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World Journal of Diabetes Oct 2023Diabetes mellitus is one of the most common causes of chronic kidney disease. Kidney involvement in patients with diabetes has a wide spectrum of clinical presentations... (Review)
Review
Diabetes mellitus is one of the most common causes of chronic kidney disease. Kidney involvement in patients with diabetes has a wide spectrum of clinical presentations ranging from asymptomatic to overt proteinuria and kidney failure. The development of kidney disease in diabetes is associated with structural changes in multiple kidney compartments, such as the vascular system and glomeruli. Glomerular alterations include thickening of the glomerular basement membrane, loss of podocytes, and segmental mesangiolysis, which may lead to microaneurysms and the development of pathognomonic Kimmelstiel-Wilson nodules. Beyond lesions directly related to diabetes, awareness of the possible coexistence of nondiabetic kidney disease in patients with diabetes is increasing. These nondiabetic lesions include focal segmental glomerulosclerosis, IgA nephropathy, and other primary or secondary renal disorders. Differential diagnosis of these conditions is crucial in guiding clinical management and therapeutic approaches. However, the relationship between diabetes and the kidney is bidirectional; thus, new-onset diabetes may also occur as a complication of the treatment in patients with renal diseases. Here, we review the complex and multifaceted correlation between diabetes and kidney diseases and discuss clinical presentation and course, differential diagnosis, and therapeutic oppor-tunities offered by novel drugs.
PubMed: 37970131
DOI: 10.4239/wjd.v14.i10.1450 -
Molecular Medicine Reports Nov 2023Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder caused by the loss of tolerance to endogenous nuclear antigens such as double‑stranded DNA,... (Review)
Review
Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder caused by the loss of tolerance to endogenous nuclear antigens such as double‑stranded DNA, leading to the proliferation of T cells and subsequent activation of B cells, which results in serious organ damage and life‑threatening complications such as lupus nephritis. Lupus nephritis (LN) develops as a frequent complication of SLE, accounting for >60% of SLE cases, and is characterized by proteinuria and heterogeneous histopathological findings. Glomerular injury serves a role in proteinuria as podocyte damage is the leading contributor. Numerous studies have reported that podocytes are involved in the immune response that promotes LN progression. In LN, immune complex deposition stimulates dendritic cells to secrete inflammatory cytokines that activate T cells and B cells. B cells secrete autoantibodies that attack and damage the renal podocytes, leading to renal podocyte injury. The injured podocytes trigger inflammatory cells through the expression of toll‑like receptors and trigger T cells through major histocompatibility complexes and CD86, thereby participating in the local immune response and the exacerbation of podocyte injury. Based on the existing literature, the present review summarizes the research progress of podocytes in LN under the local immune microenvironment of the kidney, explores the mechanism of podocyte injury under the immune microenvironment, and evaluates podocytes as a potential therapeutic target for LN.
Topics: Humans; Lupus Nephritis; Podocytes; Kidney; Lupus Erythematosus, Systemic; Proteinuria
PubMed: 37711069
DOI: 10.3892/mmr.2023.13091 -
Renal Failure Dec 2024Diabetic kidney disease (DKD) is a common chronic microvascular complication of diabetes mellitus. Although studies have indicated the therapeutic potential of...
Diabetic kidney disease (DKD) is a common chronic microvascular complication of diabetes mellitus. Although studies have indicated the therapeutic potential of mesenchymal stem cells (MSCs) for DKD, the underlying molecular mechanisms remain unclear. Herein, we explored the renoprotective effect of placenta-derived MSCs (P-MSCs) and the potential mechanism of SIRT1/FOXO1 pathway-mediated autophagy in DKD. The urine microalbumin/creatinine ratio was determined using ELISA, and renal pathological changes were detected by special staining techniques. Immunofluorescence was used for detecting the renal tissue expression of podocin and nephrin; immunohistochemistry for the renal expression of autophagy-related proteins (LC3, Beclin-1, SIRT1, and FOXO1); and western blotting and PCR for the expression of podocyte autophagy- and pathway-related indicators. We found that P-MSCs ameliorated renal tubular injury and glomerular mesangial matrix deposition and alleviated podocyte damage in DKD rats. PMSCs enhanced autophagy levels and increased SIRT1 and FOXO1 expression in DKD rat renal tissue, whereas the autophagy inhibitor 3-methyladenine significantly attenuated the renoprotective effect of P-MSCs. P-MSCs improved HG-induced Mouse podocyte clone5(MPC5)injury, increased podocyte autophagy, and upregulated SIRT1 and FOXO1 expression. Moreover, downregulation of SIRT1 expression blocked the P-MSC-mediated enhancement of podocyte autophagy and improvement of podocyte injury. Thus, P-MSCs can significantly improve renal damage and reduce podocyte injury in DKD rats by modulating the SIRT1/FOXO1 pathway and enhancing podocyte autophagy.
