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Nan Fang Yi Ke Da Xue Xue Bao = Journal... Feb 2023To study the toxic effects of short-term exposure to gossypol on the testis and kidney in mice and whether these effects are reversible.
OBJECTIVE
To study the toxic effects of short-term exposure to gossypol on the testis and kidney in mice and whether these effects are reversible.
METHODS
Twenty 7 to 8-week-old male mice were randomized into blank control group, solvent control group, gossypol treatment group and drug withdrawal group. In the former 3 groups, the mice were subjected to daily intragastric administration of 0.3 mL of purified water, 1% sodium carboxymethylcellulose solution, and 30 mg/mL gossypol solution for 14 days, respectively; In the drug withdrawal group, the mice were treated with gossypol solution in the same manner for 14 days followed by treatment with purified water for another 14 days. After the last administration, the mice were euthanized and tissue samples were collected. The testicular tissue was weighed and observed microscopically with HE and PAS staining; the kidney tissue was stained with HE and examined for mitochondrial ATPase activity.
RESULTS
Compared with those in the control group, the mice with gossypol exposure showed reduced testicular seminiferous epithelial cells with rounded seminiferous tubules, enlarged space between the seminiferous tubules, interstitium atrophy of the testis, and incomplete differentiation of the spermatogonia. The gossypol-treated mice also presented with complete, non-elongated spermatids, a large number of cells in the state of round spermatids, and negativity for acrosome PAS reaction; diffuse renal mesangial cell hyperplasia, increased mesangial matrix, and adhesion of the mesangium to the wall of the renal capsule were observed, with significantly shrinkage or even absence of the lumens of the renal capsules and reduced kidney mitochondrial ATPase activity. Compared with the gossypol-treated mice, the mice in the drug withdrawal group showed obvious recovery of morphologies of the testis and the kidney, acrosome PAS reaction and mitochondrial ATPase activity.
CONCLUSIONS
Shortterm treatment with gossypol can cause reproductive toxicity and nephrotoxicity in mice, but these toxic effects can be reversed after drug withdrawal.
Topics: Mice; Male; Animals; Gossypol; Testis; Seminiferous Tubules; Spermatids; Spermatogenesis; Adenosine Triphosphatases
PubMed: 36946045
DOI: 10.12122/j.issn.1673-4254.2023.02.13 -
Poultry Science Apr 2024Goose astrovirus (GAstV)-2, a novel pathogen identified in 2018, mainly causes visceral gout in goslings, leading to approximately 50% mortality. At present, no...
Goose astrovirus (GAstV)-2, a novel pathogen identified in 2018, mainly causes visceral gout in goslings, leading to approximately 50% mortality. At present, no commercial veterinary products are available to prevent and treat the disease. Our previous studies showed that nitric oxide (NO) and inducible NO synthase (iNOS) were markedly higher in the kidney and spleen of goslings infected with GAstV-2, but their effects during GAstV-2 infection remain unclear. In the present study, goslings were intraperitoneally injected with aminoguanidine (AG)-an iNOS inhibitor-to examine the role of NO during GAstV-2 infection. AG significantly decreased the serum NO concentration and iNOS mRNA expression in the kidney. Moreover, AG reduced the mortality, serum uric acid and creatinine content, and urate deposition in visceral organs and joints. Histopathological analysis demonstrated that AG reduced renal tubular cell necrosis, inflammatory cell infiltration, glycogen deposition in glomerular mesangium, and interstitial fibrosis, suggesting alleviation of kidney lesions. Furthermore, AG decreased the expression of renal injury markers such as KIM-1 and desmin; inflammatory cytokine-related genes such as IL-1β, IL-8, and MMP-9; and autophagy-related genes and proteins such as LC3II, ATG5, and Beclin1. However, quantitative real-time PCR and immunohistochemistry showed that treatment with AG did not affect the kidney and liver viral load. These findings suggest that AG decreases the mortality rate and kidney lesions in goslings infected with GAstV-2 through mechanisms associated with autophagy and inhibition of inflammatory cytokine production in the kidney but not with GAstV-2 replication.
Topics: Animals; Geese; Uric Acid; Chickens; Astroviridae; Gout; Astroviridae Infections; Kidney; Cytokines; Avastrovirus; Guanidines
PubMed: 38306918
DOI: 10.1016/j.psj.2024.103484 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... Nov 2023To investigate the role of histone deacetylase 6 (HDAC6) in podocyte injury in diabetic kidney disease (DKD) in mice.
OBJECTIVE
To investigate the role of histone deacetylase 6 (HDAC6) in podocyte injury in diabetic kidney disease (DKD) in mice.
