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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 -
Lupus Science & Medicine Dec 2023This study aimed to investigate the clinical significance of exostosin 1 (EXT1) in confirmed and suspected lupus membranous nephropathy (LMN).
OBJECTIVE
This study aimed to investigate the clinical significance of exostosin 1 (EXT1) in confirmed and suspected lupus membranous nephropathy (LMN).
METHODS
EXT1 was detected in 67 renal tissues of M-type phospholipase A2 receptor (PLA2R)-negative and ANA-positive membranous nephropathy by immunohistochemistry, and cases were divided into confirmed LMN and suspected LMN. The clinicopathological data were compared among the above groups, as well as EXT1-positive group and EXT1-negative group.
RESULTS
Twenty-two cases (73.3%) of confirmed LMN and six cases (16.2%) of suspected LMN exhibited EXT1 expression on the glomerular basement membrane and/or mesangium area, showing a significant difference (p<0.001). Concurrently, lupus nephritis (LN) of pure class V demonstrated a lower frequency of EXT1 positivity compared with mixed class V LN in the confirmed LMN group (31.8% vs 68.2%, p=0.007). EXT1-positive patients in the confirmed and suspected LMN group showed significant differences in some clinicopathological data comparing with EXT1-negative patients (p<0.05). Follow-up data revealed that a greater proportion of patients in the EXT1-positive group achieved complete remission post-treatment (p<0.05). Cox regression analysis showed that EXT1 positivity was significantly correlated with complete remission across the entire study cohort (HR 5.647; 95% CI, 1.323 to 12.048; p=0.019). Kaplan-Meier analysis indicated that the EXT1-positive group had a higher rate of accumulated nephrotic remission compared with the EXT1-negative group in the whole study cohort (p=0.028).
CONCLUSIONS
The EXT1-positive group exhibited a higher active index and a more favourable renal outcome than the EXT1-negative group. It would be better to recognise suspected LMN with EXT1 positivity as a potential autoimmune disease and maintain close follow-up due to its similarities with confirmed LMN.
Topics: Humans; Clinical Relevance; Glomerulonephritis, Membranous; Kidney; Lupus Erythematosus, Systemic; Lupus Nephritis
PubMed: 38154829
DOI: 10.1136/lupus-2023-001051 -
Nature Reviews. Disease Primers Nov 2023IgA nephropathy (IgAN), the most prevalent primary glomerulonephritis worldwide, carries a considerable lifetime risk of kidney failure. Clinical manifestations of IgAN... (Review)
Review
IgA nephropathy (IgAN), the most prevalent primary glomerulonephritis worldwide, carries a considerable lifetime risk of kidney failure. Clinical manifestations of IgAN vary from asymptomatic with microscopic or intermittent macroscopic haematuria and stable kidney function to rapidly progressive glomerulonephritis. IgAN has been proposed to develop through a 'four-hit' process, commencing with overproduction and increased systemic presence of poorly O-glycosylated galactose-deficient IgA1 (Gd-IgA1), followed by recognition of Gd-IgA1 by antiglycan autoantibodies, aggregation of Gd-IgA1 and formation of polymeric IgA1 immune complexes and, lastly, deposition of these immune complexes in the glomerular mesangium, leading to kidney inflammation and scarring. IgAN can only be diagnosed by kidney biopsy. Extensive, optimized supportive care is the mainstay of therapy for patients with IgAN. For those at high risk of disease progression, the 2021 KDIGO Clinical Practice Guideline suggests considering a 6-month course of systemic corticosteroid therapy; however, the efficacy of systemic steroid treatment is under debate and serious adverse effects are common. Advances in understanding the pathophysiology of IgAN have led to clinical trials of novel targeted therapies with acceptable safety profiles, including SGLT2 inhibitors, endothelin receptor blockers, targeted-release budesonide, B cell proliferation and differentiation inhibitors, as well as blockade of complement components.
Topics: Humans; Glomerulonephritis, IGA; Antigen-Antibody Complex; Galactose; Immunoglobulin A
PubMed: 38036542
DOI: 10.1038/s41572-023-00476-9 -
Journal of Nephrology Nov 2023Immunoglobulin A nephropathy (IgAN) is a common primary glomerulonephropathy. There is evidence that mesangial C3 deposition plays a role in the development of the...
BACKGROUND
Immunoglobulin A nephropathy (IgAN) is a common primary glomerulonephropathy. There is evidence that mesangial C3 deposition plays a role in the development of the disease. The aim of this study was to examine the effect of C3 deposition on the prognosis of IgAN patients.
