Ameliorated Kidney Function Research Articles

TGFBR1 Inhibition Attenuates Expansion of Maladaptive Tubule Cells and Ameliorates Kidney Function Decline in the Adenine Nephropathy Mouse Model of CKD

TGFBR1 Inhibition Attenuates Expansion of Maladaptive Tubule Cells and Ameliorates Kidney Function Decline in the Adenine Nephropathy Mouse Model of CKD

Epidural block with lidocaine ameliorates kidney function deterioration and fibrosis of chronic kidney disease in rats

BackgroundAccording to evidences from clinical practices and experiments, renal denervation achieved by removing both the afferent and sympathetic nerves has therapeutic impacts on poor renal function and hypertension in chronic kidney disease (CKD). Epidural anesthesia is presumed to function on the target spine segments with a complete sympathetic block. Based on this perspective, we hypothesized that epidural block with lidocaine could ameliorate renal injury in CKD rats. Method and ResultsMale Sprague-Dawley rats weighing 250–300 g were randomized into four groups: control, CKD, CKD + sham, and CKD + epidural block with lidocaine groups. CKD was induced by resection of the lower and upper thirds of the left kidney followed by right nephrectomy one week later. Significant differences in renal function, sympathetic activation as well as renal fibrosis parameters were observed between CKD and control rats. These parameters corresponded with typical phenotypes of CKD rats. Epidural block with lidocaine improved renal function as well as renal fibrosis, and reversed the abnormalities of the renal function and cardiovascular parameters either fully or partially. ConclusionEpidural block with lidocaine confers renal protection, which is presumably mediated by decreasing sympathetic nerve activities in the renal region and other target organs in CKD.

Efficacy evaluation of B cell targeting drugs and the involved mechanism of action study in humanized BAFF transgenic SLE mice model

Abstract The B cell activating factor (BAFF) functions as a crucial factor in B cell survival, and heightened BAFF expression can augment the presence of autoreactive B cells, thereby fostering autoimmunity like Systemic Lupus Erythematosus (SLE). This study introduces transgenic mouse strains with human BAFF overexpression, offering insights into SLE mechanisms and B cell-targeting therapies. Human BAFF overexpression in B6-hBAFF mice led to a substantial rise in Igs and anti-dsDNA levels from 6 weeks of age, persistently escalating with time compared to wild-type mice. A heightened population of B cells but a reduced ratio of T cells was observed. At week 25 of age, B6-hBAFF mice developed lupus nephritis. Belimumab, a BAFF antibody administrated to BAFF transgenic mice demonstrated the effectively reduced serum antibody levels after 16 weeks of dosing. Belimumab ameliorated kidney function by decreasing urine albumin-to-creatinine ratio and IgA deposition after 20 weeks of treatment. Mice were also treated with Enpatoran (TLR7/8 inhibitors) and BTK inhibitor Orelabrutinib. Only the BTK inhibitor Orelabrutinib significantly eliminated serum Igs levels. Enpatoran exhibited a similar ability to Orelabrutinib in reducing T follicular helper cell and plasma cell populations spleen and lymph nodes. In summary, the humanized BAFF transgenic SLE model proves to be a valuable tool for preclinical efficacy studies in SLE treatment and understanding pathogenesis.

A Prospective Study of Eplerenone in the Treatment of Patients with Glomerulonephritis.

High aldosterone levels contribute to kidney disease progression, while spironolactone in combination with ACEi or ARBs can potentially reduce proteinuria and ameliorate kidney function deterioration. However, evidence on the impact of eplerenone in patients with glomerulonephritis is scarce. In this prospective observational study, we assessed the effects of eplerenone in patients with biopsy-proven glomerulonephritis who were already treated with ACEi or ARBs. Patients received either eplerenone (25 mg daily) on top of ACEi or ARBs or standard treatment alone. Proteinuria (24 h total protein excretion), kidney function, blood pressure and serum K+ levels were assessed at 3, 6 and 12 months after the initiation of treatment. Sixty-six patients were included in the study. Eplerenone was administered in 30 patients, while 36 received only ACEi or ARB. Proteinuria decreased from 1768 to 1152 mg/24 h after 1 year of eplerenone treatment, while it remained stable in controls. Eplerenone showed significant impact on proteinuria in those with baseline proteinuria of >1000 mg/24 h. Patients who received eplerenone showed a reduction in systolic blood pressure, while eGFR and serum K+ levels remained stable. Addition of eplerenone has a beneficial effect on proteinuria in patients with glomerulonephritis and significant baseline proteinuria.