METHODS
1) The 8-week-old male CD-1 mice were selected to construct the model of DKD with streptozocin (STZ). After the model was established, the mice were intraperitoneally injected with HDAC6 inhibitor CAY10603 (5mg/kg/daily) or same volume vehicle as control. The mice were divided into four groups, control (CTL)+vehicle (Veh) (=5), CLT+CAY10603 (=3), STZ+Veh (=9), and STZ+CAY10603 (=7). Mice in STZ+Veh and STZ+CAY10603 groups developed DKD, while mice in the CTL+Veh and CTL+CAY10603 groups were served as normal controls. The therapeutic effect was evaluated through urine albumin-to-creatinine ratio (uACR) and renal pathology after the 2-week treatment with CAY10603. 2) Human podocytes were cultured and were divided into four groups as follows: CTL, transforming growth factor-β (TGFβ), TGFβ+CAY10603 (250 nmol/L), and TGFβ+CAY10603 (500 nmol/L) groups. The control group did not receive any treatment, the last three groups were given 36-h TGFβ treatment at 5 ng/µL, with or without CAY10603 as indicated for an additional 12 h. Western blot was performed to determine the inhibitory effect of CAY10603 on NLRP3 inflammasome. 3) 6 knockout (KO) mice were generated and used to create STZ-induced model of DKD. The mice were divided into four groups: C57BL/6J wild type (WT) (=6), 6 KO (=6), WT+STZ (=10), and 6 KO+STZ (=9). Samples were collected 16 weeks after successful modeling and changes in uACR and renal pathology were evaluated accordingly.
RESULTS
After 2 weeks of treatment, mice in the STZ+CAY10603 group exhibited reduction in uACR (<0.05) and inhibition of glomerular mesangium expansion (<0.05) compared with those of the mice in the STZ+Veh group. There was no statistically significant difference in the indicators between the CTL+Veh group and the CTL+CAY10603 group. cultured podocytes, compared with the control group, NLRP3 inflammasome activation was seen in the TGFβ group. CAY10603 treatment significantly inhibited the activation of NLRP3 in the dosage-dependent manner (<0.05). Compared with those of the WT group, the WT+STZ group showed increased uACR (<0.05), obvious glomerulosclerosis and loss of podocytes numbers. Compared with those of the WT+STZ group, the 6 KO+STZ group showed effectively reduction of uACR (<0.05) and improvement in the renal pathological changes in mice. There was no significant difference in these aspects between the WT and 6 KO groups.
CONCLUSION
Inhibition of HDAC6 alleviates proteinuria and podocyte injury in the mouse model of DKD by suppressing the activation of NLRP3 inflammasome.
Topics: Animals; Humans; Male; Mice; Diabetes Mellitus; Diabetic Nephropathies; Histone Deacetylase 6; Inflammasomes; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Podocytes; Transforming Growth Factor beta
PubMed: 38162083
DOI: 10.12182/20231160207 -
American Journal of Physiology. Renal... Jan 2023Although mesangial cell-glomerular basement membrane (GBM) connections play a key role in maintaining the glomerular capillary loop structure, information remains...
Although mesangial cell-glomerular basement membrane (GBM) connections play a key role in maintaining the glomerular capillary loop structure, information remains limited about how these connections are formed during glomerulogenesis. We have previously shown that weakened podocyte-GBM interactions owing to tensin 2 () deficiency lead to abnormal GBM maturation during postnatal glomerulogenesis. Here, we investigated whether abnormal GBM maturation affected mesangial cell-GBM connections and mesangial cell differentiation. Histological analysis of the outer cortical glomeruli in -deficient mice revealed that GBM materials overproduced by stressed immature podocytes accumulated in the mesangium and interrupted the formation of mesangial cell-GBM connections, resulting in fewer capillary loops compared with that of normal glomeruli. In addition, expression of α-smooth muscle actin, an immature mesangial cell marker, persisted in mesangial cells of -deficient outer cortical glomeruli even after glomerulogenesis was completed, resulting in mesangial expansion. Furthermore, analysis of mouse primary mesangial cells revealed that mesangial cell differentiation depended on the type of extracellular matrix components to which the cells adhered, suggesting the participation of mesangial cell-GBM connections in mesangial cell differentiation. These findings suggest that abnormal GBM maturation affects mesangial cell differentiation by impairing mesangial cell-GBM connections. Mesangial cell-glomerular basement membrane (GBM) connections play an important role in maintaining the structural integrity of the glomerular tuft. However, information remains scarce about how GBM maturation affects the formation of these connections during glomerular development. Here, we show that abnormal GBM maturation due to tensin 2 deficiency affects mesangial cell differentiation by impairing mesangial cell-GBM connections during postnatal glomerulogenesis.
Topics: Mice; Animals; Glomerular Basement Membrane; Basement Membrane; Tensins; Glomerular Mesangium; Podocytes; Cell Differentiation
PubMed: 36417276
DOI: 10.1152/ajprenal.00192.2022 -
Journal of Clinical Pathology Feb 2022Detection of one segmentally sclerosed glomerulus (SSG) identifies patients with focal segmental glomerulosclerosis (FSGS) but rare SSGs may be missed in kidney...
