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Matrix metalloproteinase-10 (MMP-10) is a zinc-dependent endopeptidase with the ability to degrade a broad spectrum of extracellular matrices and other protein substrates. The expression of MMP-10 is induced in acute kidney injury (AKI) and chronic kidney disease (CKD), as well as in renal cell carcinoma (RCC). During the different stages of kidney...
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Background:
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Citations
... Nephrotic syndrome is initiated when severe damage occurs in the kidney nephropathies and skinny blood vessels in the kidney, resulting in falling to filter waste and water from the blood (Gupta et al. 2018). Several cellular factors were identified as critical factors involved in repairing and regeneration of renal nephrons, such as the small proline-rich region 2f (Sprr2f ) and Matrix metalloproteinase-10 (MMP-10) (Huynh et al. 2020;Sun and Liu 2022). Evidence indicated that the expression of the Sprr2f gene is increased a hundredfold in response to renal injury in unilateral ureteral obstruction (UUO) mouse model (Huynh et al. 2020). ...
... For instance, sprr2f knockout mice showed more renal damage after unilateral ureteral obstruction compared with wild-type mice approved by a high level of hydroxyproline and denser collagen staining, indicating a role of Sprr2f in repairing renal injury (Huynh et al. 2020). Recent evidence reported the protective role of MMP-10 in AKI by stimulating HB-EGF-mediated glomerular repair and tubular regeneration (Sun and Liu 2022). Furthermore, our findings confirm the beneficial role of liquorice extract as having protective and therapeutic effects in renal disorders because of its antioxidant properties. ...
In the current work, we aimed to evaluate the protective effects of liquorice and halfa-bar extract against doxorubicin (DOX)-induced nephritic syndrome (NS) in rats. Twenty albino male rats were intraperitoneally injected with 50 mg/kg of DOX. The injected rats were supplied daily with 400 mg/kg of liquorice, halfa-bar extract, or their combination for 2 weeks. Our findings confirmed the induction of NS in rats indicated by alteration in Bowman's space, damaged in glomerular capsules, and tubules. Moreover, the levels of produced tumour necrosis factor-alpha (TNF-α) and interleukin-8 (IL-8) were increased, accompanied by decreasing levels of IL-4 and IL-10. Supplement NS-rats with liquorice and halfa-bar extracts restored the glomerular and tubules damage and adjusted the level of produced TNF-α and IL-8. Interestingly, both extracts can stimulate the expression profile of small proline-rich protein 2 F (sprr2f) and metalloproteinase-10 (MMP-10), which are responsible for repairing and regeneration mechanisms of renal syndromes.
... Various agents targeting the extracellular matrix, such as lysyl oxidases (LOXs) inhibitors and matrix metalloproteinase inhibitors, have been investigated for their potential antifibrotic effects in DKD. These agents may disrupt the synthesis, cross-linking, or degradation of extracellular matrix proteins and prevent the development of renal fibrosis [194]. While these anti-inflammatory and antifibrotic approaches show promise in preclinical studies, their efficacy and safety in humans with DKD require further investigation in well-designed clinical trials. ...
Diabetic kidney disease (DKD) is a major microvascular complication of both type 1 and type 2 diabetes. DKD is characterised by injury to both glomerular and tubular compartments, leading to kidney dysfunction over time. It is one of the most common causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Persistent high blood glucose levels can damage the small blood vessels in the kidneys, impairing their ability to filter waste and fluids from the blood effectively. Other factors like high blood pressure (hypertension), genetics, and lifestyle habits can also contribute to the development and progression of DKD. The key features of renal complications of diabetes include morphological and functional alterations to renal glomeruli and tubules leading to mesangial expansion, glomerulosclerosis, homogenous thickening of the glomerular basement membrane (GBM), albuminuria, tubulointerstitial fibrosis and progressive decline in renal function. In advanced stages, DKD may require treatments such as dialysis or kidney transplant to sustain life. Therefore, early detection and proactive management of diabetes and its complications are crucial in preventing DKD and preserving kidney function.