Mildronate Ameliorates Kidney Function and Reduces Inflammation in SCD Mice

INTRODUCTION:Sickle cell disease (SCD) is a genetic hemoglobin disorder characterized by hemolytic anemia, vaso-occlusive crisis and inflammation that affects organs such as the kidney, liver, brain, spleen, and heart. SCD is driven by a mutation in the β-globin gene that causes sickling of red blood cells (RBCs). More than 50% of SCD patients are affected by chronic kidney diseases (CKD) and other comorbidities. Vasculopathy is caused by hemolysis-related endothelial dysfunction and inflammation, which collectively contribute to the development of renal disease. Mildronate (also known as Meldonium) is an anti-ischemic and cardio protecting medication approved in Eastern Europe. Mildronate facilitates a switch from fatty acid oxidation to less oxygen-intensive glycolysis that allows less oxygen consumption by peripheral tissues and higher oxygenation of heart. We hypothesized that mildronate administration would reduce tissue hypoxia and decrease inflammation in SCD mice. METHODS: The study was approved by the Institutional Animal Care and Use Committee at Howard University (IACUC). We employed the Townes SCD mouse model, which mimics SCD complications. SCD and control mice were injected with mildronate (400 mg/kg in saline) intraperitoneally or saline as vehicle control over the course of ten days. Blood and plasma were collected and used for hematological parameters analysis. Cytokines were measured by Bio-plex suspension array in plasma and real-time RT-PCR or ELISA in organs. Protein expression of HO-1, HIF-1α, NFκB and NRF2 was measured by Western blot. The effect of Mildronateon systemic and renal oxidative stress was measured by malondialdehyde (MDA) using ELISA (Abcam). RESULTS: We observed significant reduction in the cytokine's levels of IFN-γ, IL-1, and TNF-α in plasma of SCD mice after mildronate injection. We also observed reduction in IL-6, IL-10 and IL-17 levels but differences were not statistically significant. There were no significant changes in hematological parameters (Hematocrit, MCV, MCH, CMCH, Erythrocytes, Hemoglobin) after mildronate injection. Also, we did not observe changes in MDA levels in plasma or kidney in SCD mice compared to control mice, both non-injected and mildronate injected. We further evaluated HO-1 and NRF2 protein expression by western blot and observed no significant differences between SCD mice with or without mildronate injection. In H&E staining, cortex glomerular area and medullar congestion area were significantly reduced after mildronate injection. We also observed reduction of proteinuria in SCD mice injected with mildronate. DISCUSSION: Our examination of the effect of mildronate showed decreases inflammation in the mildronate injected SCD mice evidenced by reduced levels of IFN-γ, IL-1, IL-17, IL-6, IL-10, and TNF-α in circulation. There was a slight decrease in the expression levels of Nrf2 and HO-1 after mildronate injection. HO-1 is crucial for the catabolism of hemoglobin and protects against tissue damage in hemolysis. The HO-1 promoter has binding sites for several transcription factors, including phosphorylated Nrf2. Previous studies from our lab showed increased HIF-1α expression in PBMCs obtained from SCD patients. Here we did not detect significant changes in NFκB-p65 or HIF-1α expression levels. While we expected mildronate to decrease the oxidative stress, we did not observe significant reduction in MDA levels in treated mice compared to control mice. CONCLUSION: Mildronate improved kidney function in SCD mice by reducing circulatory and renal inflammation. In future, we plan to assess in more details the mildronate's impact on kidney function and inflammation. ACKNOWLEDGMENTS: This work was supported by NIH grants 1R01HL125005, 5U54MD007597, and 1SC1HL150685.

JMJD3 ablation in myeloid cells confers renoprotection in mice with DOCA/salt-induced hypertension.

