lactoferrin and Kidney-Diseases

Topics: Antibodies, Antineutrophil Cytoplasmic; Antibody Specificity; Autoantibodies; Autoantigens; Cell Nucleus; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Kidney Diseases; Lactoferrin

Renal fibrosis is a hallmark feature of chronic kidney diseases (CKDs). However, despite the increased prevalence of renal fibrosis, there is no approved antifibrotic drug for the management of renal fibrosis. Cerium oxide nanoparticles (CONPs) have been demonstrated to possess a number of properties including antioxidant, anti-inflammatory and nephroprotective activity. As the kidneys are rich in lactoferrin (Lf) receptors, we synthesised the lactoferrin-CONP (Lf-CONP) system to be used for active targeting of the kidneys and provide antifibrotic effects of CONPs to the kidneys. We used the unilateral ureteral obstruction (UUO)-induced renal fibrosis model and treated the animals with Lf-CONP to observe the antifibrotic effects of Lf-CONP. Lf-CONP was found to inhibit the progression of renal fibrosis in a superior manner when compared to CONPs alone.

Topics: Animals; Fibrosis; Kidney; Kidney Diseases; Lactoferrin; Renal Insufficiency, Chronic; Transforming Growth Factor beta1

Cyclophosphamide is an alkylating agent with vast arrays of therapeutic activity. Currently, its medical use is limited due to its numerous adverse events, including nephrotoxicity. This study aimed to follow the molecular mechanisms behind the potential renoprotective action of lactoferrin (LF) against cyclophosphamide (CP)-induced renal injury.. For fulfillment of our aim, Spragw-Dwaly rats were orally administrated LF (300 mg/kg) for seven consecutive days, followed by a single intraperitoneal injection of CP (150 mg/kg).. Treatment of CP-injured rats with LF significantly reduced the elevated creatinine and blood urea nitrogen (BUN), markedly upregulated Nrf2/HO-1 signaling with consequent increase in renal total antioxidant capacity (TAC) and decrease in renal malondialdehyde (MDA) level. Furthermore, LF treatment significantly reduced the elevated renal p-ERK1/2 expression, tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), nuclear factor-kappa B (NF-κB) levels in CP-treated animals. Interestingly, LF treatment downregulated Wnt4/β-catenin signaling and increased both renal klotho gene expression and serum klotho level. Furthermore, LF treatment reduced apoptosis in kidney tissue via suppressing GSK-3β expression and modulating caspase-3 and Bcl2 levels. Histopathological examination of kidney tissue confirmed the protective effect of LF against CP-induced renal injury.. The present findings document the renoprotective effect of LF against CP-induced nephropathy, which may be mediated via suppressing ERK1/2/ NF-κB and Wnt4/β-catenin trajectories and enhancing klotho expression and Nrf2/HO-1 signaling.

Topics: Animals; beta Catenin; Cyclophosphamide; Glycogen Synthase Kinase 3 beta; Kidney; Kidney Diseases; Lactoferrin; MAP Kinase Signaling System; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Rats

