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Journal of Cellular Biochemistry Nov 2023In this study, we investigated the effects of sweroside on podocyte injury in diabetic nephropathy (DN) mice and elucidated its molecular mechanisms. We conducted in...
In this study, we investigated the effects of sweroside on podocyte injury in diabetic nephropathy (DN) mice and elucidated its molecular mechanisms. We conducted in vivo experiments using a C57BL/6 mice model of DN to explore the effects of sweroside on proteinuria and podocyte injury in DN mice. In in vitro experiments, conditionally immortalized mouse podocytes were treated with high glucose and sweroside, and the protective effects of sweroside on podocyte injury were analyzed. In vitro, Akt/BAD pathways were detected using gene siRNA silencing assays and found to be involved in the protective roles of sweroside in high glucose-mediated podocyte injury. In vivo, sweroside significantly decreased albuminuria in DN mice (p < 0.01). periodic acid-Schiff staining showed that sweroside alleviated the glomerular volume and mesangium expansion in DN mice. Consistently, western blot and reverse transcription-polymerase chain reaction analyses showed that the profibrotic molecule expression in the glomeruli declined in sweroside-treated DN mice. Immunofluorescent results showed that sweroside preserved nephrin and podocin expression, and transmission electron microscopy showed that sweroside attenuated podocyte injury. In DN mice, sweroside decreased podocyte apoptosis, and increased nephrin, podocin expression and decreased desmin and HIF1α expression. These results confirmed that sweroside ameliorated albuminuria, glomerulomegaly, and glomerulosclerosis in these mice. Experiments in vitro revealed that sweroside improved HG-induced podocyte injury and apoptosis. Sweroside stimulated activation of the Akt/BAD pathway and upregulated Bcl-2-associated death promoter (BAD) and p-Akt. Overall, sweroside protected podocytes from injury and prevented the progression of DN, providing a novel strategy for the treatment of DN.
Topics: Mice; Animals; Podocytes; Proto-Oncogene Proteins c-akt; Albuminuria; Diabetes Mellitus, Experimental; Mice, Inbred C57BL; Diabetic Nephropathies; Glucose; Apoptosis
PubMed: 37796169
DOI: 10.1002/jcb.30484 -
Wiener Klinische Wochenschrift Aug 2023Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis. It leads to end-stage kidney disease in about a third of the patients within 10 to...
Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis. It leads to end-stage kidney disease in about a third of the patients within 10 to 20 years. The pathogenesis of IgAN is incompletely understood. It is believed that a dysregulation of the mucosal immune system leads to undergalactosylation of IgA, followed by formation of IgG autoantibodies against undergalactosylated IgA, circulation of these IgG-IgA immune complexes, deposition of the immune complexes in the mesangium, ultimately resulting in glomerular inflammation. IgAN can occasionally be triggered by other diseases, these secondary causes of IgAN should be identified or ruled out (chronic inflammatory bowel disease, infections, tumors, rheumatic diseases). Characteristic findings of IgAN of variable extent are a nephritic urinary sediment (erythrocytes, acanthocytes, erythrocyte casts), proteinuria, impaired renal function, arterial hypertension, or intermittent painless macrohematuria, especially during infections of the upper respiratory tract. However, the diagnosis of IgAN can only be made by a kidney biopsy. A histological classification (MEST‑C score) should always be reported to be able to estimate the prognosis. The most important therapeutic measure is an optimization of the supportive therapy, which includes, among other things, a consistent control of the blood pressure, an inhibition of the RAS, and the administration of an SGLT2 inhibitor. A systemic immunosuppressive therapy with corticosteroids is discussed controversially, should be used restrictively and only administered after an individual benefit-risk assessment under certain conditions that speak for a progressive IgAN. New promising therapeutics are enteral Budesonide or the dual angiotensin-II-receptor- and endothelin-receptor-antagonist Sparsentan. Rapidly progressive IgAN should be treated with corticosteroids and cyclophosphamide like ANCA-associated vasculitis.
Topics: Humans; Glomerulonephritis, IGA; Antigen-Antibody Complex; Autoantibodies; Immunoglobulin A; Immunoglobulin G
PubMed: 37728647
DOI: 10.1007/s00508-023-02257-6 -
Internal Medicine (Tokyo, Japan) May 2024An elderly woman showed positive conversion of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCAs) following the diagnosis of interstitial lung disease...