Topics: Rats; Mice; Animals; Diabetic Nephropathies; Sirtuin 1; Autophagy; Kidney; Mesenchymal Stem Cells; Podocytes; Diabetes Mellitus
PubMed: 38234193
DOI: 10.1080/0886022X.2024.2303396 -
Inflammation Oct 2023The activation of nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome has been reported to importantly contribute to...
The activation of nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome has been reported to importantly contribute to glomerular inflammation and injury under different pathological conditions such as obesity. However, the mechanism mediating NLRP3 inflammasome activation in podocytes and subsequent glomerular injury remains poorly understood. Given that the ceramide signaling pathway has been reported to be implicated in obesity-related glomerulopathy (ORG), the present study was designed to test whether the ceramide-producing enzyme, acid sphingomyelinase (ASM), determines NLRP3 inflammasome activation and inflammatory exosome release in podocytes leading to glomerular inflammation and injury during ORG. In Smpd1/Podo mice, podocyte-specific overexpression of Smpd1 gene which encodes ASM significantly exaggerated high-fat diet (HFD)-induced NLRP3 inflammasome activation in podocytes and immune cell infiltration in glomeruli compared to WT/WT mice. Smpd1 gene deletion, however, blocked these pathological changes induced by HFD in Smpd1 mice. Accompanied with NLRP3 inflammasome activation and glomerular inflammation, urinary excretion of exosomes containing podocyte marker and NLRP3 inflammasome products (IL-1β and IL-18) in Smpd1/Podo mice on the HFD was much higher than that in WT/WT mice. In contrast, Smpd1 mice on the HDF had significantly lower urinary exosome excretion than WT/WT mice. Correspondingly, HFD-induced podocyte injury, glomerular sclerosis, and proteinuria were more severe in Smpd1/Podo mice, but milder in Smpd1 mice compared to WT/WT mice. Using podocytes isolated from these mice, we demonstrated that visfatin, a prototype pro-inflammatory adipokine, induced NLRP3 inflammasome activation and enrichment of multivesicular bodies (MVBs) containing IL-1β in podocytes, which was much stronger in podocytes from Smpd1/Podo mice, but weaker in those from Smpd1 mice than WT/WT podocytes. By quantitative analysis of exosomes, it was found that upon visfatin stimulation, podocytes from Smpd1/Podo mice released much more exosomes containing NLRP3 inflammasome products, but podocytes from Smpd1 mice released much less exosomes compared to WT/WT podocytes. Super-resolution microscopy demonstrated that visfatin inhibited lysosome-MVB interaction in podocytes, indicating impaired MVB degradation by lysosome. The inhibition of lysosome-MVB interaction by visfatin was amplified by Smpd1 gene overexpression but attenuated by Smpd1 gene deletion. Taken together, our results suggest that ASM in podocytes is a crucial regulator of NLRP3 inflammasome activation and inflammatory exosome release that instigate glomerular inflammation and injury during obesity.
Topics: Animals; Mice; Ceramides; Exosomes; Inflammasomes; Inflammation; Nicotinamide Phosphoribosyltransferase; NLR Family, Pyrin Domain-Containing 3 Protein; Obesity; Podocytes; Sphingomyelin Phosphodiesterase
PubMed: 37477734
DOI: 10.1007/s10753-023-01861-y -
Frontiers in Immunology 2023Podocyte injury, which involves the podocyte epithelial-mesenchymal transition (EMT) process, is a crucial factor contributing to the progression of diabetic nephropathy...