... CCL20 promotes T-cell recruitment, renal tissue injury and reduced renal function 43 . We also found, using the Olink proteomic platform, that TNF-α and TMAO enhanced the secretion of additional inflammatory-and growth mediators associated with kidney disease; VEGFA, GDNF, CDCP1, OPG, uPA, AXIN1, MMP-1, MMP-10, PD-L1, HGF, Flt3L, 4E-BP1, CD40, CASP-8, ADA, TNFRSF9, TWEAK [44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61] . Increased systemic levels of TWEAK has been shown to trigger kidney injury, inflammation, and renal fibrosis. ...
Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite and TNF-α is proinflammatory cytokine, both known to be associated with renal inflammation, fibrosis and chronic kidney disease. However, today there are no data showing the combined effect of TMAO and TNF-α on renal fibrosis-and inflammation. The aim of this study was to investigate whether TMAO can enhance the inflammatory and fibrotic effects of TNF-α on renal fibroblasts. We found that the combination of TNF-α and TMAO synergistically increased fibronectin release and total collagen production from renal fibroblasts. The combination of TMAO and TNF-α also promoted increased cell proliferation. Both renal proliferation and collagen production were mediated through Akt/mTOR/ERK signaling. We also found that TMAO enhanced TNF-α mediated renal inflammation by inducing the release of several cytokines (IL-6, LAP TGF-beta-1), chemokines (CXCL-6, MCP-3), inflammatory-and growth mediators (VEGFA, CD40, HGF) from renal fibroblasts. In conclusion, we showed that TMAO can enhance TNF-α mediated renal fibrosis and release of inflammatory mediators from renal fibroblasts in vitro. Our results can promote further research evaluating the combined effect of TMAO and inflammatory mediators on the development of kidney disease.
... Matrix metalloproteinase-10 (MMP-10), a zinc-dependent endopeptidase, can degrade various extracellular matrices and other protein substrates. The expression of MMP-10 is induced in both acute kidney injury (AKI) and CKD [36]. At different stages of renal injury, MMP-10 performs diverse functions by cleaving various bioactive substrates, such as heparinbinding EGF (HB-EGF), zonula occludens-1 (ZO-1), and pro-MMP-1, -7, -8, -9, -10, and -13. ...
The Adriamycin (ADR) nephropathy model, which induces podocyte injury, is limited to certain mouse strains due to genetic susceptibilities, such as the PrkdcR2140C polymorphism. The FVB/N strain without the R2140C mutation resists ADR nephropathy. Meanwhile, a detailed analysis of the progression of ADR nephropathy in the FVB/N strain has yet to be conducted. Our research aimed to create a novel mouse model, the FVB-PrkdcR2140C, by introducing PrkdcR2140C into the FVB/NJcl (FVB) strain. Our study showed that FVB-PrkdcR2140C mice developed severe renal damage when exposed to ADR, as evidenced by significant albuminuria and tubular injury, exceeding the levels observed in C57BL/6J (B6)-PrkdcR2140C. This indicates that the FVB/N genetic background, in combination with the R2140C mutation, strongly predisposes mice to ADR nephropathy, highlighting the influence of genetic background on disease susceptibility. Using RNA sequencing and subsequent analysis, we identified several genes whose expression is altered in response to ADR nephropathy. In particular, Mmp7, Mmp10, and Mmp12 were highlighted for their differential expression between strains and their potential role in influencing the severity of kidney damage. Further genetic analysis should lead to identifying ADR nephropathy modifier gene(s), aiding in early diagnosis and providing novel approaches to kidney disease treatment and prevention.
... Moreover, TJP1 establishes a framework for podocyte connection, while playing a critical role in renal development and the maintenance of renal function (34). TJP1 expression in podocytes and its interactions with slit diaphragm components (e.g., nephrin, NEPH1, and NEPH3) are necessary to maintain glomerular filtration barrier integrity (35). Selective knockout of TJP1 in renal podocytes can cause severe proteinuria in mice, leading to renal impairment and global sclerosis (36). ...