An elderly woman showed positive conversion of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCAs) following the diagnosis of interstitial lung disease (ILD) and glomerular hematuria and subsequently experienced slowly progressive glomerulonephritis. A kidney biopsy revealed chronic damage and necrotizing crescentic glomerulonephritis with mesangial MPO deposits. After corticosteroid treatment, the patient's urinalysis results and MPO-ANCA titers almost normalized and her renal function stabilized. This case is similar to recently reported cases of slowly progressive ANCA-associated glomerulonephritis. ILD likely triggered the production of MPO-ANCAs, and the accumulation of MPO deposits in the glomeruli may have contributed to the progression of her renal disease.
Topics: Humans; Female; Lung Diseases, Interstitial; Antibodies, Antineutrophil Cytoplasmic; Glomerulonephritis; Peroxidase; Disease Progression; Aged; Glomerular Mesangium
PubMed: 37722892
DOI: 10.2169/internalmedicine.2512-23 -
Pediatric Nephrology (Berlin, Germany) Mar 2024Tubulointerstitial lesions and glomerular inflammation severity have been shown to correlate with proteinuria in children with IgA nephropathy (cIgAN). However, there is...
BACKGROUND
Tubulointerstitial lesions and glomerular inflammation severity have been shown to correlate with proteinuria in children with IgA nephropathy (cIgAN). However, there is a lack of data regarding severity of histopathologic findings in cIgAN in patients with minimal to absent proteinuria since kidney biopsy indications are not well defined in these cases.
METHODS
Twenty-eight cIgAN patients with kidney biopsy from 4 different centers in Paris (France) and Montreal (Canada) with a urine protein/creatinine ratio (UPCr) ≤ 0.03 g/mmol and a normal estimated glomerular filtration rate (eGFR > 90 ml/min/1.73 m) on the day of kidney biopsy prior to treatment were included.
RESULTS
Median age was 11.82 (9.32-13.45) years, and median follow-up was 4 years (2.87-6.53). At time of biopsy, median eGFR was 116 (102.3-139.7) ml/min/1.73 m, and median UPCr was 0.02 (0.011-0.03) g/mmol. Microscopic or macroscopic hematuria was present in 35.7% and 64.3% of cases, respectively. Kidney biopsy microscopy analysis showed mesangial (M1), endocapillary (E1), or extracapillary (C1) hypercellularity in 53.5%, 32.1%, and 7.1% of patients, respectively. Chronic histological lesions were also present: glomerulosclerosis (S1) in 42.8% and tubular atrophy/interstitial fibrosis in 7.1%. Podocytopathic features were detected in 21.4%. An ACE inhibitor or immunosuppressive therapy (IS) was prescribed in 42.8% and 21.4% of these patients respectively. One-third (35.7%) received no treatment. At last follow-up, median eGFR was 111.9 (90.47-136.1) ml/min/1.73 m, and median UPCr was 0.028 (0.01-0.03) g/mmol.
CONCLUSION
cIgAN with minimal proteinuria at time of biopsy might be linked with acute and chronic glomerular lesions.
Topics: Child; Humans; Biopsy; Glomerular Filtration Rate; Glomerular Mesangium; Glomerulonephritis, IGA; Kidney; Kidney Glomerulus; Proteinuria; Retrospective Studies; Adolescent
PubMed: 37698655
DOI: 10.1007/s00467-023-06121-7 -
Acta Physiologica (Oxford, England) Oct 2023When discussing glomerular function, one cell type is often left out, the mesangial cell (MC), probably since it is not a part of the filtration barrier per se. The MCs... (Review)
Review
When discussing glomerular function, one cell type is often left out, the mesangial cell (MC), probably since it is not a part of the filtration barrier per se. The MCs are instead found between the glomerular capillaries, embedded in their mesangial matrix. They are in direct contact with the endothelial cells and in close contact with the podocytes and together they form the glomerulus. The MCs can produce and react to a multitude of growth factors, cytokines, and other signaling molecules and are in the perfect position to be a central hub for crosstalk communication between the cells in the glomerulus. In certain glomerular diseases, for example, in diabetic kidney disease or IgA nephropathy, the MCs become activated resulting in mesangial expansion. The expansion is normally due to matrix expansion in combination with either proliferation or hypertrophy. With time, this expansion can lead to fibrosis and decreased glomerular function. In addition, signs of complement activation are often seen in biopsies from patients with glomerular disease affecting the mesangium. This review aims to give a better understanding of the MCs in health and disease and their role in glomerular crosstalk and inflammation.