Hypertension-induced renal injury is characterized by robust inflammation and tubulointerstitial fibrosis. Jumonji domain containing-3 (JMJD3) is closely linked with inflammatory response and fibrogenesis. Here we examined the effect of myeloid JMJD3 ablation on kidney inflammation and fibrosis in deoxycorticosterone acetate (DOCA)/salt hypertension. Our results showed that JMJD3 is notably induced in the kidneys with hypertensive injury. DOCA/salt stress causes an elevation in blood pressure that was no difference between myeloid specific JMJD3-deficient mice and wild-type control mice. Compared with wild-type control mice, myeloid JMJD3 ablation ameliorated kidney function and injury of mice in response to DOCA/salt challenge. Myeloid JMJD3 ablation attenuated collagen deposition, extracellular matrix proteins expression, and fibroblasts activation in injured kidneys following DOCA/salt treatment. Furthermore, myeloid JMJD3 ablation blunts inflammatory response in injured kidneys after DOCA/salt stress. Finally, myeloid JMJD3 ablation precluded myeloid myofibroblasts activation and protected against macrophages to myofibroblasts transition in injured kidneys. These beneficial effects were accompanied by reduced expression of interferon regulator factor 4. In summary, JMJD3 ablation in myeloid cells reduces kidney inflammation and fibrosis in DOCA salt-induced hypertension. Inhibition of myeloid JMJD3 may be a novel potential therapeutic target for hypertensive nephropathy. Myeloid JMJD3 deficiency reduces inflammatory response, myeloid fibroblasts activation, macrophages to myofibroblasts transition, and delays kidney fibrosis progression.

Inactivation of Invs/Nphp2 in renal epithelial cells drives infantile nephronophthisis like phenotypes in mouse.

Nephronophthisis (NPHP) is a ciliopathy characterized by renal fibrosis and cyst formation, and accounts for a significant portion of end stage renal disease in children and young adults. Currently, no targeted therapy is available for this disease. INVS/NPHP2 is one of the over 25 NPHP genes identified to date. In mouse, global knockout of Invs leads to renal fibrosis and cysts. However, the precise contribution of different cell types and the relationship between epithelial cysts and interstitial fibrosis remains undefined. Here, we generated and characterized cell-type-specific knockout mouse models of Invs, investigated the impact of removing cilia genetically on phenotype severity in Invs mutants and evaluated the impact of the histone deacetylase inhibitor valproic acid (VPA) on Invs mutants. Epithelial-specific knockout of Invs in Invsflox/flox;Cdh16-Cre mutant mice resulted in renal cyst formation and severe stromal fibrosis, while Invsflox/flox;Foxd1-Cre mice, where Invs is deleted in stromal cells, displayed no observable phenotypes up to the young adult stage, highlighting a significant role of epithelial-stromal crosstalk. Further, increased cell proliferation and myofibroblast activation occurred early during disease progression and preceded detectable cyst formation in the Invsflox/flox;Cdh16-Cre kidney. Moreover, concomitant removal of cilia partially suppressed the phenotypes of the Invsflox/flox;Cdh16-Cre mutant kidney, supporting a significant interaction of cilia and Invs function in vivo. Finally, VPA reduced cyst burden, decreased cell proliferation and ameliorated kidney function decline in Invs mutant mice. Our results reveal the critical role of renal epithelial cilia in NPHP and suggest the possibility of repurposing VPA for NPHP treatment.

Rosmarinic acid mitigates chlorpyrifos-induced oxidative stress, inflammation, and kidney injury in rats by modulating SIRT1 and Nrf2/HO-1 signaling

Chlorpyrifos (CPF) is a widely used broad-spectrum pesticide with multi-organ toxic effects. Oxidative stress was found to play a role in the deleterious effects of CPF, including nephrotoxicity. This study investigated the protective effect of the antioxidant polyphenol rosmarinic acid (RA) against CPF-induced kidney injury, with an emphasis on oxidative injury, inflammation, SIRT1, and Nrf2/HO-1 signaling. Rats received 10 mg/kg CPF and 25, 50, and 100 mg/kg RA orally for 28 days, and the samples were collected for analysis. CPF increased serum urea and creatinine and kidney Kim-1 and caused several histopathological alterations. ROS, MDA, NO, NF-κB p65, TNF-α, and IL-1β were elevated in the kidney of CPF-intoxicated rats. RA ameliorated kidney function markers, prevented tissue injury, suppressed ROS, MDA, and NO, and downregulated NF-κB p65, TNF-α, and IL-1β in CPF-intoxicated rats in a dose-dependent manner. RA decreased Bax, caspase-3, oxidative DNA damage, and Keap1, boosted antioxidant enzymes and Bcl-2, and upregulated Nrf2, HO-1, and SIRT1 in CPF-administered rats. Molecular docking simulation revealed the binding affinity of RA toward NF-κB, Keap1, HO-1, and SIRT1. In conclusion, RA prevented CPF nephrotoxicity by attenuating oxidative stress, inflammation, and apoptosis and upregulating SIRT1 and Nrf2/HO-1 signaling.

