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1.
Pflugers Arch ; 475(3): 391-403, 2023 03.
Article in English | MEDLINE | ID: mdl-36520238

ABSTRACT

The renal renin-angiotensin system (RAS) is involved in the development of chronic kidney disease. Here, we investigated whether mice with reduced renal angiotensin I-converting enzyme (ACE-/-) are protected against aristolochic acid nephropathy (AAN). To further elucidate potential molecular mechanisms, we assessed the renal abundances of several major RAS components. AAN was induced using aristolochic acid I (AAI). Glomerular filtration rate (GFR) was determined using inulin clearance and renal protein abundances of renin, angiotensinogen, angiotensin I-converting enzyme (ACE) 2, and Mas receptor (Mas) were determined in ACE-/- and C57BL/6J control mice by Western blot analyses. Renal ACE activity was determined using a colorimetric assay and renal angiotensin (Ang) (1-7) concentration was determined by ELISA. GFR was similar in vehicle-treated mice of both strains. AAI decreased GFR in controls but not in ACE-/- mice. Furthermore, AAI decreased renal ACE activity in controls but not in ACE-/- mice. Vehicle-treated ACE-/- mice had significantly higher renal ACE2 and Mas protein abundances than controls. AAI decreased renal ACE2 protein abundance in both strains. Furthermore, AAI increased renal Mas protein abundance, although the latter effect did not reach statistical significance in the ACE-/- mice. Renal Ang(1-7) concentration was similar in vehicle-treated mice of both strains. AAI increased renal Ang(1-7) concentration in the ACE-/- mice but not in the controls. Mice with reduced renal ACE are protected against AAN. Our data suggest that in the face of renal ACE deficiency, AAI may activate the ACE2/Ang(1-7)/Mas axis, which in turn may deploy its reno-protective effects.


Subject(s)
Peptidyl-Dipeptidase A , Renal Insufficiency, Chronic , Mice , Animals , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Proto-Oncogene Mas , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin II/metabolism , Mice, Inbred C57BL , Renin-Angiotensin System/physiology , Renal Insufficiency, Chronic/chemically induced , Angiotensin I , Peptide Fragments/pharmacology
2.
Am J Physiol Renal Physiol ; 304(12): F1458-70, 2013 Jun 15.
Article in English | MEDLINE | ID: mdl-23552865

ABSTRACT

Osteopontin (OPN) expression has been reported to be elevated in experimental models of renal injury such as arterial hypertension or diabetic nephropathy finally leading to focal segmental glomerulosclerosis (FSGS). FSGS is characterized by glomerular matrix deposition and loss or damage of podocytes that represent the main constituents of the glomerular filtration barrier. To evaluate the role of OPN in the kidney we investigated WT and OPN knockout mice (OPN-/-) without treatment, after uninephrectomy (UNX), as well as after UNX and desoxycorticosterone acetate (DOCA)-salt treatment with respect to urine parameters, glomerular morphology, and expression of podocyte markers. OPN-/- mice showed normal urine parameters while a thickening of the glomerular basement membrane was evident. Intriguingly, following UNX, OPN-/- mice exhibited prominent FSGS, proteinuria, and glomerular matrix deposition. Electron microscopy revealed bulgings of the glomerular basement membrane and occasionally an effacement of podocytes. After UNX and DOCA-salt treatment, severe glomerular lesions as well as proteinuria and albuminuria were seen in WT and OPN-/- mice. Moreover, we found a reduction of specific markers such as Wilm's tumor-1, podocin, and synaptopodin in both experimental groups indicating a loss of podocytes. Podocyte damage was accompanied by increased number of Ki-67-positive cells in the parietal epithelium of Bowman's capsule. We conclude that OPN plays a crucial role in adaptation of podocytes following renal ablation and is renoprotective when glomerular mechanical load is increased.