BACKGROUND
Podocyte injury, which involves the podocyte epithelial-mesenchymal transition (EMT) process, is a crucial factor contributing to the progression of diabetic nephropathy (DN) and proteinuria. Our study aimed to examine the protective properties of Angiopoietin-like protein 3 (Angptl3) knockout on podocyte damage and macrophage polarization in DN mice and podocytes treated with HG. Furthermore, we also sought to investigate the underlying molecular mechanism responsible for these effects.
METHODS
DN was induced in B6;129S5 mice through intraperitoneal injection of 40 mg/kg of streptozotocin (STZ). Subsequently, the changes in renal function, podocyte apoptosis, inflammatory factors (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], and interleukin-1β [IL-1β]), IL-10, TGF-β1, IL-1Ra, IL-10Ra, and nephrin were evaluated. Moreover, we investigated the mechanism underlying the role of Angptl3 in macrophages polarization, podocyte injury, podocyte EMT.
RESULTS
Our findings revealed that Angptl3 knockout significantly attenuated STZ or HG-induced renal dysfunction and podocyte EMT. In both and studies, Angptl3 knockout led to (1) promote the transformation of M1 type macrophages into M2 type macrophages; (2) amelioration of the reduced expression of nephrin, synaptopodin, and podocin; (3) inhibition of NLRP3 inflammasome activation and release of IL-1β; and (4) regulation of α-SMA expression via the macrophage polarization. (5) After HG treatment, there was an increase in pro-inflammatory factors and foot cell damage. These changes were reversed upon Angptle knockdown.
CONCLUSION
Our study suggests that the knockout of Angptl3 alleviates podocyte EMT and podocyte injury by regulating macrophage polarization.
Topics: Animals; Mice; Angiopoietin-Like Protein 3; Apoptosis; Diabetes Mellitus; Diabetic Nephropathies; Epithelial-Mesenchymal Transition; Podocytes
PubMed: 37638046
DOI: 10.3389/fimmu.2023.1228399 -
The Journal of Clinical Investigation Oct 2023Enabling the early detection and prevention of diabetic kidney damage has potential to substantially reduce the global burden of kidney failure. There is a critical need...
Enabling the early detection and prevention of diabetic kidney damage has potential to substantially reduce the global burden of kidney failure. There is a critical need for identification of mechanistic biomarkers that can predict progression and serve as therapeutic targets. In this issue of the JCI, Sharma and colleagues used an integrated multiomics approach to identify the metabolite adenine as a noninvasive biomarker of progression in early diabetic kidney disease (DKD). The highest tertile of urine adenine/creatinine ratio (UAdCR) was associated with higher risk for end-stage kidney disease and mortality across independent cohorts, including participants with early DKD without macroalbuminuria. Spatial metabolomics, single-cell transcriptomics, and experimental studies localized adenine to regions of tubular pathology and implicated the mTOR pathway in adenine-mediated tissue fibrosis. Inhibition of endogenous adenine production was protective in a diabetic model. These findings exemplify the potential for multiomics to uncover mechanistic biomarkers and targeted therapies in DKD.
