Female ; Glomerulonephritis, IGA ; metabolism ; pathology ; Glomerulonephritis, Membranous ; metabolism ; pathology ; Glomerulosclerosis, Focal Segmental ; metabolism ; pathology ; Humans ; Kidney ; metabolism ; pathology ; Male ; Renal Insufficiency, Chronic ; metabolism ; pathology

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 ; Animals ; Apoptosis ; genetics ; physiology ; Cell Line ; Female ; Flow Cytometry ; Glomerulosclerosis, Focal Segmental ; genetics ; Humans ; Immunohistochemistry ; Mice ; Mutation ; genetics ; Podocytes ; metabolism ; pathology ; RNA, Messenger ; genetics ; RNA, Small Interfering ; genetics ; metabolism ; Ubiquinone ; analogs & derivatives ; genetics ; metabolism

Focal segmental glomerulosclerosis (FSGS) is characterized by focal and segmental obliteration of glomerular capillary tufts with increased matrix. FSGS is classified as collapsing, tip, cellular, perihilar and not otherwise specified variants according to the location and character of the sclerotic lesion. Primary or idiopathic FSGS is considered to be related to podocyte injury, and the pathogenesis of podocyte injury has been actively investigated. Several circulating factors affecting podocyte permeability barrier have been proposed, but not proven to cause FSGS. FSGS may also be caused by genetic alterations. These genes are mainly those regulating slit diaphragm structure, actin cytoskeleton of podocytes, and foot process structure. The mode of inheritance and age of onset are different according to the gene involved. Recently, the role of parietal epithelial cells (PECs) has been highlighted. Podocytes and PECs have common mesenchymal progenitors, therefore, PECs could be a source of podocyte repopulation after podocyte injury. Activated PECs migrate along adhesion to the glomerular tuft and may also contribute to the progression of sclerosis. Markers of activated PECs, including CD44, could be used to distinguish FSGS from minimal change disease. The pathogenesis of FSGS is very complex; however, understanding basic mechanisms of podocyte injury is important not only for basic research, but also for daily diagnostic pathology practice.
Actin Cytoskeleton ; Age of Onset ; Capillaries ; Diaphragm ; Epithelial Cells ; Foot ; Glomerulosclerosis, Focal Segmental* ; Nephrosis, Lipoid ; Pathology ; Permeability ; Podocytes ; Rabeprazole ; Sclerosis ; Wills

OBJECTIVETo explore the correlation between pathological characteristics of target organs and excess evil syndrome in IgA nephropathy.

METHODSData were collected in multicenter cooperation. Totally 266 IgA nephropathy patients were typed into exogenous wind-heat affection syndrome (49 cases), lower energizer damp-heat syndrome (100 cases), damp-phlegm syndrome (43 cases), and blood stasis syndrome (74 cases). Meanwhile, percutaneous renal biopsy was performed in all patients for Hass classification, Oxford classification, Katafuchi integral, and Jiang's classification methods. The correlation between excess evil syndrome and pathological index was analyzed.

RESULTSFour syndrome types were correlated with their Hass levels (r = 0. 341, P <0. 01). Affection of exogenous wind-heat syndrome was correlated with segmental proliferation of endothelial cells and damaged active lesions of segmental capillary loops. Lower-energizer damp-heat syndrome was associated with Hass III level, destroying active lesions of capillary loops, segmental proliferation of endothelial cells, glomerular segmental lesions, focal interstitial infiltration of inflammatory cells, focal interstitial fibrosis and tubular atrophy. Blood stasis syndrome was associated with Hass IV level, glomerular sclerosis, segmental glomerulosclerosis (S)/adhesion, mesangial hypercellularity (M), angiohyalinosis, multi-foci interstitial infiltration of inflammatory cells, multi-foci interstitial fibrosis and tubular atrophy. Phlegm-damp syndrome had higher proportions of Hass I and III levels, but with no association with other pathological parameters.

CONCLUSIONSExcess evil syndrome was associated with partial pathological characteristics of IgA nephropathy. It could reflect pathological damage degree of target organs, activities, chronic lesions, and prognosis of IgA nephropathy to certain extent. Correlated pathological characteristics and its evolution could indicate excess evil syndrome types and their evolution rules.