Subject(s)
Glomerulosclerosis, Focal Segmental/etiology , Kidney/physiology , Osteopontin/deficiency , Podocytes/physiology , Actins/biosynthesis , Animals , Autophagy , Desoxycorticosterone/pharmacology , Glomerular Basement Membrane/pathology , Glomerulosclerosis, Focal Segmental/pathology , Glomerulosclerosis, Focal Segmental/physiopathology , Kidney/pathology , Kidney Glomerulus/metabolism , Kidney Glomerulus/pathology , Macrophage Activation , Male , Mice , Mice, Knockout , Microtubule-Associated Proteins/biosynthesis , Nephrectomy , Podocytes/pathology
3.
Eur Arch Otorhinolaryngol ; 269(1): 87-92, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21590482

ABSTRACT

An animal model of chronic tympanic membrane (TM) perforation is needed for experiments on supporting healing of TM perforations. The basic fibroblast growth factor is important in TM wound healing. The object of this study was to investigate the efficacy of fibroblast growth factor receptor 1 (FGFR1) inhibition to arrest wound healing of experimental TM perforation. Bilateral instrumental myringotomies were performed in 12 rats. A specific inhibitor of the FGFR1 tyrosine kinase (SU5402) was applied to the left TM (2 mg/ml) and to the right TM (10 mg/ml) of each animal daily for 12 consecutive days. Thereafter, TMs were observed weekly for a total of 30 days. TM healing was delayed in a dose-dependent manner. We observed differences in the histologic parameters between both groups. SU 5402 is a strong inhibitor of TM healing but seems not to be suitable to create a chronic TM perforation in rat.


Subject(s)
Pyrroles/pharmacology , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Tympanic Membrane Perforation/physiopathology , Wound Healing/drug effects , Animals , Dose-Response Relationship, Drug , Female , Male , Protein-Tyrosine Kinases/antagonists & inhibitors , Rats , Rats, Inbred Lew , Tympanic Membrane/pathology , Tympanic Membrane Perforation/pathology
4.
Pharmacogenet Genomics ; 22(6): 408-20, 2012 Jun.
Article in English | MEDLINE | ID: mdl-21869731

ABSTRACT

OBJECTIVE: Multidrug resistance-related protein 2 (Mrp2) is expressed in apical membranes of renal proximal tubular cells and contributes to the renal secretion of cyclosporine A (CsA). Mrp2⁻/⁻ deficiency may lead to local renal CsA accumulation. We investigated whether kidney-specific Mrp2 deficiency enhances acute CsA nephrotoxicity in rats. METHODS: Kidney-specific Mrp2 deletion was achieved by bilateral nephrectomy and transplantation of a congenic Mrp2-deficient kidney into wild-type recipients. Controls received a wild-type kidney. Animals were treated with CsA (10 or 30 mg/kg/day) for 7 days. Renal hemodynamics and renal cortical mRNA expression profile, oxidative stress, and the abundance of multidrug resistance protein 1 (Mdr1) and Mrp2 were assessed. RESULTS: CsA accumulation and CsA-induced reduction in glomerular filtration rate were similar in wild-type and Mrp2⁻/⁻ kidneys. Renal vascular resistance and agonist-induced renal vascular responses were similar in both groups. A PCR array on 84 genes involved in the biotransformation and antioxidant defense revealed increased CsA-induced mRNA expression of genes involved in oxidative and metabolic stress, inflammation, and apoptosis. This gene expression pattern was similar in wild-type and Mrp2⁻/⁻ kidneys. CsA increased the renal cortical oxidized glutathione, did not affect xanthine oxidase-dependent superoxide formation, and decreased renal cortical NADPH oxidase-dependent superoxide formation. Furthermore, CsA increased Mdr1 protein abundance to a greater extent in Mrp2⁻/⁻ than in wild-type kidneys. CONCLUSION: Mrp2 is not critical for renal CsA disposition and its deficiency does not enhance acute CsA nephrotoxicity. The high Mdr1 abundance may at least in part prevent exaggerated CsA accumulation in Mrp2⁻/⁻ kidneys.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B/genetics , Cyclosporine/adverse effects , Gene Deletion , Kidney Diseases/chemically induced , Kidney Diseases/genetics , Kidney/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Blood Pressure/drug effects , Cyclosporine/blood , Gene Expression Regulation/drug effects , Glomerular Filtration Rate/drug effects , Glutathione Disulfide/metabolism , Hemodynamics/drug effects , Kidney/drug effects , Kidney/pathology , Kidney/physiopathology , Kidney Cortex/metabolism , Kidney Cortex/pathology , Kidney Cortex/physiopathology , Kidney Diseases/pathology , Kidney Diseases/physiopathology , Male , Organ Specificity/drug effects , Organ Specificity/genetics , Polymerase Chain Reaction , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Superoxides/metabolism
5.
Laryngoscope ; 121(4): 823-7, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21305552

