1.Role of cofilin in kidney disease.
Journal of Central South University(Medical Sciences) 2018;43(10):1159-1163
Cofilin is a actin-binding protein in eukaryotic cells. It plays a role in maintaining the steady state of the internal environment through regulating actin dynamics, which contributes to the development of various kinds of diseases. In recent 20 years, cofilin has been widely attracted due to its regulatory effect on cell phenotype, gene transcription, apoptosis and inflammation in renal tissue. Cofilin plays a regulatory role in pathological changes in proteinuria diseases such as minimal change nephropathy, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy. It could be one of the diagnosis index for glomerular podocyte injury. At the same time, cofilin plays a key role in maintaining the polarity and function of proximal tubular epithelial cells and it is involved in the regulation of kidney inflammation in a variety of kidney diseases, such as renal ischemia/reperfusion injury, diabetic nephropathy, and hypertensive nephropathy reaction. In addition, cofilin plays an important role in epithelial-to-mesenchymal transition (EMT) of tumor cells and epithelial cells in various tissues, suggesting that cofilin may be involved in the regulation of peritoneal dialysis-related EMT and fibrosis. Cofilin might turn into the new diagnosis and treatment target of kidney diseases.
Cofilin 1
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metabolism
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Glomerulosclerosis, Focal Segmental
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physiopathology
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Humans
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Kidney
;
physiopathology
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Kidney Diseases
;
physiopathology
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Proteinuria
;
genetics
;
physiopathology
2.Genetics of hereditary nephrotic syndrome: a clinical review.
Korean Journal of Pediatrics 2017;60(3):55-63
Advances in podocytology and genetic techniques have expanded our understanding of the pathogenesis of hereditary steroid-resistant nephrotic syndrome (SRNS). In the past 20 years, over 45 genetic mutations have been identified in patients with hereditary SRNS. Genetic mutations on structural and functional molecules in podocytes can lead to serious injury in the podocytes themselves and in adjacent structures, causing sclerotic lesions such as focal segmental glomerulosclerosis or diffuse mesangial sclerosis. This paper provides an update on the current knowledge of podocyte genes involved in the development of hereditary nephrotic syndrome and, thereby, reviews genotype-phenotype correlations to propose an approach for appropriate mutational screening based on clinical aspects.
Genetic Association Studies
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Genetic Techniques
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Genetics*
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Glomerulosclerosis, Focal Segmental
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Humans
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Mass Screening
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Nephrotic Syndrome*
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Podocytes
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Sclerosis
;
Wills
3.Analysis of a pedigree with autosomal dominant intermediate Charcot-Marie-Tooth disease type E and nephropathy.
Jun FU ; Mingming MA ; Mi PANG ; Liang YANG ; Gang LI ; Jia SONG ; Jiewen ZHANG
Chinese Journal of Medical Genetics 2019;36(9):918-921
OBJECTIVE:
To explore phenotypic and mutational characteristics of a pedigree affected with autosomal dominant Charcot-Marie-Tooth disease (CMT) and nephropathy.
METHODS:
Clinical data of the proband and his family members was collected. Electrophysiology, renal biopsy and next-generation sequencing were carried out for the proband.
RESULTS:
The proband presented with distal lower limb weakness and proteinuria in childhood. His mother and brother had similar symptoms. Electrophysiological test of the proband revealed demyelination and axonal changes in both motor and sensory nerves. Renal biopsy suggested focal segmental glomerulosclerosis. Genetic testing revealed a heterozygous c.341G>A (p.G114D) mutation in exon 2 of the INF2 gene.
CONCLUSION
The phenotypic feature of the pedigree is autosomal dominant intermediate CMT and focal segmental glomerulosclerosis, which may be attributed to the c.341G>A mutation of the INF2 gene.
Charcot-Marie-Tooth Disease
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complications
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genetics
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Child
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Female
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Glomerulosclerosis, Focal Segmental
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complications
;
genetics
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Heterozygote
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Humans
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Male
;
Microfilament Proteins
;
genetics
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Mutation
;
Pedigree
4.Study of a family affected with focal segmental glomerulosclerosis due to mutation of COL4A5 gene.
Jing ZHANG ; Jing YANG ; Zhangxue HU
Chinese Journal of Medical Genetics 2017;34(3):373-376
OBJECTIVETo analyze the clinicopathologic features and genetic mutation in a patient diagnosed with focal segmental glomerulosclerosis (FSGS).
METHODSClinicopathologic data of the patient, who was diagnosed with primary FSGS by renal biopsy, was collected. Mutations of FSGS-related genes were screened with next-generation sequencing. Suspected pathogenic mutation was verified with Sanger sequencing.