Topics: Humans; Endothelial Cells; Glomerular Mesangium; Kidney Glomerulus; Diabetic Nephropathies; Podocytes
PubMed: 37658606
DOI: 10.1111/apha.14045 -
Clinical Journal of the American... Dec 2023IgA nephropathy is the most common primary GN worldwide, with dominant deposition of IgA and co-deposits of complement component 3 (C3). Phenotypes and progression of...
BACKGROUND
IgA nephropathy is the most common primary GN worldwide, with dominant deposition of IgA and co-deposits of complement component 3 (C3). Phenotypes and progression of IgA nephropathy varies among different ethnic populations, while patients with IgA nephropathy from Asia showed more severe clinical phenotypes, active kidney lesions, and rapid progression. Our previous genome-wide association study identified complement factor H ( CFH ) variant rs6677604, tightly linked with the deletion of CFH -related protein 3 and CFH -related protein 1 genes ( ΔCFHR3-1 ), as IgA nephropathy susceptible variant, and additionally revealed its effect on complement regulation in IgA nephropathy.
METHODS
To further explore the effect of rs6677604 on IgA nephropathy progression, here we enrolled a Chinese IgA nephropathy cohort of 1781 patients with regular follow-up for analysis. The rs6677604 genotype was measured, and the genotype-phenotype correlation was analyzed using the t test, the chi-squared test, or the nonparametric test, and the association between rs6677604 genotype or mesangial C3 deposition and IgA nephropathy prognosis was analyzed using Kaplan-Meier analysis and Cox regression.
RESULTS
We found that patients with rs6677604-GG genotype had a stronger intensity of mesangial C3 deposition than those with the rs6677604-AA/AG genotype. Patients with IgA nephropathy who had stronger intensity of C3 deposition manifested with more severe clinical and pathological manifestations, including lower eGFR and higher Oxford-M/S/T/C (mesangial hypercellularity, endocapillary cellularity, segmental sclerosis, interstitial fibrosis/tubular atrophy, and crescent) scores. In the survival analysis, stronger intensity of mesangial C3 deposition, but not rs6677604-GG genotypes, was associated with poor long-term kidney outcome in IgA nephropathy.
CONCLUSIONS
We found that in Chinese patients with IgA nephropathy, variant rs6677604 was associated with mesangial C3 deposition, and mesangial C3 deposition, but not rs6677604, was associated with IgA nephropathy severity and progression.
Topics: Humans; Disease Progression; Genome-Wide Association Study; Glomerular Mesangium; Glomerulonephritis, IGA; Kidney; Prognosis; Complement Factor H
PubMed: 37651123
DOI: 10.2215/CJN.0000000000000290 -
Clinical Nephrology. Case Studies 2023Kidneys are commonly involved in systemic amyloidosis. Systemic AA amyloidosis is known to be associated with states of chronic inflammation such as autoimmune...
Kidneys are commonly involved in systemic amyloidosis. Systemic AA amyloidosis is known to be associated with states of chronic inflammation such as autoimmune conditions, chronic infections, and malignancies. Obesity is increasingly recognized to be a risk factor for low-grade, chronic inflammation. We report a 48-year-old female with morbid obesity who presented with unexplained persistent mild kidney dysfunction and low-grade proteinuria. Attempt at evaluating the cause of kidney dysfunction included performing kidney biopsy despite technical challenges. Kidney biopsy showed AA amyloidosis with predominant vascular deposition, explaining the absence of nephrotic-range proteinuria. Evaluation for secondary causes of systemic AA amyloidosis was negative. While our patient was treated with sleeve gastrectomy for morbid obesity with reasonable response, it is likely that ongoing chronic inflammation, reflected by her laboratory markers, resulted in AA amyloidosis. Treatment with anakinra, an interleukin-1 antagonist, led to improvement in the laboratory markers in the next 6 months, and her kidney function remained stable. This report highlights an important cause of kidney dysfunction in morbid obesity, an atypical presentation of AA amyloidosis, and emphasizes the value of kidney biopsy in such patients.