Background
For IgA nephropathy (IgAN), tubular atrophy/interstitial fibrosis is the most important prognostic pathological indicator in the mesangial and endocapillary hypercellularity, segmental sclerosis, interstitial fibrosis/tubular atrophy, and presence of crescents (MEST-C) score. The identification of non-invasive biomarkers for tubular atrophy/interstitial fibrosis would aid clinical monitoring of IgAN progression and improve patient prognosis.
Methods
The study included 188 patients with primary IgAN in separate confirmation and validation cohorts. The associations of miR-92a-3p, miR-425-5p, and miR-185-5p with renal histopathological lesions and prognosis were explored using Spearman correlation analysis and Kaplan-Meier survival curves. Bioinformatics analysis and dual luciferase experiments were used to identify hub genes for miR-185-5p. The fibrotic phenotypes of tubular epithelial cells were evaluated in vivo and in HK-2 cells.
Results
miRNA sequencing and cohort validation revealed that the expression levels of miR-92a-3p, miR-425-5p, and miR-185-5p in urine were significantly increased among patients with IgAN; these levels could predict the extent of tubular atrophy/interstitial fibrosis in such patients. The combination of the three biomarkers resulted in an area under the receiver operating characteristic curve of 0.742. The renal prognosis was significantly worse in the miR-185-5p high expression group than in the low expression group (P=0.003). Renal tissue in situ hybridization, bioinformatics analysis, and dual luciferase experiments confirmed that miR-185-5p affects prognosis in patients with IgAN mainly by influencing expression of the target gene tight junction protein 1 (TJP1) in renal tubular epithelial cells. In vitro experiment revealed that an miR-185-5p mimic could reduce TJP1 expression in HK-2 cells, while increasing the levels of α-smooth muscle actin, fibronectin, collagen I, and collagen III; these changes promoted the transformation of renal tubular epithelial cells to a fibrotic phenotype. An miR-185-5p inhibitor can reverse the fibrotic phenotype in renal tubular epithelial cells. In a unilateral ureteral obstruction model, the inhibition of miR-185-5p expression alleviated tubular atrophy/interstitial fibrosis.
Conclusion
Urinary miR-185-5p, a non-invasive biomarker of tubular atrophy/interstitial fibrosis in IgAN, may promote the transformation of renal tubular epithelial cells to a fibrotic phenotype via TJP1.
... The stimulation of TGF-β signaling by the secretion of TGF-β from the LLC is facilitated by various ways, such as proteolysis by plasmin or matrix metalloproteinases (MMPs), or integrin binding-mediated LLC conformational changes and subsequent force dependent activation (Shi et al., 2011;Hinz, 2013;Hu et al., 2021;Peeters et al., 2022;Sun and Liu, 2022). The stimulation of TGF-β occurs via its binding to the TGF-β receptor 2 (TGFBR2), which subsequently triggers the phosphorylation of TGFBR1 (Yuan et al., 2022). ...
Fibrillin-1 (FBN1) is a large, cysteine-rich, calcium binding extracellular matrix glycoprotein encoded by FBN1 gene. It serves as a structural component of microfibrils and provides force-bearing mechanical support in elastic and nonelastic connective tissue. As such, mutations in the FBN1 gene can cause a wide variety of genetic diseases such as Marfan syndrome, an autosomal dominant disorder characterized by ocular, skeletal and cardiovascular abnormalities. FBN1 also interacts with numerous microfibril-associated proteins, growth factors and cell membrane receptors, thereby mediating a wide range of biological processes such as cell survival, proliferation, migration and differentiation. Dysregulation of FBN1 is involved in the pathogenesis of many human diseases, such as cancers, cardiovascular disorders and kidney diseases. Paradoxically, both depletion and overexpression of FBN1 upregulate the bioavailability and signal transduction of TGF-β via distinct mechanisms in different settings. In this review, we summarize the structure and expression of FBN1 and present our current understanding of the functional role of FBN1 in various human diseases. This knowledge will allow to develop better strategies for therapeutic intervention of FBN1 related diseases.