ABSTRACT

OBJECTIVES/HYPOTHESIS: It is generally assumed that glycemic control in diabetic patients is important in optimizing wound healing. The goal of this study was to examine tympanic membrane (TM) wound healing in spontaneously diabetic rats depending on the diabetic metabolic state compared to nondiabetic control animals. STUDY DESIGN: Prospective controlled study in experimental animals. METHODS: Right-sided myringotomy was performed in 20 normoglycemic rats, 17 well-compensated, and 23 poorly compensated diabetic rats. TMs were observed for a total of 3 weeks. Effect of diabetic metabolic state on the healing of the TMs was evaluated by closure rates and histology. RESULTS: Diabetic rats showed a significant delay in TM wound healing compared to the control group, but there were no significant differences between both diabetes groups. CONCLUSIONS: Glycemic control does not influence TM wound repair in an animal model of type 1 diabetes.


Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 1/pathology , Fructosamine/blood , Tympanic Membrane Perforation/pathology , Tympanic Membrane/pathology , Wound Healing/physiology , Animals , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/genetics , Rats , Rats, Inbred BB
6.
Growth Factors ; 28(4): 286-92, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20166887

ABSTRACT

Recently, a report on a bilateral tympanic membrane (TM) perforation in a patient after long-term treatment with erlotinib was published. The object of this study was to investigate the destructive potential of topical applied epidermal growth factor receptor (EGFR) inhibitors on wound healing of experimental TM perforation in rats by evaluating closure rates and histology. In 12 rats, erlotinib (10 mg/ml) was applied to one TM of each animal and cetuximab (5 mg/ml) to the other side daily for 12 consecutive days. Both the erlotinib group (11.8 days) and cetuximab group (9 days) had prolonged healing latencies compared to a reference value (7 days). We observed differences in the histologic parameters between both groups. Our results suggest that in normal TM, the inhibition of EGFR does not lead to a persistent perforation. However, in case of preexisting TM pathology, a spontaneous perforation in patients under long-term treatment of EGFR inhibitors seems to be possible.


Subject(s)
ErbB Receptors/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Tympanic Membrane Perforation/physiopathology , Tympanic Membrane/physiology , Wound Healing/drug effects , Administration, Topical , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cetuximab , Disease Models, Animal , ErbB Receptors/metabolism , Erlotinib Hydrochloride , Female , Male , Quinazolines/administration & dosage , Quinazolines/pharmacology , Rats , Rats, Inbred Lew , Tympanic Membrane/anatomy & histology , Tympanic Membrane/drug effects , Tympanic Membrane Perforation/pathology
7.
Cardiovasc Res ; 85(4): 814-24, 2010 Mar 01.
Article in English | MEDLINE | ID: mdl-19843513

ABSTRACT

AIMS: The present study was performed to investigate the contribution of NADPH oxidases (Nox) to superoxide formation in human renal proximal resistance arteries and to test whether superoxide formation contributes to acute vasoconstrictor responses and endothelium-dependent vasodilation in these vessels. METHODS AND RESULTS: Arcuate and proximal interlobular artery segments were from patients who underwent nephrectomy because of a renal tumour. Vessels were dissected from tumour-free parts of the kidneys. Additional intrarenal arteries were obtained from rats. Superoxide formation was measured by lucigenin-enhanced chemiluminescence, expression of Nox isoforms was analysed by RT-PCR, and functional studies were performed by small vessel wire myography. Sixty per cent of superoxide formation in human arcuate and proximal interlobular arteries was due to Nox activity. mRNA expression analyses revealed the presence of Nox2 and Nox4 but not Nox1. Phenylephrine and endothelin-1 induced powerful concentration-dependent vasoconstrictions that were unaffected by superoxide scavengers. Vasopressin elicited small and variable vasoconstrictions with signs of tachyphylaxis. Endothelium-dependent vasodilation was blunted by tiron and Nomega-nitro-L-arginine methyl ester but not by superoxide dismutase or catalase. Exogenous hydrogen peroxide elicited vasoconstriction. CONCLUSION: Nox activity is the major source of superoxide formation in renal proximal resistance arteries from elderly patients. Acute vasoconstrictor responses to alpha1-adrenoreceptor activation and to endothelin-1 do not depend on superoxide formation, while endothelium-dependent vasodilation in intrarenal arteries is reactive oxygen species-dependent.