PubMed: 37533546
DOI: 10.5414/CNCS111133 -
American Journal of Physiology. Renal... Aug 2023Renin cells are precursors for other cell types in the kidney and show high plasticity in postnatal life in response to challenges to homeostasis. Our previous...
Renin cells are precursors for other cell types in the kidney and show high plasticity in postnatal life in response to challenges to homeostasis. Our previous single-cell RNA-sequencing studies revealed that the dual zinc-finger transcription factor , which is important for cell lineage commitment and differentiation, is expressed in mouse renin cells under normal conditions and homeostatic threats. We identified a potential Gata3-binding site upstream of the renin gene leading us to hypothesize that is essential for renin cell identity. We studied adult mice with conditional deletion of in renin cells: ; () and control Gata3; counterparts. Gata3 immunostaining revealed that mice had significantly reduced Gata3 expression in juxtaglomerular, mesangial, and smooth muscle cells, indicating a high degree of deletion of in renin lineage cells. mice exhibited a significant increase in blood urea nitrogen, suggesting hypovolemia and/or compromised renal function. By immunostaining, renin-expressing cells appeared very thin compared with their normal plump shape in control mice. Renin cells were ectopically localized to Bowman's capsule in some glomeruli, and there was aberrant expression of actin-α signals in the mesangium, interstitium, and Bowman's capsule in mice. Distal tubules showed dilated morphology with visible intraluminal casts. Under physiological threat, mice exhibited a lower increase in mRNA levels than controls. Hematoxylin-eosin, periodic acid-Schiff, and Masson's trichrome staining showed increased glomerular fusion, absent cubical epithelial cells in Bowman's capsule, intraglomerular aneurysms, and tubular dilation. In conclusion, our results indicate that is crucial to the identity of cells of the renin lineage. , a dual zinc-finger transcription factor, is responsible for the identity and localization of renin cells in the kidney. Mice with a conditional deletion of in renin lineage cells have abnormal kidneys with juxtaglomerular cells that lose their characteristic location and are misplaced outside and around arterioles and glomeruli. The fundamental role of in renin cell development offers a new model to understand how transcription factors control cell location, function, and pathology.
Topics: Mice; Animals; Renin; GATA3 Transcription Factor; Kidney; Kidney Glomerulus; Kidney Diseases; Zinc
PubMed: 37345845
DOI: 10.1152/ajprenal.00098.2023 -
Nephrology, Dialysis, Transplantation :... Sep 2023This review summarizes the pathomorphological sequences of nephron loss in human diabetic nephropathy (DN). The relevant changes may be derived from two major... (Review)
Review
This review summarizes the pathomorphological sequences of nephron loss in human diabetic nephropathy (DN). The relevant changes may be derived from two major derangements. First, a failure in the turnover of the glomerular basement membrane (GBM) based on an increased production of GBM components by podocytes and endothelial cells leading to the thickening of the GBM and accumulation of worn-out GBM in the mesangium. This failure may account for the direct pathway to glomerular compaction and sclerosis based on the continuous deposition of undegraded GBM material in the mesangium. Second, an increased leakiness together with an increased propensity of glomerular capillaries to proliferate leads to widespread plasma exudations. Detrimental are those that produce giant insudative spaces within Bowman's capsule, spreading around the entire glomerular circumference and along the glomerulo-tubular junction onto the tubule resulting in tubular obstruction and retroactively to glomerulosclerosis. Tubular atrophy and interstitial fibrosis develop secondarily by transfer of the glomerular damage onto the tubule. Interstitial fibrosis is locally initiated and apparently stimulated by degenerating tubular epithelia. This leads to a focal distribution of interstitial fibrosis and tubular atrophy accompanied by a varying interstitial mononuclear cell infiltration. Spreading of fibrotic areas between intact nephrons, much less to the glomerulus, has not been encountered.
Topics: Humans; Diabetic Nephropathies; Endothelial Cells; Glomerular Basement Membrane; Fibrosis; Atrophy; Diabetes Mellitus
PubMed: 36918205
DOI: 10.1093/ndt/gfad052