AIMS
Detection of one segmentally sclerosed glomerulus (SSG) identifies patients with focal segmental glomerulosclerosis (FSGS) but rare SSGs may be missed in kidney biopsies. It is unknown whether alterations of unaffected glomeruli in patients with infrequent SSG can be detected by quantitative morphometrics.
METHODS
We determined SSG frequency and obtained quantitative morphometrics in glomeruli without a pathologic phenotype in large kidney sections of non-involved kidney tissue from 137 patients undergoing total nephrectomy. We used multivariate modelling to identify morphometrics independently associated with increasing frequency of SSG and Receiver Operator Curve (ROC) analysis to determine the ability of quantitative morphometrics to identify patients with FSGS. We used the geometric distribution to estimate the sensitivity and specificity of a needle biopsy to identify patients with FSGS.
RESULTS
In seventy-one patients (51.8%), at least one SSG was observed, and of those, 39 (54.9%) had an SSG lesion in less than 2% of all glomeruli (mean of 249 glomeruli per specimen). Increasing percent of SSG was independently associated with decreasing podocyte density and increasing mesangial index in multivariate modelling. For infrequent SSG lesions (<1% of glomeruli), kidney biopsy could miss FSGS diagnosis more than 74% of the time, and podocyte density had an area under the curve (AUC) of 0.77, and mesangial index, an AUC of 0.79 to identify patients with FSGS.
CONCLUSIONS
More than half of patients had FSGS, although 30% had infrequent SSG. Quantitative morphometrics in glomeruli without pathology, such as podocyte density and mesangial index, identified patients with infrequent SSG and may serve as clinical markers to identify patients with FSGS.
Topics: Aged; Biopsy, Needle; Female; Glomerular Mesangium; Glomerulosclerosis, Focal Segmental; Humans; Kidney Glomerulus; Male; Middle Aged; Phenotype; Podocytes; Predictive Value of Tests; Reproducibility of Results
PubMed: 33431484
DOI: 10.1136/jclinpath-2020-207149 -
Advanced Science (Weinheim,... Nov 2023The function of the glomerulus depends on the complex cell-cell/matrix interactions and replication of this in vitro would aid biological understanding in both health...
The function of the glomerulus depends on the complex cell-cell/matrix interactions and replication of this in vitro would aid biological understanding in both health and disease. Previous models do not fully reflect all cell types and interactions present as they overlook mesangial cells within their 3D matrix. Herein, the development of a microphysiological system that contains all resident renal cell types in an anatomically relevant manner is presented. A detailed transcriptomic analysis of the contributing biology of each cell type, as well as functionally appropriate albumin retention in the system, is demonstrated. The important role of mesangial cells is shown in promoting the health and maturity of the other cell types. Additionally, a comparison of the incremental advances that each individual cell type brings to the phenotype of the others demonstrates that glomerular cells in simple 2D culture exhibit a state more reflective of the dysfunction observed in human disease than previously recognized. This in vitro model will expand the capability to investigate glomerular biology in a more translatable manner by the inclusion of the important mesangial cell compartment.
Topics: Humans; Glomerular Mesangium; Microphysiological Systems; Kidney; Phenotype
PubMed: 37867234
DOI: 10.1002/advs.202303131 -
Clinical Nephrology. Case Studies 2023We performed a kidney biopsy in a 36-year-old man to evaluate microscopic hematuria and proteinuria. Light microscopy showed increased mesangial matrix and partial...
We performed a kidney biopsy in a 36-year-old man to evaluate microscopic hematuria and proteinuria. Light microscopy showed increased mesangial matrix and partial swelling of the glomerular basement membrane (GBM), and immunofluorescence showed positive staining only for C3. Immunoelectron microscopy showed that gold particle-labeled C3 was localized in the electron-dense and moderately electron-dense deposits shown by electron microscopy in the mesangium, the thickened GBM near the paramesangium, and the thickened distal portion of the GBM but was not localized in the non-thickened GBM. Gold-labeled immunoglobulin G, κ, and λ were not seen. C3 glomerulonephritis was more evident in gold-labeled electron microscopy, which further clarified the localization of C3 deposition.
PubMed: 37363300
DOI: 10.5414/CNCS111091 -
Medicine Apr 2023Polycythemia vera (PV) is a myeloproliferative neoplasm which is characterized by excessive production of erythrocytes as well as myeloid and megakaryocytic...
BACKGROUND
Polycythemia vera (PV) is a myeloproliferative neoplasm which is characterized by excessive production of erythrocytes as well as myeloid and megakaryocytic proliferation. PV associated with IgA nephropathy (IgAN) has rarely been reported in the literature. The long-term renal prognosis of these patients is unknown.
