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Bioengineered Mar 2022Obstructive sleep apnea syndrome (OSAS) is a respiratory disorder and chronic intermittent hypoxia (CIH) is an important pathological characteristic of OSAS. Injuries on...
Obstructive sleep apnea syndrome (OSAS) is a respiratory disorder and chronic intermittent hypoxia (CIH) is an important pathological characteristic of OSAS. Injuries on renal tubular epithelial cells were observed under the condition of CIH. Pyroptosis is a programmed mode of cell death following cell apoptosis and cell necrosis, which is mediated by NLRP3 signaling. The present study aims to investigate the effects of CIH on the pyroptosis of renal tubular epithelial cells and the underlying mechanism. Firstly, CIH was induced in two renal tubular epithelial cell lines, HK-2 cells and TCMK-1 cells. As the aggravation of hypoxia, an increasing trend of elevated apoptotic rate was observed in HK-2 cells and TCMK-1 cells, accompanied by the excessive release of ROS and LDH, and upregulation of NLRP3. Subsequently, the CIH model was established on rats. The pathological analysis results indicated that in CIH rats, the glomerular bottom membrane and mesangium were slightly thickened and edema was observed in the renal tubule epithelium. More serious injury was observed in the moderate intermittent hypoxia group. The expression level of IL-1β and IL-18 was promoted as the aggravation of hypoxia, accompanied by the elevated production of LDH and ROS. The expression level of cleaved Caspase-1, Caspase-1, GSDMD, TLR4, MyD88, NF-κB, p-NF-κB, and NLRP3 was found significantly upregulated as the aggravation of hypoxia. Lastly, the pathological changes in rats induced by CIH were dramatically abolished by MCC950, a specific inhibitor of NLRP3. Collectively, CIH triggered the pyroptosis of renal tubular epithelial cells by activating the NLRP3 inflammasome.
Topics: Animals; Caspases; Epithelial Cells; Hypoxia; Inflammasomes; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Rats; Reactive Oxygen Species; Sleep Apnea, Obstructive
PubMed: 35263214
DOI: 10.1080/21655979.2022.2047394 -
CEN Case Reports Nov 2022Fibrillary glomerulonephritis (FGN) is a rare glomerular disease. FGN is characterized by the deposition of randomly arranged, nonbranching microfibrils in the mesangium...
Fibrillary glomerulonephritis (FGN) is a rare glomerular disease. FGN is characterized by the deposition of randomly arranged, nonbranching microfibrils in the mesangium and glomerular basement membrane. The discovery of DNAJ homolog subfamily B member 9 (DNAJB9) in 2017 was a breakthrough, and DNAJB9 has been proven to be extremely useful for the definitive diagnosis of FGN. While FGN often occurs in middle-aged individuals, this case was diagnosed at a relatively young age of 17. We performed renal biopsy, and light microscopic study revealed mesangial proliferation with expansion and subepithelial deposits. Electron microscopic study showed glomerular deposition of randomly oriented nonbranching fibrils with a mean of 20 nm. However, direct first scarlet stain for amyloidosis was weakly positive. Therefore, we confirmed the diagnosis of FGN and eliminated the presence of amyloidosis with mass spectrometry. This is the first case in Japan in which the complication of amyloidosis was ruled out with mass spectrometry and FGN was diagnosed using immunostaining and mass spectrometry of DNAJB9. We began treatment with cyclosporine A. One and a half years after the start of the treatment, kidney function continues to be normal.
Topics: Middle Aged; Humans; Immunohistochemistry; Glomerulonephritis; Kidney Glomerulus; Mass Spectrometry; Amyloidosis; Membrane Proteins; Molecular Chaperones; HSP40 Heat-Shock Proteins
PubMed: 35199316
DOI: 10.1007/s13730-022-00693-3 -
Frontiers in Medicine 2021The glomerulus is the functional unit for filtration of blood and formation of primary urine. This intricate structure is composed of the endothelium with its glycocalyx... (Review)
Review
The glomerulus is the functional unit for filtration of blood and formation of primary urine. This intricate structure is composed of the endothelium with its glycocalyx facing the blood, the glomerular basement membrane and the podocytes facing the urinary space of Bowman's capsule. The mesangial cells are the central hub connecting and supporting all these structures. The components as a unit ensure a high permselectivity hindering large plasma proteins from passing into the urine while readily filtering water and small solutes. There has been a long-standing interest and discussion regarding the functional contribution of the different cellular components but the mesangial cells have been somewhat overlooked in this context. The mesangium is situated in close proximity to all other cellular components of the glomerulus and should be considered important in pathophysiological events leading to glomerular disease. This review will highlight the role of the mesangium in both glomerular function and intra-glomerular crosstalk. It also aims to explain the role of the mesangium as a central component involved in disease onset and progression as well as signaling to maintain the functions of other glomerular cells to uphold permselectivity and glomerular health.