Ameliorative Effects of a Rhenium (V) Compound with Uracil-Derived Ligand Markers Associated with Hyperglycaemia-Induced Renal Dysfunction in Diet-Induced Prediabetic Rats

Kidney disease is characterised by the improper functioning of the kidney as a result of kidney damage caused by hyperglycaemia-induced oxidative stress. The moderate hyperglycaemia seen in prediabetes can be treated using a combination of metformin and lifestyle interventions (low-calorie diets and exercising). However, patients have been reported to over-rely on pharmacological interventions, thus decreasing the efficacy of metformin, which leads to the development of type 2 diabetes mellitus (T2DM). In this study, we investigated the effects of a rhenium (V) compound in ameliorating renal dysfunction in both the presence and absence of dietary modification. Kidney function parameters, such as fluid intake and urine output, glomerular filtration rate (GFR), kidney injury molecule (KIM 1), creatinine, urea, albumin and electrolytes, were measured after 12 weeks of treatment. After treatment with the rhenium (V) compound, kidney function was restored, as evidenced by increased GRF and reduced KIM 1, podocin and aldosterone. The rhenium (V) compound ameliorated kidney function by preventing hyperglycaemia-induced oxidative stress in the kidney in both the presence and absence of dietary modification.

Primaquine activates Keratin 7 to treat diabetes and its complications.

The global prevalence of type 2 diabetes mellitus (T2DM) raises the rates of its complications, such as diabetic nephropathy and cardiovascular diseases. To conquer the complications, new strategies to reverse the deterioration of T2DM are urgently needed. In this project, we aimed to examine the hypoglycemic effect of primaquine and explore its specific target. In vitro T2DM insulin resistance model was built in HepG2 cells to screen the potential anti-diabetic chemicals. On the other hand, the potential protein targets were explored by molecular docking. Accordingly, we chose C57BL/6N mice to establish T2DM model to verify the effect of the chemicals on anti-hyperglycemia and diabetic complications. By targeting the Keratin 7 (K7) to activate EGFR/Akt glucose metabolism signaling pathway, primaquine poses a potent hypoglycemic effect. The level of acetyl-CoA is enhanced markedly, supporting that primaquine upregulates the aerobic glycolysis. Moreover, primaquine ameliorates kidney function by reducing the secretion of urinary proteins and creatinine, especially for the urea nitrogen which is significantly decreased compared to no-treatment T2DM mice. Notably, primaquine restores the level of plasma low-density lipoprotein cholesterol (LDL-C) nearly to normal, minimizing the incidence of cardiovascular diseases. We find that primaquine may reverse the dysregulated metabolism to prevent diabetic complications by stimulating EGFR/Akt signaling axis, shedding new light on the therapy of T2DM. Insulin resistance is characterized by reduced p-Akt and glucose metabolism, dominated by anaerobic glycolysis. Primaquine activates the complex made of K7 and EGFR, further stimulating Akt phosphorylation. Then, p-Akt promotes the aerobic glucose metabolism and upregulates Ac-CoA to mobilize TCA cycle, improving insulin sensitivity. The online version contains supplementary material available at 10.1007/s40200-022-01135-8.

Effect of Structured, Moderate Exercise on Kidney Function Decline in Sedentary Older Adults