RESULTSNext-generation sequencing detected a missense mutation (c.2215C to G, p.P739A) in exon 28 of the COL4A5 gene in the patient. The same mutation was also detected in his mother who was asymptomatic. Another missense mutation (c.2215C to T, p.P739S) in the same codon has been related with Alport syndrome.
CONCLUSIONThe c.2215C to G (p.P739A) mutation may be one of pathogenic mutations underlying FSGS. This has provided further evidence for the phenotypic heterogeneity of COL4A5 gene mutations.
Adult ; Base Sequence ; Collagen Type IV ; genetics ; Exons ; Female ; Glomerulosclerosis, Focal Segmental ; genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Male ; Molecular Sequence Data ; Mutation ; Young Adult
5.Genetic analysis of a child with Focal segmental glomerulosclerosis and neurodevelopmental syndrome.
Xuhui SUN ; Min XIN ; Jingmei TIAN ; Yingying ZHANG ; Qinqin JIAO ; Yong YANG ; Jinxiu LIU
Chinese Journal of Medical Genetics 2023;40(9):1155-1159
OBJECTIVE:
To explore the genetic characteristics of a child with Focal segmental glomerulosclerosis and neurodevelopmental syndrome (FSGSNEDS).
METHODS:
A child with FSGSNEDS who had visited Shengli Oilfield Central Hospital on September 15, 2019 was selected as the study subject. Clinical data of the child was collected, and trio-whole exome sequencing (trio-WES), Sanger sequencing, chromosomal karyotyping analysis, and copy number variation sequencing (CNV-seq) were used to analyze the child and his parents.
RESULTS:
The child, a 3-year-old boy, had manifested developmental delay, nephrotic syndrome, and epilepsy. Trio-WES and Sanger sequencing showed that he has carried a heterozygous c.1375C>T (p.Q459*) variant of the TRIM8 gene, for which both his parents were of the wild type. Based on guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic. No abnormality was found in the chromosomal karyotyping and CNV-seq results of the child and his parents.
CONCLUSION
The child was diagnosed with FSGSNEDS, for which the c.1375C>T variant of the TRIM8 gene may be accountable.
Male
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Humans
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Child
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Child, Preschool
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DNA Copy Number Variations
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Glomerulosclerosis, Focal Segmental/genetics*
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Genomics
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Heterozygote
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Karyotyping
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Carrier Proteins
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Nerve Tissue Proteins
6.New Mutation of Coenzyme Q Monooxygenase 6 Causing Podocyte Injury in a Focal Segmental Glomerulosclerosis Patient.
Cheng-Cheng SONG ; Quan HONG ; Xiao-Dong GENG ; Xu WANG ; Shu-Qiang WANG ; Shao-Yuan CUI ; Man-Di GUO ; Ou LI ; Guang-Yan CAI ; Xiang-Mei CHEN ; Di WU
Chinese Medical Journal 2018;131(22):2666-2675
Background:
Focal segmental glomerulosclerosis (FSGS) is a kidney disease that is commonly associated with proteinuria and the progressive loss of renal function, which is characterized by podocyte injury and the depletion and collapse of glomerular capillary segments. The pathogenesis of FSGS has not been completely elucidated; however, recent advances in molecular genetics have provided increasing evidence that podocyte structural and functional disruption is central to FSGS pathogenesis. Here, we identified a patient with FSGS and aimed to characterize the pathogenic gene and verify its mechanism.
Methods:
Using next-generation sequencing and Sanger sequencing, we screened the causative gene that was linked to FSGS in this study. The patient's total blood RNA was extracted to validate the messenger RNA (mRNA) expression of coenzyme Q monooxygenase 6 (COQ6) and validated it by immunohistochemistry. COQ6 knockdown in podocytes was performed in vitro with small interfering RNA, and then, F-actin was determined using immunofluorescence staining. Cell apoptosis was evaluated by flow cytometry, the expression of active caspase-3 was determined by Western blot, and mitochondrial function was detected by MitoSOX.
Results:
Using whole-exome sequencing and Sanger sequencing, we screened a new causative gene, COQ6, NM_182480: exon1: c.G41A: p.W14X. The mRNA expression of COQ6 in the proband showed decreased. Moreover, the expression of COQ6, which was validated by immunohistochemistry, also had the same change in the proband. Finally, we focused on the COQ6 gene to clarify the mechanism of podocyte injury. Flow cytometry showed significantly increased in apoptotic podocytes, and Western blotting showed increases in active caspase-3 in si-COQ6 podocytes. Meanwhile, reactive oxygen species (ROS) levels were increased and F-actin immunofluorescence was irregularly distributed in the si-COQ6 group.