METHODS
Clinical and pathological characteristics of 7 patients with renal biopsy-proven IgAN associated with PV were retrospectively analyzed.
RESULTS
The 7 patients were all males, with a mean age of 49.1 ± 18.8 years when admitted to our hospital. Systemic symptoms include: hypertension in case 2, 3, 5, and 6, splenomegaly in case 2, 4, and 5, and multiple lacunar infarction in case 6. Bone marrow biopsy test revealed relative erythroid hyperplasia and atypical megakaryocyte proliferation which consistent with a chronic myeloproliferative neoplasm. All patients had JAK2V617F and BCR-ABL tested, and JAK2V617F positive in 2 patients. Mild mesangial proliferation was observed in 5 patients and moderate/severe mesangial proliferation in 2patients. Immunofluorescence mainly showed diffuse granular deposition of dominant IgA in mesangium. After follow-up of 56.7 ± 44.0 months, hemoglobin level was 144 ± 29 g/L and hematocrit lever was 0.470 ± 0.03, compared with 187 ± 29 g/L and 0.563 ± 0.087 respectively when admitted to our hospital. The urine protein was 0.85 ± 0.64 g/24 h compared with 3.97 ± 4.68 g/24 h. Case 3 progressed to end stage renal disease and had received hemodialysis for 5 years before renal transplantation.
CONCLUSIONS
The results of this study showed that PV associated with IgAN mainly occurs in males and is often accompanied by hematuria and mild-to-moderate renal insufficiency. The long-term prognosis was good for most patients, and few progressed relatively quickly to end stage renal disease.
Topics: Male; Humans; Adult; Middle Aged; Aged; Glomerulonephritis, IGA; Polycythemia Vera; Retrospective Studies; East Asian People; Kidney Failure, Chronic; Myeloproliferative Disorders
PubMed: 37026962
DOI: 10.1097/MD.0000000000033493 -
Journal of Clinical Medicine Sep 2021Immunoglobulin M nephropathy (IgMN) is an idiopathic glomerulonephritis characterized by diffuse deposits of IgM in the glomerular mesangium. However, its renal...
Immunoglobulin M nephropathy (IgMN) is an idiopathic glomerulonephritis characterized by diffuse deposits of IgM in the glomerular mesangium. However, its renal prognosis remains unknown. We compared renal outcomes of IgMN patients with those of patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), or mesangial proliferative glomerulonephritis (MsPGN) from a prospective observational cohort, with 1791 patients undergoing native kidney biopsy in eight hospitals affiliated with The Catholic University of Korea between December 2014 and October 2020. IgMN had more mesangial proliferation and matrix expansion than MsPGN and more tubular atrophy and interstitial fibrosis than MCD. IgMN patients had decreased eGFR than MCD patients in the earlier follow-up. However, there was no significant difference in urine protein or eGFR among all patients at the last follow-up. When IgMN was divided into three subtypes, patients with FSGS-like IgMN tended to have lower eGFR than those with MCD-like or MsPGN-like IgMN but higher proteinuria than MsPGN-like IgMN without showing a significant difference. The presence of hypertension at the time of kidney biopsy predicted ≥20% decline of eGFR over two years in IgMN patients. Our data indicate that IgMN would have a clinical course and renal prognosis similar to MCD, FSGS, and MsPGN.
PubMed: 34575298
DOI: 10.3390/jcm10184191 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Jul 2020In this paper, 2 cases of collagen Type Ⅲ glomerulopathy were analyzed. The clinical manifestations mainly included nephrotic syndrome, proteinuria, hypertension and...
In this paper, 2 cases of collagen Type Ⅲ glomerulopathy were analyzed. The clinical manifestations mainly included nephrotic syndrome, proteinuria, hypertension and renal dysfunction. One patient showed that the complement factor H-related protein 5 (CFHR5) gene was likely a disease-causing mutation. The pathological examination of renal tissues showed hyperplasia of mesangial matrix, sub-endothelial insertion, and double-track formation. Immunohistochemistry of Type III collagen was positive. Electron microscopy revealed that massive collagen fibers (40-70 nm in diameter) deposited in the mesangial matrix and basement membrane. As for the follow-up results, the normal renal function had kept steady and the proteinuria was moderate in 1 case treated with angiotensin Ⅱ receptor blocker. Due to other system disease, another case developed into acute kidney injury and then received hemodialysis. The clinical manifestations of collagen Type Ⅲ glomerulopathy was atypical, the light microscope pathological features were various, and the disease was mainly diagnosed by electron microscopy and immunohistochemistry.
Topics: Collagen Type III; Glomerular Mesangium; Humans; Kidney Diseases; Kidney Glomerulus; Proteinuria
PubMed: 32879092
DOI: 10.11817/j.issn.1672-7347.2020.190130