Observational evidence suggests that higher physical activity is associated with slower kidney function decline; however, to our knowledge, no large trial has evaluated whether activity and exercise can ameliorate kidney function decline in older adults. To evaluate whether a moderate-intensity exercise intervention can affect the rate of estimated glomerular filtration rate per cystatin C (eGFRCysC) change in older adults. This ancillary analysis of the Lifestyle Interventions and Independence For Elders randomized clinical trial enrolled 1199 community-dwelling, sedentary adults aged 70 to 89 years with mobility limitations and available blood specimens. The original trial was conducted across 8 academic centers in the US from February 2010 through December 2013. Data for this study were analyzed from March 29, 2021, to February 28, 2022. Structured, 2-year, partially supervised, moderate-intensity physical activity and exercise (strength, flexibility) intervention compared with a health education control intervention with 2-year follow-up. Physical activity was measured by step count and minutes of moderate-intensity activity using accelerometers. The primary outcome was change in eGFRCysC. Rapid eGFRCysC decline was defined by the high tertile threshold of 6.7%/y. Among the 1199 participants in the analysis, the mean (SD) age was 78.9 (5.2) years, and 800 (66.7%) were women. At baseline, the 2 groups were well balanced by age, comorbidity, and baseline eGFRCysC. The physical activity and exercise intervention resulted in statistically significantly lower decline in eGFRCysC over 2 years compared with the health education arm (mean difference, 0.96 mL/min/1.73 m2; 95% CI, 0.02-1.91 mL/min/1.73 m2) and lower odds of rapid eGFRCysC decline (odds ratio, 0.79; 95% CI, 0.65-0.97). Results of this ancillary analysis of a randomized clinical trial showed that when compared with health education, a physical activity and exercise intervention slowed the rate of decline in eGFRCysC among community-dwelling sedentary older adults. Clinicians should consider targeted recommendation of physical activity and moderate-intensity exercise for older adults as a treatment to slow decline in eGFRCysC. ClinicalTrials.gov Identifier: NCT01072500.

Salvianolic acid B attenuates membranous nephropathy by activating renal autophagy via microRNA-145-5p/phosphatidylinositol 3-kinase/AKT pathway

ABSTRACT The abnormal proliferation and inflammatory response of the mesangial cells play a crucial role in the progression of membranous nephropathy (MN). Herein, this study aimed to investigate the therapeutic effect of Salvianolic acid B (SalB) on MN-induced mesangial abnormalities and its underlying mechanisms. MN models were established in cationic bovine serum albumin-induced Sprague-Dawley rats and lipopolysaccharide-induced human mesangial cells (HMCs). Following SalB and microRNA-145-5p antagomir treatment, kidney function was investigated by 24-hours urine protein, serum creatinine, and blood urea nitrogen. Pathological changes of kidney were investigated by Periodic acid Schiff staining. CD68 and IgG were detected by immunofluorescence in glomerulus. Mesangial autophagosomes were observed by transmission electron microscope. MicroRNA-145-5p inhibitor, mimic, LY294002, and SalB were used to treat with HMCs. In kidney and HMCs, IL-1 , IL-2, IL-6, TNF- and microRNA-145-5p was detected by quantitative real-time PCR. Phosphatidylinositol 3-kinase (PI3K), phosphorylated AKT, AKT, beclin1, and microtubule-associated protein light chain 3 (LC3) levels were detected by Western blot. HMCs proliferation and cycle were detected by Cell Counting Kit-8 and flow cytometry. LC3 were detected by LC3-dual-fluorescent adenovirus in HMCs. Our results showed that SalB significantly ameliorated kidney function and pathological changes. Furthermore, it significantly alleviated proliferation, inflammation and activated autophagy in mesangial cells. Moreover, microRNA-145-5p antagomir accentuated MN while microRNA-145-5p inhibitor and LY294002 encouraged proliferation and inflammation through PI3K/AKT pathway in HMCs. Collectively, our study demonstrated that SalB activated renal autophagy to reduce cell proliferation and inflammation of MN, which was mediated by microRNA-145-5p to inhibit PI3K/AKT pathway, and ultimately attenuated MN.

Jujube polysaccharides mitigated anemia in rats with chronic kidney disease: Regulation of short chain fatty acids release and erythropoietin production

• Jujube polysaccharides stimulates EPO expression via HIF-α accumulation. • Jujube polysaccharides treatment improves kidney function and anemia in CKD rats. • Jujube polysaccharides significantly increases the release of SCFAs in CKD rats. • A derivatization-based LC-MS method is developed for SCFAs determination in feces. Jujube polysaccharides (JP) is one of the active food sourced glycans in dietary fruit of Ziziphus jujuba , which has been considered for the treatment of blood deficiency. In this study, a chronic kidney disease (CKD) rat model was used to evaluate the effect of JP and its mechanism on CKD-associated anemia. In CKD rats, JP treatment significantly ameliorated kidney function, kidney pathological injury and hematological parameters, including increasing red blood cells, hemoglobin, hematocrit and platelet count. Moreover, LC-MS/MS targeted metabolomics results showed that JP promoted short chain fatty acids (SCFAs) release in CKD rats. Besides, JP alternated the serum erythropoietin (EPO) level, kidney EPO mRNA and kidney EPO protein via HIF-α signaling. Collectively, these results provide evidence that the effect of JP on CKD-associated anemia may be involved in regulation of SCFAs release and erythropoietin production, supporting further development of JP as food supplements in treating CKD-associated anemia.