Conclusions
This study reported a possible mechanism for FSGS and suggested that a new mutation in COQ6, which could cause respiratory chain defect, increase the generation of ROS, destroy the podocyte cytoskeleton, and induce apoptosis. It provides basic theoretical basis for the screening of FSGS in the future.
Adolescent
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Animals
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Apoptosis
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genetics
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physiology
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Cell Line
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Female
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Flow Cytometry
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Glomerulosclerosis, Focal Segmental
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genetics
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Humans
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Immunohistochemistry
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Mice
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Mutation
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genetics
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Podocytes
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metabolism
;
pathology
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RNA, Messenger
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genetics
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RNA, Small Interfering
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genetics
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metabolism
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Ubiquinone
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analogs & derivatives
;
genetics
;
metabolism
7.Progress in mitochondrial nephropathy.
Chinese Journal of Pediatrics 2014;52(7):503-505
Alkyl and Aryl Transferases
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genetics
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Child
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DNA, Mitochondrial
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genetics
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Fibroblasts
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metabolism
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Glomerulosclerosis, Focal Segmental
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diagnosis
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drug therapy
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genetics
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Humans
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Kidney Diseases
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diagnosis
;
drug therapy
;
genetics
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Mitochondrial Diseases
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diagnosis
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drug therapy
;
genetics
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Mutation
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Nephrotic Syndrome
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diagnosis
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drug therapy
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genetics
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Protein Kinases
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genetics
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Ubiquinone
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analogs & derivatives
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biosynthesis
;
deficiency
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therapeutic use
8.The effect of losartan on glomerular sclerosis in rats with diabetic nephropathy.
Jun-ying XU ; Li-jian TAO ; Ling WANG ; Wang-bin NING ; Ji-shi LIU
Journal of Central South University(Medical Sciences) 2008;33(9):836-840
OBJECTIVE:
To explore the degradation mechanism of losartan on extracellular matrix in rats with diabetic nephropathy.
METHODS:
The rat model of diabetic nephropathy was established by streptozotozin(STZ) injection, and the rats were randomly divided into 3 groups: (a normal group, a model group and a losartan group). For 16 weeks, the serum creatinine and urea nitrogen were measured, and glomerular sclerosis index(GSI) were caculated. The expression of collagen Type IV,connective tissue growth factor and transforming growth factor-beta1 were examined by Western blot and real time-PCR respectively.
RESULTS:
Blood urea nitrogen, GSI and the expressions of collagen Type IV and CTGF protein in the losartan group were lower than those in the model group(all P<0.05), and the expressions of collagen Type IV mRNA,TGF-beta1 mRNA and CTGF mRNA were lower than those in the model group (all P<0.05).
CONCLUSION
Losartan modulates glomerular sclerosis and decreases the accumulation of collagen Type IV by inhibiting TGF-beta1 and CTGF.
Animals
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Collagen Type IV
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biosynthesis
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genetics
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Connective Tissue Growth Factor
;
biosynthesis
;
genetics
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Diabetes Mellitus, Experimental
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pathology
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Diabetic Nephropathies
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metabolism
;
pathology
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Glomerulosclerosis, Focal Segmental
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etiology
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prevention & control
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Losartan
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pharmacology
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therapeutic use
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Male
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RNA, Messenger
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biosynthesis
;
genetics
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Random Allocation
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Rats
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Rats, Wistar
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Transforming Growth Factor beta
;
biosynthesis
;
genetics
9.Effects of yishen huoxue decoction on proliferating cell nuclear antigen expression and extracellular matrix in 5/6 nephrectomized rats.
Fang-fang HUANG ; Rong WANG ; Dong-Mei XU
Chinese Journal of Integrated Traditional and Western Medicine 2006;26(10):903-908
OBJECTIVETo investigate the effects and mechanisms of Yishen Huoxue decoction (YHD) on chronic renal failure (CRF) rats induced by 5/6 nephrectomy.
METHODSThe glomerulosclerosis model was established by 5/6 nephrectomy in rats. Experimental animals were allocated into the normal group, the model group, the YHD group and the benazepril group. Urine protein of 24 h (UP) at the 6th and 12th weekend after operation, blood urea nitrogen (BUN) and creatinine (SCr), albumin (Alb) and haemoglobin (HB) at the 12th weekend were measured, renal pathology changes were examined with light microscope, the expressions of proliferating cell nuclear antigen (PCNA) and fibronectin (Fn) were examined by immunohistochemistry and mRNA expressions of connective tissue growth factor (CTGF) and plasminogen activator inhibitor-1 (PAI-1) by RT-PCR at the 12th weekend.