Whey protein (WH)-enriched diets are reported to aid in weight loss and to improve cardiovascular health. However, the bioactive components in whey responsible for causing such effects remain unidentified.. We determined the effects of whey and its components [α-lactalbumin (LA) and lactoferrin (LF)] on energy balance, glucose tolerance, gut hormones, renal damage, and stroke onset in rats.. Male spontaneously hypertensive stroke-prone (SHRSP) rats (age 8 wk) were fed isocaloric high-fat (40% kcal) and high-salt (4% wt/wt) diets (n = 8-10/group) and randomized for 8 wk to diets enriched as follows: control (CO): 15% kcal from egg albumin, 45% kcal from carbohydrate; WH: 20%kcal WH isolate + 15% kcal egg albumin; LA: 20% kcal LA  + 15% kcal egg albumin; or LF: 20% kcal lactoferrin + 15% kcal egg albumin. Measurements included energy balance (food intake, energy expenditure, and body composition), stroke-related behaviors, brain imaging, glucose tolerance, metabolic hormones, and tissue markers of renal damage. Data were analyzed by linear mixed models with repeated measures or 1-way ANOVA.. Diets enriched with WH, LA, or LF increased survival, with 25% of rats fed these diets exhibiting stroke-associated morbidity, whereas 90% of CO rats were morbid by 8 wk (P < 0.05). The nephritis scores of rats fed WH-, LA-, or LF-enriched diets were 80%, 92%, and 122% lower than those of COs (P = 0.001). The mRNA abundances of renin and osteopontin were 100-600% lower in rats fed WH-, LA-, or LF-enriched diets than in COs (P < 0.05). Urine albumin concentrations and albumin-to-creatinine ratios were 200% lower in rats fed LF-enriched diets than in COs (P < 0.05). Compared with COs, rats fed LF-enriched diets for 2-3 wk had food intake decreased by 29%, body weight decreased by 13-19%, lean mass decreased by 12-19%, and fat mass decreased by 20% (P < 0.001). Relative to COs, rats fed WH and LA had food intake decreased by 10% (P < 0.1), but COs had 12-45% lower weight than rats fed LA- and WH-enriched diets by 3 wk (P < 0.01). Compared with COs, rats fed WH-enriched diets increased energy expenditure by 7%, whereas, rats fed LA-enriched diets had energy expenditure acutely decreased by 7% during the first 4 d, and rats fed LF-enriched diets had energy expenditure decreased by 7-17% throughout the first week ( P < 0.001). Rats fed LA- and LF-enriched diets had blood glucose decreased by 14-19% (P < 0.05) and WH by 9% (P = 0.1), relative to COs. Compared with COs, rats fed LF had GIP decreased by 90% and PYY by 87% (P < 0.05).. Together, these findings indicate that whey and its components α-lactalbumin and lactoferrin improved energy balance and glycemic control, and protected against the onset of neurological deficits associated with stroke and renal damage in male SHRSP rats.

Topics: Animals; Behavior, Animal; Blood Glucose; Brain; Diet; Diet, High-Fat; Eating; Energy Metabolism; Kidney Diseases; Lactalbumin; Lactoferrin; Male; Motor Activity; Rats; Rats, Inbred SHR; Sodium Chloride, Dietary; Stroke; Whey Proteins

High levels of oxygen are usually used in ventilatory support and extracorporeal membrane oxygenation (ECMO) in the intensive care unit of hospitals. Hyperoxia may induce the production of reactive oxygen species (ROS) that can cause lung damage and even systemic injury. In this study, the NF-κB/luciferase transgenic mouse model with non-invasive real-time in vivo imaging was established to test the functions of lactoferrin (LF) in antioxidant and anti-inflammation.. The NF-κB/luciferase transgenic mice were used to assess the effects of oral administration of LF on attenuation of the systemic inflammatory response and organ damage after 72 h of hyperoxia (FiO. Using luciferase IVIS imaging, we found that the lungs and kidneys were the most evidently affected organs after hyperoxia treatment. The groups treated with low dose (150 mg/kg) or high dose (300 mg/kg) of LF had lower luciferase expression and less injury, with a dose-dependent effect on the lungs and kidneys. Moreover, ROS, mitogen-activated protein kinases (MAPK), and pro-inflammatory cytokine (TNF-α, IL-1ß, and IL-6) expression levels were all significantly decreased (P < 0.01), and the protein level of IκB was statistically increased (P < 0.01) after LF treatment.. Our results suggest that hyperoxia can induce systemic inflammation, and the oral administration of LF as a natural antioxidant decreases the production of ROS, attenuates inflammation, and lessens kidney and lung injuries from hyperoxia via the use of live image monitoring of the response in NF-kB/luciferase transgenic mice.

Topics: Animals; Anti-Infective Agents; Disease Models, Animal; Female; Hyperoxia; Kidney Diseases; Lactoferrin; Luciferases; Male; Mice; Mice, Transgenic; NF-kappa B; Oxygen Consumption; Pneumonia; Reactive Oxygen Species