METHOD
The study included 1135 patients with biopsy-confirmed IgAN from the database of the Turkish Nephrology Association Glomerular Diseases Working Group (TSN-GOLD). Patients were excluded from the study if they were aged < 18 or > 75 years or if C3 staining had not been performed in the immunofluorescent analysis. C3 deposition was defined as an immunofluorescence intensity of C3 ≥ 2 + within the mesangium. The primary endpoints were the development of end-stage renal disease, a 30% decrease in glomerular filtration rate compared to the basal value or an elevation in proteinuria to a nephrotic level (3.5 gr/day).
RESULTS
Mesangial C3 deposition was observed in 603 (53.1%) patients. No statistically significant difference was found at baseline between the groups with and without mesangial C3 deposition, as for age, sex, BMI, proteinuria level, or the presence of hypertension. In the follow-up period with a mean duration of 78 months, no significant difference was found between the two groups regarding the primary endpoints (p = 0.43). A significant correlation between C3 deposition and segmental glomerulosclerosis (S1) according to the Oxford MEST-C classification was found (p = 0.001).
CONCLUSION
Although a correlation was observed between mesangial C3 deposition and the S1 MEST-C classification, mesangial C3 deposition was not a prognostic factor in IgAN.
PubMed: 37947938
DOI: 10.1007/s40620-023-01770-1 -
Cureus Oct 2023Fibrillary glomerulonephritis (FGN) is a rare immune-mediated glomerular disease traditionally characterized by the presence of amyloid-like, randomly aligned,...
Fibrillary glomerulonephritis (FGN) is a rare immune-mediated glomerular disease traditionally characterized by the presence of amyloid-like, randomly aligned, fibrillary deposits in the capillary wall, measuring approximately 20 nm in diameter and composed of polyclonal IgG. FGN is usually a primary disease with no pathognomonic clinical or laboratory findings. More than that, on light microscopic evaluation, it can receive various histological patterns, rendering its diagnosis indistinguishable. However, the identification by immunohistochemistry of a novel biomarker, DNA-J heat-shock protein family member B9 (DNAJB9), has created a new era in FGN diagnosis even in the absence of electron microscopy. Typically, most patients manifest various degrees of renal insufficiency, hypertension, microscopic hematuria, proteinuria, and occasionally frank nephrotic syndrome. The prognosis is usually severe and progression to end-stage kidney disease (ESKD) is the rule, given that no specific treatment is available until now, despite the fact that in small studies rituximab-based therapy seems to alleviate the severity and improve the disease progression. Herein, we report the case of a 63-year-old Caucasian man presenting with uncontrolled hypertension, headache, shortness of breath, and lower limb edema. Diagnostic evaluation revealed mild deterioration of kidney function, nephrotic range proteinuria, and faint IgGκ monoclonal bands in serum and urine immunofixation. After negative meticulous investigation for secondary nephrotic syndrome causes, the patient underwent a kidney biopsy. Biopsy sample showed two glomeruli with mesangial expansion and thickened glomerular basement membrane (GBM) on light microscopy, a pattern masquerading as membranous nephropathy stage III-IV, while IgG and C3 were 1-2+ on GBM and mesangium in immunofluorescence. Thickened GBM with fibrils on electron microscopy were found, while DNAJB9 in immunohistochemistry was positive, confirming FGN. Once diagnosis of FGN was made, a combination of steroids with rituximab was initiated while the patient was receiving the standard anti-hypertensive therapy, simultaneously with a sodium-glucose cotransporter-2 (SGLT2) inhibitor. The 12-month follow-up showed approximately 85% decrease in proteinuria alongside stabilization of kidney function and blood pressure normalization. Hence, in this article, we aim to highlight that DNAJB9-associated FGN may mimic membranous glomerulopathy stage III-IV on light microscopy, especially when a small kidney sample with extensive involvement by fibrils of GBM is examined. Moreover, we underscore the fact that ultramicroscopic examination is of crucial importance in the differential diagnosis of glomerular deposition diseases and that DNAJB9 identification on immunohistochemistry consists of a revolutionary and robust biomarker in FGN diagnosis.
PubMed: 37899889
DOI: 10.7759/cureus.47862 -
Cureus Sep 2023IgA vasculitis and IgA nephropathy are characterized by IgA deposition in blood vessels and glomerular mesangium, respectively. The former is far more common in the...