Capillaries ; Fibrosis ; Glomerulonephritis, IGA ; pathology ; Glomerulosclerosis, Focal Segmental ; Humans ; Kidney Glomerulus ; Medicine, Chinese Traditional ; Prognosis ; Syndrome

OBJECTIVE: To explore the eff ect of Qiluxiaobai (QLXB) decoction on rats with adriamycin (ADR)- induced focal segmental glomerular sclerosis (FSGS) nephropathy (ADN). METHODS: Adriamycin was injected into tail vein at total dose of 7.5 mg/kg for twice per week. According to random number table, rats were divided into 4 groups: the control group, the ADN group, the Losartan group [intragastric, 5.19 mg/(kg.d)], and the QLXB group [intragastric,134.40 mg/(kg.d)]. Eight weeks later, serum creatinine (SCr), blood urea nitrogen (BUN), serum cholesterol (CHO), serum triglycerides (TG) and albuminuria (ALB) were measured by routine biochemical methods. Pathological changes in the rat kidneys were observed under light microscopes. Connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA) and fibronectin (FN) mRNA and protein expression levels were measured by real-time PCR and Western blot, respectively. RESULTS: In the ADN group, SCr, BUN, CHO, TG was increased (P<0.05) while ALB was decreased (P<0.05), ALB was decreased (P<0.05) compared to the control group. In the QLXB and Losartan group, SCr, BUN, CHO, TG and ALB was improved compared to the ADN group (P<0.05). CTGF, FN, α-SMA mRNA and protein expression was decreased in QLXB group compared to ADN group (P<0.05). CONCLUSION QLXB could partly improve glomerular sclerosis in adriamycin-induced nephropathy, which was related to inhibition of CTGF, FN and α-SMA expression.
Actins ; metabolism ; Animals ; Connective Tissue Growth Factor ; metabolism ; Doxorubicin ; adverse effects ; Drugs, Chinese Herbal ; pharmacology ; Fibronectins ; metabolism ; Glomerulosclerosis, Focal Segmental ; chemically induced ; drug therapy ; Kidney ; pathology ; Rats ; Real-Time Polymerase Chain Reaction ; Sclerosis

OBJECTIVETo investigate the mechanism of "Jianpi Qinghua Decoction" (JQD) on renal fibrosis by observing the impact of JQD on serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), and kidney tumor necrosis factor-Α (TNF-Α) expressions in focal segmental glomerulosclerosis rats induced by nephrectomy combined with adriamycin.

METHODSTotally 56 male SD rats were divided into normal group, sham operation group, model group, JQD group, Yiqi Jianpi group, Qingre Huashi group, and Niaoduqing group (all n=8). The model of focal segmental glomerulosclerosis was established by the unilateral nephrectomy and the injection of adriamycin in caudal vein of rat at a dose of 3 mg/kg in the latter 5 groups. JQD, the disassembled prescription of Jianpi Qinghua Decoction (Yiqi Jianpi Decoction and Qingre Huashi Decoction), and Niaoduqing Capsule were administered separately for 8 weeks. The serum TC, TG, LDL, and VLDL levels and the expression of Kidney TNF-Α were determined.

RESULTSCompared with normal group and sham operation group, the serum TC, TG, LDL, and VLDL levels and the kidney TNF-Α expression in the model group were significantly higher (all P<0.01). Compared with the model group, the JQD group, Qingre Huashi group, and Niaoduqing group had significantly lower serum TC, TG, LDL, and VLDL levels and kidney TNF-Α expression (all P<0.01). Compared with the model group, the Yiqi Jianpi group had significantly lower serum TC ,TG, and VLDL levels (all P<0.01), while the serum LDL level and kidney TNF-Α expression remained unchanged (all P>0.05).

CONCLUSIONSJQD can regulate serum lipids and lower the TNF-Α expression in kidney tissue and thus improve the renal inflammation and relieve renal fibrosis. The heat-clearing and dampness-removing herbs in the prescription play a central role in fighting against renal fibrosis.

Animals ; Disease Models, Animal ; Drugs, Chinese Herbal ; therapeutic use ; Fibrosis ; Glomerulosclerosis, Focal Segmental ; blood ; drug therapy ; Kidney ; metabolism ; pathology ; Lipids ; blood ; Male ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha ; metabolism

Churg-Strauss syndrome (CSS), or allergic granulomatosis, is a rare disease manifested by tissue infiltration, hypereosinophilia and vasculitis. Renal involvement may be seen in up to 50% of cases. We report the case of a 25-year old man who presented with a history of fever for two months, tingling, numbness, and paraesthesia of the upper limbs and left lower limb, along with diarrhoea for one month and an inability to walk for the past seven days. Serial laboratory investigations helped to reach the final diagnosis of CSS with mononeuritis multiplex, and skin, pulmonary and gastrointestinal involvement with hypertension. This is due to renal involvement in the form of focal segmental glomerulosclerosis without any nephrotic range proteinuria, which is a very rare clinical entity. The patient's symptoms were relieved after the administration of an unconventional mode of therapy.
Adult ; Biopsy ; Churg-Strauss Syndrome ; complications ; diagnosis ; Fever ; Glomerulosclerosis, Focal Segmental ; complications ; diagnosis ; Humans ; Kidney ; pathology ; Kidney Diseases ; complications ; Male ; Proteinuria ; diagnosis ; Radiography, Thoracic ; Skin ; pathology ; Treatment Outcome

OBJECTIVETo study the effect of Jianpi Qinghua decoctions in ameliorating kidney fibrosis in rats with focal segmental glomurular sclerosis (FSGS) nephropathy in light of blocking the functions of the inflammatory cells.