Subject(s)
Membrane Glycoproteins/metabolism , NADPH Oxidases/metabolism , Renal Artery/enzymology , Superoxides/metabolism , Vasodilation/physiology , 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt/pharmacology , Aged , Aged, 80 and over , Endothelin-1/pharmacology , Endothelium, Vascular/enzymology , Female , Free Radical Scavengers/pharmacology , Gene Expression Regulation, Enzymologic/physiology , Humans , Hydrogen Peroxide/pharmacology , Male , Membrane Glycoproteins/genetics , Middle Aged , NADPH Oxidase 1 , NADPH Oxidase 2 , NADPH Oxidase 4 , NADPH Oxidases/genetics , Oxidants/pharmacology , Polyethylene Glycols/pharmacology , RNA, Messenger/metabolism , Reactive Oxygen Species/metabolism , Superoxide Dismutase/pharmacology , Vasoconstriction/drug effects , Vasoconstriction/physiology , Vasodilation/drug effects
8.
Wound Repair Regen ; 16(3): 364-9, 2008.
Article in English | MEDLINE | ID: mdl-18471254

ABSTRACT

An animal model of chronic tympanic membrane (TM) perforation is needed for experiments on supporting wound healing of TM perforations. The epidermal growth factor receptor (EGFR) has been implicated in the regulation of wound healing. The object of this study was to investigate the efficacy of topical EGFR-inhibitor (erlotinib) to arrest wound healing of experimental TM perforation in rats. Bilateral instrumental myringotomies were performed in 13 male rats. A solution of erlotinib (10 mg/mL) was applied to one TM of each animal and vehicle only (control group) to the other side. The application procedure was repeated on both sides daily for 12 consecutive days. Thereafter, tympanic membranes were observed weekly for a total of 30 days. The mean healing period was found to be 12.1 days in the group with erlotinib and 6.4 days in the control group. The difference was significant. We observed differences in the histologic parameters between erlotinib group and control group. The inhibition of EGFR by topical application of erlotinib did delay the healing rate of myringotomies but seems not to be suitable to create a chronic TM perforation in rat.


Subject(s)
Protein Kinase Inhibitors/administration & dosage , Quinazolines/administration & dosage , Tympanic Membrane Perforation/drug therapy , Wound Healing/drug effects , Administration, Topical , Animals , Disease Models, Animal , Erlotinib Hydrochloride , Male , Random Allocation , Rats , Rats, Inbred Lew , Time Factors , Tympanic Membrane Perforation/diagnosis
9.
Ann Anat ; 189(3): 269-75, 2007.
Article in English | MEDLINE | ID: mdl-17534034

ABSTRACT

The condylar cartilage of the mandible is considered a secondary growth center and represents a joint cartilage different from other cartilage structures regarding its histological structure, its histochemical and immunohistochemical properties and its growth pattern. This study aimed to histologically and histomorphometrically investigate the condylar cartilage after anterior mandibular displacement similar to functional orthopedic treatment. A total of 12 pigs (sus scrofa domesticus) aged 10 weeks were divided into an experimental group and a control group comprising 6 animals each. The experimental animals were provided bilaterally with synthetic occlusal build-ups in the posterior area which induced anterior displacement of the mandible in terminal occlusion. After 4 weeks, the temporomandibular structures were removed en bloc and the condylar cartilage was analyzed histologically and histomorphometrically. As a result, the experimental animals displayed a significantly increased total cartilage thickness of the posterocranial mandibular condyle which was primarily caused by an increase in thickness of the hypertrophic and chondogenic layers. Similarly, the proliferative layer showed a significant increase, whereas significant differences in thickness were absent in the articular layer. Increased cell proliferation was not observed in the experimental animals as compared to the controls. The changes found in the condylar cartilage area suggest that the zonal structure of the condylar cartilage may be modified by an altered spatial relationship between the mandibular condyle and the glenoid fossa.