IgA vasculitis and IgA nephropathy are characterized by IgA deposition in blood vessels and glomerular mesangium, respectively. The former is far more common in the pediatric population, while the latter presents more often in adulthood. A consensus regarding whether these two conditions are manifestations of the same disease that occurs on a spectrum has not yet been reached, and, to our knowledge, no clinical trials to address this question have been conducted. Here, we describe a 27-year-old patient who presented to the emergency department multiple times before being diagnosed with IgA vasculitis with no identifiable trigger and soon after developed IgA nephropathy. This case highlights the importance of ruling out these conditions, especially IgA vasculitis, in adults presenting with a petechial rash, but also the need for studies that investigate whether and how these conditions are related so that patients can be appropriately diagnosed and treated as efficiently as possible.
PubMed: 37868543
DOI: 10.7759/cureus.45639 -
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 -
Kidney International Nov 2023
Topics: Animals; Humans; Mesangial Cells; Diabetic Nephropathies; Glomerular Mesangium; Diabetes Mellitus, Experimental
PubMed: 37863632
DOI: 10.1016/j.kint.2023.03.033 -
Anatomia, Histologia, Embryologia Jan 2024The development of the metanephros in one-humped camels involves a complex series of interactions between epithelial and mesenchymal cells. As a result, there is a...
The development of the metanephros in one-humped camels involves a complex series of interactions between epithelial and mesenchymal cells. As a result, there is a synchronized differentiation process of stromal, vascular and epithelial cell types during glomerulogenesis, angiogenesis and tubulogenesis. In the current work, the metanephros of camel foetuses were divided into four stages where kidneys from each stage were processed and immunoassayed, followed by quantitative analysis to determine target protein intensities throughout metanephrogenesis in the camel. This study demonstrated robust expression of α-smooth muscle actin (α-SMA) in the glomerular mesangium, as well as in interlobular and glomerular arterioles during the earlier stages of development. However, in the late stages, α-SMA expression became more localized around the blood capillaries in both the cortex and medulla. Strong expression of CD34 was observed in the immature glomerular and peritubular endothelial cells within the subcapsular zone, as well as in the glomerular, proximal tubular and distal tubular epithelium of stage one foetuses, although its expression gradually diminished with foetal maturation. The expression pattern of osteopontin was prominently observed in the distal convoluted tubules throughout all stages, however, no expression was detected in the proximal tubules, glomeruli and arterioles. E-cadherin was detected in the developing renal tubular epithelial cells but not in the glomeruli. In conclusion, this study reveals the spatiotemporal distribution of key proteins, including α-SMA, CD34, Osteopontin and E-cadherin, which play a crucial role in metanephrogenesis in camel foetuses.
Topics: Animals; Camelus; Osteopontin; Endothelial Cells; Fetus; Actins; Cadherins; Muscle, Smooth; Embryonic Structures; Kidney
PubMed: 37814965
DOI: 10.1111/ahe.12985 -
JCI Insight Oct 2023Transglutaminase 2 (TGase2) has been shown to contribute to the mesangial IgA1 deposition in a humanized mouse model of IgA nephropathy (IgAN), but the mechanism is not...
Transglutaminase 2 (TGase2) has been shown to contribute to the mesangial IgA1 deposition in a humanized mouse model of IgA nephropathy (IgAN), but the mechanism is not fully understood. In this study, we found that inhibition of TGase2 activity could dramatically decrease the amount of polymeric IgA1 (pIgA1) isolated from patients with IgAN that interacts with human mesangial cells (HMC). TGase2 was expressed both in the cytosol and on the membrane of HMC. Upon treatment with pIgA1, there were more TGase2 recruited to the membrane. Using a cell model of mesangial deposition of pIgA1, we identified 253 potential TGase2-associated proteins in the cytosolic fraction and observed a higher concentration of cellular vesicles and increased expression of Ras homolog family member A (RhoA) in HMC after pIgA1 stimulation. Both the amount of pIgA1 deposited on HMC and membrane TGase2 level were decreased by inhibition of the vesicle trafficking pathway. Mechanistically, TGase2 was found to be coprecipitated with RhoA in the cellular vesicles. Membrane TGase2 expression was greatly increased by overexpression of RhoA, while it was reduced by knockdown of RhoA. Our in vitro approach demonstrated that TGase2 was transported from the cytosol to the membrane through a RhoA-mediated vesicle-trafficking pathway that can facilitate pIgA1 interaction with mesangium in IgAN.
Topics: Animals; Mice; Humans; Glomerulonephritis, IGA; Immunoglobulin A; Protein Glutamine gamma Glutamyltransferase 2; rhoA GTP-Binding Protein; Glomerular Mesangium; Polymers
PubMed: 37811653
DOI: 10.1172/jci.insight.160374