the tail vein. Rats in the PAN + HBSP group were injected intraperitoneally with HBSP (8 nmol/kg) 4 h before the model was induced, followed by intraperitoneal injections of HBSP once every 24 h for 7 consecutive days. The 24-hour urinary protein level was measured once every other day, and blood and renal tissue samples were collected on the 7th day for the examination of renal function, complete blood count, renal pathological changes and the expression levels of GDNF. Results Compared with the control group, the PAN nephropathy rat model showed a large amount of urinary protein. The pathological manifestations were mainly extensive fusion and disappearance of foot processes, along with vacuolar degeneration of podocytes and their separation from the glomerular basement membrane. GDNF expression was upregulated. Compared with the PAN + vehicle group, the PAN + HBSP group showed decreased urinary protein (p < 0.05). Pathological examination revealed ameliorated glomerular injury and vacuolar degeneration of podocytes. The expression of GDNF in the PAN nephropathy group was increased, when compared with the control group. The greatest expression of GDNF observed in the PAN + HBSP group (p < 0.05). Conclusions The expression of GDNF in the kidney of PAN rat model was increased. HBSP reduced urinary protein, ameliorated pathological changes in renal podocytes, increased the expression of GDNF in the PAN rat model. HBSP is likely to exert its protective effects on podocytes through upregulation of GDNF expression.

Renal protective and immunoregulatory effects of Lactobacillus casei strain Shirota in nephropathy-prone mice.

The incidence of severe acute kidney injury (AKI) is considerably high worldwide. A previous study showed that gut microbial dysbiosis was a hallmark of AKI in mice. Whether the probiotic Lactobacillus casei strain Shirota (LcS) plays a role in kidney disease, particularly AKI, remains unclear. To investigate the effects of LcS on kidney injury, tubule-specific conditional von Hippel-Lindau gene-knockout C57BL/6 mice (Vhlhdel/del mice) were supplemented without (Ctrl) or with probiotics (LcS) in Experiment 1, and their lifespan was monitored. Additionally, the Vhlhdel/+ mice were supplemented without (Ctrl and AA) or with probiotics (LcS and LcS + AA) in Experiment 2. Probiotic LcS (1 × 109 colony-forming units) was supplemented once daily. After 4 weeks of LcS supplementation, AA and LcS + AA mice were administered aristolochic acid (AA; 4 mg/kg body weight/day)-containing purified diet for 2 weeks to induce AA nephropathy before sacrifice. Supplementation of LcS significantly prolonged the lifespan of Vhlhdel/del mice, suggesting a potential renal protective effect. AA induced-nephropathy increased not only the indicators of renal dysfunction and injury, including urinary protein and kidney injury molecule (KIM)-1, serum blood urea nitrogen (BUN) and creatinine, but also serum interleukin (IL)-6 levels, renal macrophage infiltrations, and pathological lesions in Vhlhdel/+ mice. LcS supplementation significantly reduced urinary protein and KIM-1 levels, serum BUN and IL-6 levels, and renal M1 macrophages, tissue lesions, and injury scores. We also found that LcS maintained gut integrity under AA induction and increased intestinal lamina propria dendritic cells. Furthermore, LcS significantly reduced pro-inflammatory IL-17A and upregulated anti-inflammatory IL-10 production by immune cells from intestinal Peyer's patches (PP) or mesenteric lymph nodes (MLN), and significantly increased IL-10 and reduced IL-6 production by splenocytes. Prior supplementation with probiotic LcS significantly alleviated the severity of renal injury. This renal protective effect was partially associated with the enhancements of intestinal and systemic anti-inflammatory immune responses, suggesting that LcS-induced immunoregulation might contribute to its renal protective effects.

Liraglutide ameliorates inflammation and fibrosis by downregulating the TLR4/MyD88/NF-κB pathway in diabetic kidney disease.