PubMed: 35155460
DOI: 10.3389/fmed.2021.740527 -
Journal of the American Society of... May 2022IgA nephropathy (IgAN) primary glomerulonephritis is characterized by the deposition of circulating immune complexes composed of polymeric IgA1 molecules with altered...
BACKGROUND
IgA nephropathy (IgAN) primary glomerulonephritis is characterized by the deposition of circulating immune complexes composed of polymeric IgA1 molecules with altered O-glycans (Gd-IgA1) and anti-glycan antibodies in the kidney mesangium. The mesangial IgA deposits and serum IgA1 contain predominantly light (L) chains, but the nature and origin of such IgA remains enigmatic.
METHODS
We analyzed L chain expression in peripheral blood B cells of 30 IgAN patients, 30 healthy controls (HCs), and 18 membranous nephropathy patients selected as disease controls (non-IgAN).
RESULTS
In comparison to HCs and non-IgAN patients, peripheral blood surface/membrane bound (mb)-Gd-IgA1 cells from IgAN patients express predominantly L chains. In contrast, total mb-IgA, mb-IgG, and mb-IgM cells were preferentially positive for kappa () L chains, in all analyzed groups. Although minor in comparison to L chains, L chain subsets of mb-IgG, mb-IgM, and mb-IgA cells were significantly enriched in IgAN patients in comparison to non-IgAN patients and/or HCs. In contrast to HCs, the peripheral blood of IgAN patients was enriched with mb-Gd-IgA1, CCR10, and CCR9 cells, which preferentially home to the upper respiratory and digestive tracts. Furthermore, we observed that mb-Gd-IgA1 cell populations comprise more CD138 cells and plasmablasts (CD38) in comparison to total mb-IgA cells.
CONCLUSIONS
Peripheral blood of IgAN patients is enriched with migratory mb-Gd-IgA1 B cells, with the potential to home to mucosal sites where Gd-IgA1 could be produced during local respiratory or digestive tract infections.
Topics: Female; Galactose; Glomerulonephritis, IGA; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Male
PubMed: 35115327
DOI: 10.1681/ASN.2021081086 -
CEN Case Reports Aug 2022As mRNA COVID-19 vaccines have become widely available, cases of new-onset glomerular disease after receiving COVID-19 vaccination have been reported. Here, we present a...
As mRNA COVID-19 vaccines have become widely available, cases of new-onset glomerular disease after receiving COVID-19 vaccination have been reported. Here, we present a case of kidney biopsy-proven new-onset IgA vasculitis after receiving the mRNA-1273 (Moderna) COVID-19 vaccination. A 47-year-old man with a 10-year medical history of hypertension and hyperuricemia visited our hospital 19 days after receiving an initial mRNA-1273 COVID-19 vaccine injection for purpuric eruption on the legs and dorsal regions of the feet. Although the eruptions spontaneously improved within 5 days, they developed again at 15 days after the second injection. A histopathological examination of skin biopsy specimens was reminiscent of leukocytoclastic vasculitis, though direct immunofluorescence did not indicate IgA deposition within small vessel walls. Urinalysis indicated severe proteinuria (3 +) and occult blood (3 +). Thus, a kidney biopsy was performed and light microscopy revealed mild mesangial expansion, hypercellularity, and endocapillary hypercellularity, with cellular and fibrocellular crescents observed in three and one, respectively, of a total of 15 glomeruli. Immunofluorescence also showed diffuse granular mesangial staining (3 +) for IgA. Histopathological features were consistent with IgA vasculitis. Intravenous methylprednisolone at 1000 mg for 3 days was initiated, followed by oral prednisolone (0.6 mg/kg/day). Over the following 2-week period, serum creatinine level improved from 1.24 to 1.06 mg/dL and proteinuria decreased from 2.98 to 0.36 g/g Cr, though occult blood persisted. Findings in the present case indicate that new-onset IgA vasculitis after receiving mRNA-1273 COVID-19 vaccine can be treated with corticosteroid therapy.