Subject(s)
Cartilage/anatomy & histology , Cartilage/cytology , Mandibular Condyle/anatomy & histology , Mandibular Condyle/cytology , Animals , Dental Occlusion , Hypertrophy , Mandibular Condyle/pathology , Models, Animal , Orthopedic Fixation Devices , Swine
10.
Wound Repair Regen ; 14(4): 453-6, 2006.
Article in English | MEDLINE | ID: mdl-16939573

ABSTRACT

High transforming growth factor-beta1 (TGF-beta1) expression in combination with fibrotic scar was observed in human tympanic membranes containing a chronic perforation. The purpose of this study was to investigate whether application of exogenous TGF-beta1 to experimentally created tympanic membrane perforations might induce a nonhealing tympanic membrane perforation. Bilateral myringotomies were performed in 20 rats. In 10 animals, a single dose of TGF-beta1 (0.1 microg) was topically applied to the left tympanic membrane after perforation. In the second part of the study with 10 animals, repeated applications of TGF-beta1 at a higher concentration were tested. In both groups, the opposite ears received vehicle alone. Tympanic membranes were observed for a total of 5 weeks. The effect of TGF-beta1 on the healing of the tympanic membranes was evaluated by closure rates and histology. In the single application group, the healing process was not delayed. Repeated applications of TGF-beta1 did cause a faster perforation closure and a thicker tympanic membrane. Topical TGF-beta1 applied to a traumatic tympanic membrane perforation does not create a chronic perforation at the concentrations and modes of application used in this study.


Subject(s)
Transforming Growth Factor beta1/administration & dosage , Tympanic Membrane Perforation/pathology , Wound Healing/physiology , Administration, Topical , Animals , Chronic Disease , Disease Models, Animal , Rats , Rats, Inbred Lew , Time Factors
11.
Exp Dermatol ; 12(3): 268-77, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12823440

ABSTRACT

Despite the lack of protective melanin and increased oxidative stress due to mM concentrations of epidermal H2O2 in vitiligo, there is no significantly increased risk for chronic actinic damage and non-melanoma skin cancer. Therefore the question arises, which protective mechanisms could be involved in the skin of these patients preventing the initiation of these cancers. Recently an overexpression of p53 has been shown in vitiligo. Unfortunately there was no further characterization of this elevated p53. Employing a functional colour yeast assay, the study presented herein demonstrates for the first time the overexpression of a functioning wild-type p53 protein in both depigmented and 'normal' pigmented epidermis of patients with vitiligo compared with healthy controls. Surprisingly long-term narrowband UVB (311 nm) treatment does not alter this expression. Moreover, MDM-2, PCNA and p21 protein expression remain unchanged compared with healthy controls. This increased epidermal p53 in vitiligo coincides with decreased thioredoxin reductase (TR) protein levels in both depigmented and pigmented skin whereas mRNA expression is unaffected. Because TR is one transcriptional target of p53, these results support a wild-type functionality, which was further supported by the specific p53 FASAY yeast test. To our knowledge this is the first example of persistent elevated functioning wild-type p53 in humans. Based on our results we hypothesize that the low incidence for actinic damage, basal cell and squamous cell carcinoma as documented in vitiligo could well reside in a protective function of up-regulated wild-type p53.


Subject(s)
Epidermis/physiopathology , Nuclear Proteins , Tumor Suppressor Protein p53/genetics , Vitiligo/physiopathology , Adolescent , Adult , Aged , Cytosol/physiology , Female , Gene Expression/physiology , Gene Expression/radiation effects , Humans , Hydrogen Peroxide/metabolism , Male , Middle Aged , Proliferating Cell Nuclear Antigen/genetics , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-mdm2 , Proto-Oncogene Proteins p21(ras)/genetics , Thioredoxin Reductase 1 , Thioredoxin-Disulfide Reductase/genetics , Tumor Suppressor Protein p53/metabolism , Ultraviolet Rays , Vitiligo/genetics , Vitiligo/pathology
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