Punicalagin prevents cisplatin-induced nephrotoxicity by attenuating oxidative stress, inflammatory response, and apoptosis in rats

Nephrotoxicity is a major complication that limits the therapeutic application of cisplatin (CIS). Oxidative stress and inflammation are implicated in CIS-induced acute kidney injury (AKI) and apoptotic cell death. Punicalagin (PUN), a polyphenol in pomegranate, possesses promising anti-inflammatory and antioxidant activities, and its beneficial effect against CIS-induced AKI has not been fully elucidated. This investigation evaluated the protective effect of PUN against CIS-induced renal oxidative stress, inflammation and cell death. Rats received PUN (25 and 50 mg/kg) for 10 days and a single injection of CIS at day 7. The results showed increased serum urea and creatinine and several histopathological alterations in the kidney of CIS-intoxicated rats. Renal malondialdehyde (MDA) and nitric oxide (NO) were increased, and reduced glutathione, superoxide dismutase and catalase were declined in rats treated with CIS. PUN effectively ameliorated kidney function and attenuated tissue injury induced by CIS, decreased MDA and NO, and enhanced antioxidant defenses. Additionally, PUN downregulated NF-κB p65, iNOS, TNF-α, IL-6 and IL-1β in the kidney of rats that received CIS. Bax and caspase-3 were increased, and Bcl-2 was decreased in the kidney of CIS-intoxicated rats, an effect that was reversed by PUN. PUN upregulated Nrf2 expression in the kidney of CIS-intoxicated rats. In conclusion, PUN prevents CIS-induced AKI in rats by attenuating oxidative stress, inflammatory response and apoptosis, and upregulating Nrf2 and antioxidants.

Combined Melatonin and Extracorporeal Shock Wave Therapy Enhances Podocyte Protection and Ameliorates Kidney Function in a Diabetic Nephropathy Rat Model.

(1) Background: Diabetic nephropathy (DN) is common complication of diabetes. Current therapy for DN does not include promotion of podocyte protection. Therefore, we investigated the therapeutic effect of melatonin (Mel) combined extracorporeal shock wave (SW) therapy on a DN rat model. (2) Methods: The DN rats were treated with Mel (5 mg/kg) twice a week for 6 weeks and SW treatment once a week (0.13 mJ/mm2) for 6 weeks. We assessed urine microalbumin, albumin to creatinine ratio (ACR), glomerular hypertrophy, glomerular fibrosis, podocyte markers (Wilm’s tumor protein-1, synaptopodin and nephrin), cell proliferation, cell survival, cell apoptosis, renal inflammation and renal oxidative stress. (3) Results: The Mel combined SW therapy regimen significantly reduced urine microalbumin excretion (3.3 ± 0.5 mg/dL, p < 0.001), ACR (65.2 ± 8.3 mg/g, p < 0.001), glomerular hypertrophy (3.1 ± 0.1 × 106 μm3, p < 0.01) and glomerular fibrosis (0.9 ± 0.4 relative mRNA fold, p < 0.05). Moreover, the Mel combined SW therapy regimen significantly increased podocyte number (44.1 ± 5.0% area of synaptopodin, p < 0.001) in the Mel combined SW group. This is likely primarily because Mel combined with SW therapy significantly reduced renal inflammation (753 ± 46 pg/mg, p < 0.01), renal oxidative stress (0.6 ± 0.04 relative density, p < 0.05), and apoptosis (0.3 ± 0.03 relative density, p < 0.001), and also significantly increased cell proliferation (2.0 ± 0.2% area proliferating cell nuclear antigen (PCNA), p < 0.01), cell survival, and nephrin level (4.2 ± 0.4 ng/mL, p < 0.001). (4) Conclusions: Mel combined SW therapy enhances podocyte protection and ameliorates kidney function in a DN rat model. Mel combined SW therapy may serve as a novel noninvasive and effective treatment of DN.