Topics: 2019-nCoV Vaccine mRNA-1273; Biopsy; COVID-19; Glomerular Mesangium; Glomerulonephritis, IGA; Humans; IgA Vasculitis; Immunoglobulin A; Male; Methylprednisolone; Middle Aged; Proteinuria
PubMed: 35075622
DOI: 10.1007/s13730-021-00677-9 -
Cell Reports. Medicine Dec 2021We identify an intronic deletion in that predisposes to renal injury in high risk populations through a kidney-intrinsic process. Half of all SLE patients develop...
We identify an intronic deletion in that predisposes to renal injury in high risk populations through a kidney-intrinsic process. Half of all SLE patients develop nephritis, yet the predisposing mechanisms to kidney damage remain poorly understood. There is limited evidence of genetic contribution to specific organ involvement in SLE. We identify a large deletion in intron 7 of (), which associates with nephritis in SLE patients. The same deletion occurs at increased frequency in an indigenous population (Tiwi Islanders) with 10-fold higher rates of kidney disease compared with non-indigenous populations. hemizygosity in mice results in spontaneous IgA and IgG deposition within the glomerular mesangium in the absence of autoimmune nephritis. Serum transfer into B cell-deficient mice results in mesangial IgG deposition indicating that Ig deposits occur in a kidney-intrinsic fashion in the absence of . These results suggest that acts in the kidney to prevent Ig deposits and its deficiency may trigger nephritis in individuals with SLE.
Topics: Adult; Aged; Animals; Antibodies; Biopsy; Carrier Proteins; Cohort Studies; DNA Copy Number Variations; Gene Deletion; Homozygote; Humans; Introns; Kidney; Kidney Diseases; Lupus Nephritis; Membrane Proteins; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Risk Factors; Mice
PubMed: 35028616
DOI: 10.1016/j.xcrm.2021.100475 -
ACS Applied Bio Materials Feb 2021Modulation of mesangial cell (MC) response by disease models offers therapeutic strategies for the treatment of several glomerular diseases. However, traditional cell...
Modulation of mesangial cell (MC) response by disease models offers therapeutic strategies for the treatment of several glomerular diseases. However, traditional cell culture models lack the nanostructured extracellular matrix (ECM), which has unique physical and chemical properties, so they poorly reflect the complexities of the native microenvironment. Therefore, a cell disease model with ECM nanostructures is required to better mimic the diseased nanoenvironment. To establish a renal disease model, we used a titanium dioxide-based disease-mimic nanopattern as the physical cues and transforming growth factor-beta 1 (TGF-β1) as a chemical cue. The effects of this renal disease model on proliferation and mesangial matrix (MM) component changes in the SV40MES13 (MES13) mouse mesangial cell line were evaluated. Our results showed that both the presence of the disease-mimic nanopattern and TGF-β1 intensified proliferation and resulted in increased type I collagen and fibronectin and decreased type IV collagen expressions in MES13 cells. These effects could be involved in increased TGF-β type I receptor expression in MES13 cells. The intracellular reactive oxygen species (ROS) level as a biomarker of this renal disease model indicated that the cells were in a diseased state. A small molecule A83-01 and known drug dexamethasone markedly attenuated the intracellular ROS production in MES13 that was induced by the disease-mimic nanopattern and TGF-β1. These results highlight the significant effects of physical and chemical cues in facilitating disease-like behavior in MES13 cells, providing an important theoretical basis for developing a drug screening platform for glomerular diseases.
Topics: Animals; Cellular Microenvironment; Disease Models, Animal; Glomerular Mesangium; Humans; Kidney Diseases; Mesangial Cells; Mice
PubMed: 35014506
DOI: 10.1021/acsabm.0c01406 -
Kidney Research and Clinical Practice Dec 2021In Fabry disease, the presence of globotriaosylceramide (GL3) deposits in various kidney cells leads to progressive renal dysfunction. However, kidney biopsy studies in...
BACKGROUND
In Fabry disease, the presence of globotriaosylceramide (GL3) deposits in various kidney cells leads to progressive renal dysfunction. However, kidney biopsy studies in patients with Fabry disease are limited. In the present study, the pathologic findings of patients with Fabry nephropathy receiving enzyme replacement therapy (ERT) and untreated patients without albuminuria were investigated.