Chronic prostatitis and Pelvic Pain syndrome (CP/CPPS) is an autoimmune inflammatory disease characterized by pelvic or perineal pain and infiltration of inflammatory cells in the prostate. C-X-C chemokine receptor type 7 (CXCR7), also known as the atypical chemokine receptor 3 (ACKR3) receptor, are atypical chemokine receptors. Having been shown to play a key role in inflammatory processes, whether CXCR7 influences the role of autoimmune prostate and immune regulation and its mechanism of action are unclear. In this study, a mouse model of experimental autoimmune prostatitis was constructed by subcutaneous injection of antigen, and CXCR7 agonist was administered to investigate the effects of CXCR7 on the proportion of immune cells and fibrosis in CP/CPPS. Western blotting, immunohistochemical staining and Immunofluorescence, flow cytometry, and masson staining were used to study the possible regulatory mechanisms. CXCR7 agonists can significantly reduce pain and prostatic inflammation, and in vivo flow studies have shown that they affect the TH17/Treg cell ratio. To elucidate the potential mechanisms by which CXCR7 influences the pathogenesis of CNP, we conducted simultaneous RNA-seq and non-targeted metabolome sequencing. Our findings suggest that CXCR7 agonists alleviate fibrosis in autoimmune prostatitis by inhibiting the TGFβ/SMAD pathway. This study provides a valuable immunological basis for CNP to intervene CP/CPPS therapy with CXCR7 as the target.
Chronic kidney disease (CKD) is a severe condition and a significant public health issue worldwide, carrying the burden of an increased risk of cardiovascular events and mortality. The traditional factors that promote the onset and progression of CKD are cardiometabolic risk factors like hypertension and diabetes, but non-traditional contributors are escalating. Moreover, gut dysbiosis, inflammation, and an impaired immune response are emerging as crucial mechanisms in the disease pathology. The gut microbiome and kidney disease exert a reciprocal influence commonly referred to as “the gut-kidney axis” through the induction of metabolic, immunological, and endocrine alterations. Periodontal diseases are strictly involved in the gut-kidney axis for their impact on the gut microbiota composition and for the metabolic and immunological alterations occurring in and reciprocally affecting both conditions. This review aims to provide an overview of the dynamic biological interconnections between oral health status, gut, and renal pathophysiology, spotlighting the dynamic oral-gut-kidney axis and raising whether periodontal diseases and gut microbiota can be disease modifiers in CKD. By doing so, we try to offer new insights into therapeutic strategies that may enhance the clinical trajectory of CKD patients, ultimately advancing our quest for improved patient outcomes and well-being.
Kidney fibrosis, characterized by excessive deposition of extracellular matrix (ECM) that leads to tissue scarring, is the final common outcome of a wide variety of chronic kidney diseases. Rather than being distributed uniformly across the kidney parenchyma, renal fibrotic lesions initiate at certain focal sites in which the fibrogenic niche is formed in a spatially confined fashion. This niche provides a unique tissue microenvironment that is orchestrated by a specialized ECM network consisting of de novo-induced matricellular proteins. Other structural elements of the fibrogenic niche include kidney resident and infiltrated inflammatory cells, extracellular vesicles, soluble factors and metabolites. ECM proteins in the fibrogenic niche recruit soluble factors including WNTs and transforming growth factor-β from the extracellular milieu, creating a distinctive profibrotic microenvironment. Studies using decellularized ECM scaffolds from fibrotic kidneys show that the fibrogenic niche autonomously promotes fibroblast proliferation, tubular injury, macrophage activation and endothelial cell depletion, pathological features that recapitulate key events in the pathogenesis of chronic kidney disease. The concept of the fibrogenic niche represents a paradigm shift in understanding of the mechanism of kidney fibrosis that could lead to the development of non-invasive biomarkers and novel therapies not only for chronic kidney disease, but also for fibrotic diseases of other organs.