Polyomavirus nephropathy (PVAN) is a common cause of kidney allograft dysfunction and loss. To identify PVAN-specific gene expression and underlying molecular mechanisms, we analyzed kidney biopsies with and without PVAN.. The study included 168 posttransplant renal allograft biopsies (T cell-mediated rejection [TCMR] = 26, PVAN = 10, normal functioning graft = 73, and interstitial fibrosis/tubular atrophy = 59) from 168 unique kidney allograft recipients. We performed gene expression assays and bioinformatics analysis to identify a set of PVAN-specific genes. Validity and relevance of a subset of these genes are validated by quantitative polymerase chain reaction and immunohistochemistry.. Unsupervised hierarchical clustering analysis of all the biopsies revealed high similarity between PVAN and TCMR gene expression. Increased statistical stringency identified 158 and 252 unique PVAN and TCMR injury-specific gene transcripts respectively. Although TCMR-specific genes were overwhelmingly involved in immune response costimulation and TCR signaling, PVAN-specific genes were mainly related to DNA replication process, RNA polymerase assembly, and pathogen recognition receptors. A principal component analysis (PCA) using these genes further confirmed the most optimal separation between the 3 different clinical phenotypes. Validation of 4 PVAN-specific genes (RPS15, complement factor D, lactotransferrin, and nitric oxide synthase interacting protein) by quantitative polymerase chain reaction and confirmation by immunohistochemistry of 2 PVAN-specific proteins with antiviral function (lactotransferrin and IFN-inducible transmembrane 1) was done.. In conclusion, even though PVAN and TCMR kidney allografts share great similarities on gene perturbation, PVAN-specific genes were identified with well-known antiviral properties that provide tools for discerning PVAN and AR as well as attractive targets for rational drug design.

Topics: Adolescent; Adult; Antigens, Differentiation; Biopsy; Child; Child, Preschool; Graft Rejection; Humans; Infant; Kidney; Kidney Diseases; Kidney Transplantation; Lactoferrin; Polyomavirus Infections; T-Lymphocytes; Transplantation, Homologous

Although cisplatin (cis-diamminedichloroplatinum II) is one of the most effective chemotherapeutic agents, its clinical use is limited because of its strong side effects on the kidneys. The aim of this study was to investigate the renoprotective effect of bovine lactoferrin (bLf) in cisplatin-induced renal failure in rats. To assess the renoprotective effect of bLf, oral bLf (300 mg/kg) was administered from the day before to the fifth day after cisplatin (7 mg/kg, i.p.) injection. Daily administration of bLf histologically reduced renal tubular injury induced by cisplatin and suppressed the deterioration of renal function. Accumulated platinum content in the kidney was significantly decreased by the daily administration of bLf. Moreover, the administration of intravenous bLf caused a significant increase in urine volume in a dose-dependent manner. These results suggest that pretreatment with bLf produces a protective effect against cisplatin-induced nephrotoxicity. This protective effect of bLf involves the reduction of accumulated cisplatin in the kidney.

Topics: Animals; Antineoplastic Agents; Cisplatin; Diuresis; Dose-Response Relationship, Drug; Kidney Diseases; Lactoferrin; Rats

Because the human lactoferrin-derived peptide, hLF(1-11), exerts potent in vitro candidacidal activity, we investigated whether it displays antifungal activity against disseminated Candida albicans infections.. Neutropenic mice were intravenously infected with C. albicans and, 24 h later, were injected with hLF(1-11); 18 h later, the number of viable yeasts in the kidneys was determined microbiologically, the size and number of infectious foci were determined histologically, and serum cytokine levels were determined by immunoassays.. hLF(1-11) was effective (maximum reduction, 1.5 logs) against disseminated C. albicans infections, and its antifungal activity leveled off at a concentration of 0.4 ng of hLF(1-11)/kg of body weight. The antifungal activity of hLF(1-11) was increased in mice injected with interleukin (IL)-10 neutralizing antibodies, which suggests that IL-10 reduces the antifungal activity of hLF(1-11). In agreement with this result was the finding that injection of high doses of hLF(1-11) into infected mice was accompanied by increased levels of IL-10 in serum. Microscopic analysis revealed that infectious foci in kidneys of hLF(1-11)-treated mice contained mainly blastoconidia, whereas filamentous forms were abundant in untreated mice. The peptide inhibited the in vitro morphological transition of C. albicans, in a dose-dependent manner. : hLF(1-11) is effective against disseminated C. albicans infections; and its effects on C. albicans viability and virulence and on host cells may explain this antifungal activity.