Antidiabetic and Renoprotective Effects of Coffea arabica Pulp Aqueous Extract through Preserving Organic Cation Transport System Mediated Oxidative Stress Pathway in Experimental Type 2 Diabetic Rats.

Coffea arabica pulp (CP) is a by-product of coffee processing. CP contains polyphenols that have exhibited beneficial effects, including antioxidant and lipid-lowering effects, as well as enhanced insulin sensitivity, in in vitro and in vivo models. How polyphenols, as found in CP aqueous extract (CPE), affect type 2 diabetes (T2D) has not been investigated. Thus, the present study examined the potential antidiabetic, antioxidant, and renoprotective effects of CPE-rich polyphenols, using an experimental model of T2D in rats induced by a high-fat diet and a single low dose of streptozotocin. The T2D rats received either 1000 mg/kg body weight (BW) of CPE, 30 mg/kg BW of metformin (Met), or a combination treatment (CPE + Met) for 3 months. Plasma parameters, kidney morphology and function, and renal organic transport were determined. Significant hyperglycemia, hypertriglyceridemia, insulin resistance, increased renal lipid content and lipid peroxidation, and morphological kidney changes related to T2D were restored by both CPE and CPE + Met treatments. Additionally, the renal uptake of organic cation, 3H-1-methyl-4-phenylpyridinium (MPP+), was reduced in T2D, while transport was restored by CPE and CPE + Met, through an up-regulation of antioxidant genes and protein kinase Cα deactivation. Thus, CPE has antidiabetic and antioxidant effects that potentially ameliorate kidney function in T2D by preserving renal organic cation transport through an oxidative stress pathway.

Nifuroxazide suppresses UUO-induced renal fibrosis in rats via inhibiting STAT-3/NF-κB signaling, oxidative stress and inflammation

The current work explored the influences of nifuroxazide, an in vivo inhibitor of signal transducer and activator of transcription-3 (STAT-3) activation, on tubulointerstitial fibrosis in rats with obstructive nephropathy using unilateral ureteral obstruction (UUO) model.Thirty-two male Sprague Dawley rats were assigned into 4 groups (n = 8/group) at random. Sham and UUO groups were orally administered 0.5% carboxymethyl cellulose (CMC) (2.5 mL/kg/day), while Sham-NIF and UUO-NIF groups were treated with 20 mg/kg/day of NIF (suspended in 0.5% CMC, orally). NIF or vehicle treatments were started 2 weeks after surgery and continued for further 2 weeks.NIF treatment ameliorated kidney function in UUO rats, where it restored serum creatinine, blood urea, serum uric acid and urinary protein and albumin to near-normal levels. NIF also markedly reduced histopathological changes in tubules and glomeruli and attenuated interstitial fibrosis in UUO-ligated kidneys. Mechanistically, NIF markedly attenuated renal immunoexpression of E-cadherin and α-smooth muscle actin (α-SMA), diminished renal oxidative stress (↓ malondialdehyde (MDA) levels and ↑ superoxide dismutase (SOD) activity), lessened renal protein expression of phosphorylated-STAT3 (p-STAT-3), phosphorylated-Src (p-Src) kinase, the Abelson tyrosine kinase (c-Abl) and phosphorylated nuclear factor-kappaB p65 (pNF-κB p65), decreased renal cytokine levels of transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and monocyte chemoattractant protein-1 (MCP-1) and reduced number of cluster of differentiation 68 (CD68) immunolabeled macrophages in UUO renal tissues, compared to levels in untreated UUO kidneys.Taken together, NIF treatment suppressed interstitial fibrosis in UUO renal tissues, probably via inhibiting STAT-3/NF-κB signaling and attenuating renal oxidative stress and inflammation.

Protein intake and renal function in older patients.