METHODSRat models of FSGS nephropathy were established by left nephrectomy and intravenous injection of adriamycin and treated with Jianpi Qinghua decoction. The renal expressions of interleukin-6 (IL-6), monocyte chemotactic protein 1 (MCP-1), and intercellular adhesion molecular-1 (ICAM-1) were detected.

RESULTSTreatment with Jianpi Qinghua decoction, Jianpi decoction, Qinghua decoction, and Niaoduqing particles all significantly lowered renal tubulointerstitial expressions of IL-6 in the model rats (P<0.01). Renal tubulointerstitial MCP-1 expressions were all lowered significantly in the rats by treatments with Jianpi Qinghua decoction, Jianpi decoction, QingHua decoctions, and Niaoduqing particles (P<0.01), and Jianpi Qinghua decoction produced a stronger effect than Niaoduqing particles (P<0.05). Jianpi Qinghua decoction, Jianpi decoction, Qinghua decoctions and and Niaoduqing particles all significantly decreased renal tubulointerstitial MCP-1 and ICAM-1 expressions (P<0.01), and Jianpi Qinghua and Qinghua decoctions both showed stronger effects than Niaoduqing particles (P<0.01). Jianpi Qinghua decoctions significantly suppressed the expressions of IL-6, MCP-1, and ICAM-1 and produced stronger effects than Niaoduqing particles on MCP-1 and ICAM-1 expressions.

CONCLUSIONJianpi Qinghua decoctions can ameliorate inflammatory injury and lower the levels of inflammatory factors in rats with FSGS nephropathy, the mechanism of which is associated with inhibiting IL-6 signaling pathway.

Animals ; Chemokine CCL2 ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; Glomerulosclerosis, Focal Segmental ; metabolism ; pathology ; Intercellular Adhesion Molecule-1 ; metabolism ; Interleukin-6 ; metabolism ; Kidney ; metabolism ; pathology ; Kidney Tubules ; metabolism ; Male ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Sclerosis ; Signal Transduction ; drug effects

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

OBJECTIVETo analyze the characteristics of repeated renal biopsy-proven primary focal segmental glomerulosclerosis (PFSGS) in 8 children, and to reveal the relationship between clinical features and pathology, between the two times of renal biopsy pathology, and the indications for repeated renal biopsy.

METHODThe records of cases who ever experienced renal biopsy in this hospital were reviewed, of whom 8 cases of repeated renal biopsy-proven PFSGS were enrolled. The clinical manifestations, the reason why they had renal biopsy again, the difference in renal pathological findings, between the two biopsies and their therapeutic response. The classification of focal segmental glomerulosclerosis (FSGS) was based on the new criteria suggested by D'Agati in 2004.

RESULTOf the 8 cases, age of onset ranged from 1 to 12 years, all were diagnosed as nephrotic syndrome (NS), the age of first biopsy ranged from 1.1 to 15.0 years, and the follow-up period was 10 months to 14 years. The reason for repeated biopsy was poor therapeutic response, continuous heavy proteinuria, or the progressive renal dysfunction. Four cases had the both biopsies in this hospital, and the first renal pathology showed minimal change disease (MCD), mesangial proliferation, FSGS CELL type and FSGS GTL type. After the second biopsy, they were additionally treated with immunosuppressive agents or switched to another one, 2 cases with FSGS COLL type presented renal dysfunction or end stage renal disease (ESRD), 1 case who developed the disease at 1.4 years of age, presented renal dysfunction at 10 months follow-up. The remaining 5 cases acquired complete remission.

CONCLUSIONFSGS is a clinicopathological syndrome, NS predominates clinically. It often indicates pathologic transformation when the patients show poor therapeutic response or continuous heavy proteinuria without remission. Mesangial proliferation can convert into FSGS, and the subtype of FSGS can shift. FSGS COLL type and onset at young age may suggest poor prognosis.

Biopsy ; Child ; Child, Preschool ; Female ; Glomerulosclerosis, Focal Segmental ; pathology ; Humans ; Infant ; Kidney ; pathology ; Male