METHODS
The present study included 15 patients with Fabry disease who underwent renal biopsy while receiving ERT (group 1: n = 9, age 19-58 years, two males and seven females) or before ERT initiation (group 2: n = 6, age 11-66 years, one male and five females). All patients in group 2 were normoalbuminuric.
RESULTS
Group 1 showed improved clinical symptoms, such as acroparesthesia. The ERT duration was 1.2 to 8 years and seven of the nine patients showed GL3 deposits in various kidney cells and segmental foot process effacement (FPE) of podocytes. GL3 deposits and FPE were not observed in the two remaining patients in group 1. Group 2 showed segmental FPE and podocyte GL3 deposits. Most patients in group 2 also showed GL3 deposits in the mesangium, endothelium, or tubular epithelium.
CONCLUSION
The study results showed that segmental FPE and GL3 deposits can persist in Fabry nephropathy despite ERT. In addition, segmental FPE and GL3 deposits were observed in various kidney cells in normoalbuminuric patients with Fabry disease. These findings indicated that kidney biopsies at baseline and follow-up evaluation of Fabry nephropathy are essential for timely ERT initiation and ERT response assessment.
PubMed: 34922431
DOI: 10.23876/j.krcp.21.056 -
Cureus Oct 2021Acute glomerulonephritis is a constellation of renal disorders which are precipitated by an immunologic mechanism triggering inflammation and proliferation of glomerular...
Acute glomerulonephritis is a constellation of renal disorders which are precipitated by an immunologic mechanism triggering inflammation and proliferation of glomerular tissue resulting in damage to the basement membrane, mesangium, or capillary endothelium. Two of the most well-known manifestations of glomerulonephritis are granulomatosis with polyangiitis (GPA) and IgA nephropathy (IgAN). To our knowledge, these diseases are often found separately and are rarely diagnosed in the same patient. Here, we discuss a case of a 35-year-old male who presented and was diagnosed with simultaneous GPA and IgAN. His renal biopsy was significant for extensive, crescentic, and necrotizing glomerulonephritis and IgA staining on immunofluorescence indicating severe renal damage. Despite full immunosuppressive therapy, our patient failed to recover his renal function. In our case, we hope to raise awareness of these disorders and early recognition of the clinical features. We believe that this case would prompt providers to pursue diagnostic workups to detect these diseases early on, especially when symptoms progressively worsen and become systemic. As demonstrated in our patient, delay in diagnosis can lead to irreversible damage to a patient's renal function, especially when two types of glomerulonephritis are present.
PubMed: 34786253
DOI: 10.7759/cureus.18672 -
CEN Case Reports May 2022A 37-year-old African-British man was referred to our hospital for detailed examination because of persistent fever, swelling and pain in both ankle joints, and blurred...
A 37-year-old African-British man was referred to our hospital for detailed examination because of persistent fever, swelling and pain in both ankle joints, and blurred vision for two months. Inguinal lymph node biopsy showed a large number of epithelioid granulomas without necrosis. Granulomatous anterior uveitis, nephropathy, high serum angiotensin-converting enzyme activity, and high serum-soluble interleukin-2 receptor were observed, and the diagnosis of systemic sarcoidosis was made. His serum creatinine was 1.4 mg/dL and hematuria, leukocyturia, and urine protein were also seen. The renal biopsy finding was mesangial proliferative glomerulonephritis, with no findings of granuloma formation or tubular interstitial nephritis. Immunofluorescence staining showed deposition of IgG, C3, and C1q in the mesangial region. IgG3 was dominant in subclass staining. There was no monoclonality on kappa and lambda staining. Electron microscopy showed predominant deposition in the mesangial region with some subepithelial and endothelial deposition. His hematuria and leukocyturia disappeared with steroid therapy, suggesting sarcoidosis-related nephropathy. A case of systemic sarcoidosis with mesangial proliferative glomerulonephritis showing predominant deposition of IgG in the mesangial region is presented. No cases of such histological findings have been reported so far, and it is necessary to analyze further cases to clarify the pathogenic significance of the renal biopsy findings observed in this case.
Topics: Adult; Female; Glomerular Mesangium; Glomerulonephritis; Hematuria; Humans; Immunoglobulin G; Male; Sarcoidosis
PubMed: 34751926
DOI: 10.1007/s13730-021-00660-4