Inflammation and fibrosis play important roles in diabetic kidney disease (DKD). Previous studies have shown that glucagon-like peptide-1 receptor (GLP-1R) agonists had renal protective effects. However, the mechanisms are not clear. The present study explored the effect of liraglutide (LR), a GLP-1R agonist, on the downregulation of glomerular inflammation and fibrosis in DKD by regulating the Toll-like receptor (TLR)4/myeloid differentiation marker 88 (MyD88)/nuclear factor κB (NF-κB) signaling pathway in mesangial cells (MCs). In vitro, rat MCs were cultured in high glucose (HG). We found that liraglutide treatment significantly reduced the HG-mediated activation of the TLR4/MYD88/NF-κB signaling pathway, extracellular matrix (ECM)-related proteins, and inflammatory factors. A combination of TLR4 inhibitor (TAK242) and liraglutide did not synergistically inhibit inflammatory factors and ECM proteins. Furthermore, in the presence of TLR4 siRNA, liraglutide significantly blunted HG-induced expression of fibronectin protein and inflammatory factors. Importantly, TLR4 selective agonist LPS or TLR4 overexpression eliminated the improvement effects of liraglutide on the HG-induced response. In vivo, administration of liraglutide for 8 wk significantly improved the glomerular damage in streptozotocin-induced diabetic mice and reduced the expression of TLR4/MYD88/NF-κB signaling proteins, ECM protein, and inflammatory factors in renal cortex. TLR4-/- diabetic mice showed significant amelioration in urine protein excretion rate, glomerular pathological damage, inflammation, and fibrosis. Liraglutide attenuated glomerular hypertrophy, renal fibrosis, and inflammatory response in TLR4-/- diabetic mice. Taken together, our findings suggest that TLR4/MYD88/NF-κB signaling is involved in the regulation of inflammatory response and ECM protein proliferation in DKD. Liraglutide alleviates inflammation and fibrosis by downregulating the TLR4/MYD88/NF-κB signaling pathway in MCs.NEW & NOTEWORTHY Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has renoprotective effect in diabetic kidney disease (DKD). In DKD, TLR4/MYD88/NF-κB signaling is involved in the regulation of inflammatory responses and extracellular matrix (ECM) protein proliferation. Liraglutide attenuates renal inflammation and overexpression of ECM proteins by inhibiting TLR4/MYD88/NF-κB signaling pathway. Therefore, we have identified a new mechanism that contributes to the renal protection of GLP-1RA, thus helping to design innovative treatment strategies for diabetic patients with various complications.

Renal Protective Effect of Boeravinone B against Diabetic Nephropathy Rats via Inhibition of The Inflammatory and JAK2/STAT3 Signalling Pathway.

Chronic inflammation is a common feature in diabetes, especially when blood sugar levels are poorly controlled. This chronic low-grade inflammation can affect various organs, including the kidneys. Podocyte damage play a key role in the development of diabetic nephropathy (DN). The aim of the study was to evaluate the nephroprotective effect of Boeravinone B (BB) against streptozotocin (STZ) induced DN in rats and explore the underlying mechanism. In this experimental study, the rats received intraperitoneal injections of STZ (60 mg/kg) to induce DN. Various doses of BB (2.5, 5, and 7.5 mg/kg) were administered orally. Glucose levels, body weights, and organ weights (hepatic and renal) were assessed. Renal, histomorphological, antioxidant, hepatic, and cytokine levels were determined, as were the mRNA expression levels of JAK2 and STAT3. At end of the experimental study, the rats were sacrificed and their renal tissues were removed for histopathological assessment. BB treatment decreased glucose levels and increased body weights. This treatment suppressed hepatic weights, increased renal tissue weights, and also decreased renal parameters like uric acid, urea, bilirubin, creatinine (Cr) and, albumin. There was a decrease (P<0.001) in histomorphological parameters such as kidney hypertrophy index (KHI), mean glomerular volume (MGV), foot process fusion ratio (FPFR), and glomerular basement membrane thickness (GBMT) after treatment with BB. In addition, this treatment improved the levels of renal podocin, renal CD2- associated protein (CD2AP) and suppressed hepatic parameter levels. BB treatment (P<0.001) altered antioxidant parameters and cytokine levels, and suppressed mRNA expressions of JAK2, STAT3, RAGE, KIM-1, NAGL, and S100A8. Administration of BB showed renal protective effects against STZ-induced DN in rats via the reduction of oxidative stress and inflammatory reactions.