Chronic kidney disease (CKD) is highly prevalent in elderly patients. There is growing recognition of the importance of attention to dietary protein intake (DPI) in this population given their predisposition to age-related changes in kidney function and coexisting comorbidities (i.e., hypertension). We reviewed the impact of DPI on kidney health and survival and the role of dietary protein management in older CKD patients. While kidney function parameters including glomerular filtration rate (GFR) and renal plasma flow are slightly lower in elderly patients irrespective of CKD status, the kidneys' ability to compensate for increased DPI by augmentation of GFR is preserved until 80 years of age or less. However, long-term consumption of high DPI in individuals of older age and/or with CKD may contribute to kidney function deterioration over time. Prescription of a plant-dominant low-protein diet of 0.6-0.8 g/kg/day with more than 50% from plant sources or very low protein diets less than 0.45 g/kg/day supplemented with essential amino acids or their keto-analogues may be effective in preserving kidney function in older patients and their younger counterparts, while also monitoring for development of protein-energy wasting (PEW). Using tailored precision nutrition approaches in prescribing plant-dominant low DPI that also maintains adequate energy and nitrogen balance may ameliorate kidney function decline while also preventing development of PEW in elderly patients with CKD.

Ameliorative Effect of Linalool in Cisplatin-Induced Nephrotoxicity: The Role of HMGB1/TLR4/NF-κB and Nrf2/HO1 Pathways.

Background: The monoterpene linalool is a well-known essential oil component produced by several aromatic plants. Cisplatin is a widely used anticancer drug that produces many side effects, particularly nephrotoxicity. Here, we aimed to inspect linalool’s protective activity against cisplatin-induced nephrotoxicity and explore part of the underlying mechanisms. Methods: Male Wistar rats were given linalool (50 and 100 mg/kg/day orally) for 15 days; then challenged with cisplatin (8 mg/kg) on the 12th day. Renal function parameters, oxidative stress, inflammatory and apoptotic markers, and toll-like receptor pathway gene, and protein expressions were investigated. Histopathology, immunohistochemistry, and cell-line mediated cytotoxicity assays were conducted. Results: Linalool ameliorated kidney function after cisplatin challenge and managed all oxidation system parameters including GSH, SOD, CAT, MDA, NADPH, and particularly the Nrf2-mediated pathway markers. Linalool decreased TLR4, MYD88 and TRIF gene and protein expressions; diminished related inflammatory mediators such as TNF-α, IL-1β, IL-6, and NF-κB; and down-regulated HMBG1. Linalool mitigated cisplatin-induced apoptotic markers such as caspase 3, caspase 9, and Bax expression, and boosted the anti-apoptotic Bcl2 expression. Linalool potentiated the cytotoxic effect of cisplatin when investigated on HeLa and PC3 human cancer cell lines. Conclusion: Linalool could protect against cisplatin-induced kidney function and tissue damage.

Febuxostat attenuates vascular calcification induced by vitamin D3 plus nicotine in rats

This study was undertaken to investigate the possible ameliorative influences of febuxostat (FEB) on vitamin D3 plus nicotine (VDN)-induced vascular calcification (VC) in Wistar rats.VDN rats received a single dose of vitamin D3 (300.000 IU/kg, I.M) and two oral doses of nicotine (25 mg/kg) on day 1. They were then administrated FEB, in two doses (10 and 15 mg/kg/day, orally), or the drug vehicle, for 4 weeks. Age-matched normal rats served as control. At the end of the experiment, body weight, kidney function parameters, serum ionic composition, cardiovascular measures, aortic calcium deposition and aortic levels of oxidative stress markers, interleukin 1β (IL-1β), runt-related transcription factor 2 (Runx2) and osteopontin (OPN) were determined. Aortic immunoexpressions of tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), matrix metalloproteinase-9 (MMP-9) and α-smooth muscle actin (α-SMA) were evaluated.FEB significantly restored body weight loss, ameliorated kidney function and diminished serum disturbances of calcium and phosphorus in VDN rats. Moreover, FEB reduced VDN-induced elevations in aortic calcium deposition, SBP and DBP. FEB (15 mg/kg) markedly decreased left ventricular hypertrophy and bradycardia in VDN group. Mechanistically, FEB dose-dependently improved oxidative damage, decreased levels of IL-1β and Runx2, lessened expression of TNF-α, iNOS and MMP-9 and enhanced expression of OPN and α-SMA in VDN aortas relative to controls.These findings indicate that FEB, mainly at the higher administered dose (15 mg/kg), successfully attenuated VDN-induced VC. FEB may be useful in reducing VC in patients at high risk, including those with chronic kidney disease and diabetes mellitus.