RESULTSCompared with those in the normal group, the levels of UP, BUN and SCr, the area of glomerular mesangial matrix, the FN deposition, PCNA expression in glomeruli and tubular interstitium and mRNA expressions of CTGF and PAI-1 were all significantly higher in the model group (P < 0.05). All the above-mentioned indexes were lower in the YHD group than those in the model group (P < 0.05). PCNA positively expressed cells in glomeruli of the normal, model group, YHD group and benazepril group was 7.00 +/- 2.24,34.78 +/- 6.96,15.75 +/- 2.61 and 15.50 +/- 2.57 respectively, positively correlated to the expression of CTGF, PAI-1, FN and SCr level.
CONCLUSIONYHD could delay the progression of CRF in 5/6 nephrectomized rats, and the mechanisms were mainly related to the inhibition on renal cell proliferation and it induced over-expression of cytokines, and accumulation of extracellular matrix.
Animals ; Drugs, Chinese Herbal ; therapeutic use ; Extracellular Matrix ; drug effects ; metabolism ; Fibronectins ; biosynthesis ; genetics ; Glomerulosclerosis, Focal Segmental ; drug therapy ; etiology ; metabolism ; Kidney Failure, Chronic ; drug therapy ; etiology ; metabolism ; Male ; Nephrectomy ; Phytotherapy ; Proliferating Cell Nuclear Antigen ; biosynthesis ; genetics ; RNA, Messenger ; genetics ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reverse Transcriptase Polymerase Chain Reaction
10.Expression of neonatal Fc receptor on human nephritis and rat nephritis models.
Song-tao FENG ; Hua-lei GAN ; Jian-yong SUN ; Tao JIANG ; Bao-li LIU ; Zhong-hua ZHAO ; Mu-yi GUO ; Zhi-gang ZHANG
Chinese Journal of Pathology 2012;41(2):81-85
OBJECTIVETo study the expression of neonatal Fc receptor in podocytes in human nephritis and immune-induced rat nephritis models: anti-Thy1.1 nephritis and Heymann nephritis.
METHODSThirty-nine cases of renal biopsies were enrolled from September 2009 to February 2010, including 8 cases of minimal change disease, 4 cases of focal segmental glomerulosclerosis, 9 cases of membranous nephropathy, 12 cases of IgA nephropathy and 6 cases of lupus nephritis. Five normal kidney tissue samples adjacent to renal clear-cell carcinoma were served as normal controls. Laser capture microdissection and real-time RT-PCR were used to assess the expression level of FcRn mRNA in glomeruli of various glomerulonephritides, and immunohistochemistry (IHC) of FcRn by SuperVision method was performed. In addition, rat models of mesangial proliferative nephritis (anti-Thy1.1 nephritis) and passive membranous nephropathy (Heymann nephritis) were established and FcRn was examined in renal tissues by IHC.
RESULTSThe FcRn mRNA level in lupus nephritis was statistically higher than that of normal controls (P < 0.05). FcRn protein expression by IHC was seen in lupus nephritis (6/6), membranous nephropathy (6/9) and IgA nephropathy (7/12), significantly higher than that of normal controls (0/5), P < 0.05. Minimal change disease and focal segmental glomerular sclerosis showed minimal or none expression of FcRn (1/8, 0/4 respectively) and not statistically difference from that of normal controls. Furthermore, FcRn expression in podocytes was detected in rat anti-Thy1.1 (3/5) and Heymann nephritis models (2/7) but was not detected in normal controls.
CONCLUSIONSExpression of FcRn in podocytes was up-regulated in immune-induced human nephritis and rat nephritis models of anti-Thy1.1 nephritis and Heymann nephritis. FcRn may play a role in the development of immune-induced glomerulonephritis.
Animals ; Glomerulonephritis, IGA ; metabolism ; pathology ; Glomerulonephritis, Membranous ; metabolism ; pathology ; Glomerulosclerosis, Focal Segmental ; metabolism ; pathology ; Histocompatibility Antigens Class I ; genetics ; metabolism ; Humans ; Laser Capture Microdissection ; Lupus Nephritis ; metabolism ; pathology ; Male ; Nephritis ; genetics ; immunology ; metabolism ; pathology ; Nephrosis, Lipoid ; metabolism ; pathology ; Podocytes ; metabolism ; RNA, Messenger ; metabolism ; Rats ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction ; Receptors, Fc ; genetics ; metabolism ; Thy-1 Antigens ; immunology ; metabolism ; Up-Regulation