Topics: Humans; Diabetic Nephropathies; Adenine; Kidney Failure, Chronic; Biomarkers; Metabolomics; Diabetes Mellitus, Type 2; Kidney
PubMed: 37843281
DOI: 10.1172/JCI174015 -
Frontiers in Immunology 2023Although the "multiple hits" theory is a widely accepted pathogenesis in IgA nephropathy (IgAN), increasing evidence suggests that the mononuclear/macrophage system... (Review)
Review
Although the "multiple hits" theory is a widely accepted pathogenesis in IgA nephropathy (IgAN), increasing evidence suggests that the mononuclear/macrophage system plays important roles in the progression of IgAN; however, the exact mechanism is unclear. In the present study, we explored 1,067 patients in 15 studies and found that the number of macrophages per glomerulus was positively related with the degree of hematuria, and the macrophages in the glomeruli were mainly related to mesangial proliferation (M) in renal biopsy. In the tubulointerstitium, macrophages were significantly paralleled to tubulointerstitial α-SMA and NF-kB expression, tubulointerstitial lesion, tubule atrophy/interstitial fibrosis (T), and segmental glomerulosclerosis (S). In the glomeruli and tubulointerstitium, M1 accounted for 85.41% in the M classification according to the Oxford MEST-C, while in the blood, M1 accounted for 100%, and the patients with low CD89 monocyte mean fluorescence intensity displayed more severe pathological characteristics (S1 and T1-2) and clinical symptoms. M1 (CD80) macrophages were associated with proinflammation in the acute phase; however, M2 (CD163) macrophages participated in tissue repair and remodeling, which correlated with chronic inflammation. In the glomeruli, M2 macrophages activated glomerular matrix expansion by secreting cytokines such as IL-10 and tumor necrosis factor-β (TGF-β), and M0 (CD68) macrophages stimulated glomerular hypercellularity. In the tubulointerstitium, M2 macrophages played pivotal roles in renal fibrosis and sclerosis. It is assumed that macrophages acted as antigen-presenting cells to activate T cells and released diverse cytokines to stimulate an inflammatory response. Macrophages infiltrating glomeruli destroy the integrity of podocytes through the mesangio-podocytic-tubular crosstalk as well as the injury of the tubule.
Topics: Humans; Glomerulonephritis, IGA; Glomerulosclerosis, Focal Segmental; Prognosis; Macrophages; Cytokines
PubMed: 37529043
DOI: 10.3389/fimmu.2023.1192941 -
Heliyon Nov 2023is a herbaceous flowering medicinal plant and flavonoids are its main pharmacological active ingredients. is listed in the 2020 edition of the Chinese Pharmacopoeia... (Review)
Review
is a herbaceous flowering medicinal plant and flavonoids are its main pharmacological active ingredients. is listed in the 2020 edition of the Chinese Pharmacopoeia for the treatment of chronic kidney disease (CKD). significantly reduces proteinuria in CKD, and the effectiveness and safety of in the treatment including primary glomerulonephropathy and diabetic kidney disease (DKD) have been proved by several randomized controlled trials (RCT). Emerging pharmacological studies have explored the potential active small molecules and the underlying mechanisms in . The active constituents of are mainly seven flavonoids, including hibifolin, hyperoside, isoquercetin, rutin, quercetin, myricetin, and quercetin-3-O-robinobioside. The mechanisms of action mainly include alleviating renal fibrosis, reducing the inflammatory response and decreasing the apoptosis of podocytes. In this review, we summarize the updated information of active components and molecular mechanisms of on chronic kidney disease.
PubMed: 38058638
DOI: 10.1016/j.heliyon.2023.e22017 -
Frontiers in Pharmacology 2024The most prevalent and devastating form of organ damage in systemic lupus erythematosus (SLE) is lupus nephritis (LN). LN is characterized by glomerular injury,... (Review)
Review
The most prevalent and devastating form of organ damage in systemic lupus erythematosus (SLE) is lupus nephritis (LN). LN is characterized by glomerular injury, inflammation, cell proliferation, and necrosis, leading to podocyte injury and tubular epithelial cell damage. Assays for urine biomarkers have demonstrated significant promise in the early detection of LN, evaluation of disease activity, and tracking of reaction to therapy. This is because they are non-invasive, allow for frequent monitoring and easy self-collection, transport and storage. Podocyte injury is believed to be a essential factor in LN. The extent and type of podocyte injury could be connected to the severity of proteinuria, making podocyte-derived cellular debris and injury-related urinary proteins potential markers for the diagnosis and monitoring of LN. This article focuses on studies examining urinary biomarkers associated with podocyte injury in LN, offering fresh perspectives on the application of biomarkers in the early detection and management of LN.
PubMed: 38313309
DOI: 10.3389/fphar.2024.1324540