Topics: Animals; Antifungal Agents; Candida albicans; Candidiasis; Carrier Proteins; Dose-Response Relationship, Drug; Drug Resistance, Fungal; Female; Fluconazole; Humans; Interleukin-10; Kidney Diseases; Lactoferrin; Mice; Neutropenia; Specific Pathogen-Free Organisms

Human and bovine lactoferrins (Lfs) and bovine lactoferrin hydrolysate (LH) were assessed in vitro and in vivo for their antibacterial effects on Staphylococcus aureus. Lactoferrins showed weak in vitro antibacterial activity while Fe-saturated Lfs and LH showed no activity. Lactoferrin-treated mice (1 mg, i.v.) when injected i.v. with 10(6) staphylococci, showed 30-50% reduction in kidney infections, and viable bacterial counts in the kidneys decreased 5-12-fold. The inhibitory effect was dose-dependent up to 1 mg Lf. Lactoferrins were effective when given 1 day prior to the bacterial challenge, after which there was no significant effect even at doses up to 5 mg. Apo- and Fe-saturated forms of human and bovine Lfs were all equally effective, while LH was not protective. Human and bovine Lfs with different degrees of iron saturation (9-97%) were found to be equipotent. Feeding mice with 2% bLf in drinking water also reduced the kidney infections by 40-60%, and viable bacterial counts, 5-12-fold. The results suggest a potential for the use of Lfs as natural antibacterial proteins for preventing bacterial infections.

Topics: Animals; Cattle; Colony Count, Microbial; Humans; Iron; Kidney; Kidney Diseases; Lactoferrin; Mice; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus

The secretory immune system has been well studied in the intestinal, bronchial, and biliary systems and breast. Tissue studies of secretory immunoglobulins in the kidney are scanty, mostly related to nephropathies with IgA. Renal tissues from 37 autopsies selected for any history of renal dysfunction were processed for immunohistologic studies on frozen sections with several antisera, including a purified rabbit anti-human secretory component (SC). By immunohistology, gel diffusion, and immunoblotting, the anti-SC antibody reacted appropriately with purified human SC, saliva, intestinal epithelium, and breast milk and did not cross-react with immunoglobulin heavy or light chains, lactoferrin, and other tissue proteins. IgA and SC were seen in tubular casts in 70% of patients, whereas less impressive staining with IgM, IgG, and albumin was seen, respectively, in 24%, 13%, and 22% of the patients. SC was present in the cytoplasm of distal tubule and Henle's loop cells in 78% of specimens. A control group of 10 healthy individuals who died suddenly showed minimal staining of casts and tubules in 2 specimens. Renal pathology in the group with IgA-SC+ casts included acute tubular necrosis (54%), severe chronic renal disease (61%), and mild chronic renal injury (38%). The group with negative IgA-SC casts included acute tubular necrosis (64%), infectious interstitial nephritis (36%), and negligible renal disease (36%). This study suggests that discrete distal segments of the nephron may have the capability of secreting SC, which is probably coupled with serum-derived IgA and incorporated into luminal tubular secretions. The low level of immunosecretions in kidneys which are normal or minimally damaged suggests that this system may need to be turned on by unknown, probably pathogenic stimulating factors.

Topics: Adolescent; Adult; Aged; Fluorescent Antibody Technique; Histocytochemistry; Humans; Immunoglobulin A; Immunoglobulin Fragments; Immunoglobulin G; Immunoglobulin M; Kidney Diseases; Kidney Tubules, Distal; Lactoferrin; Middle Aged; Nephrons; Secretory Component

In an effort to determine the synthetic capacity of human kidneys for serum proteins, pieces of both kidneys removed at operation prior to transplantation were placed in organ culture. Incubation with 14C labelled amino acids and subsequent radioimmunoelectrophoresis with antisera to all five classes of immunoglobulins showed synthesis of IgG by all 5 pairs of kidneys of IgA and IgE by 4, and of IgM by 2. None synthesized IgD. Radioimmunoelectrophoresis with specific antisera to 15 non-immunoglobulin proteins revealed synthesis of lactoferrin and uromucoid while several other serum proteins, such as alpha1 antitrypsin and alpha2 macroglobulin, known for their binding properties, showed apparent synthesis. No evidence for secretory component synthesis was seen despite positive immunofluorescent localization in the tubular cells. Further, Zn alpha2 and beta2GP I also showed positive immunofluorescence but negative synthesis. It seems possible that these latter proteins may not be synthesized by the tubular cells but rather may be actively excreted or reabsorbed by them.

Topics: Blood Proteins; Humans; Immunoglobulin A, Secretory; Immunoglobulins; Kidney; Kidney Diseases; Lactoferrin; Mucoproteins; Organ Culture Techniques