MO075KLF11 DEFICIENCY ENHANCES CHEMOKINE GENERATION AND INJURY IN MURINE UNILATERAL URETERIC OBSTRUCTION

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Silvana DeLorenzo ◽  
Joseph Grande
Keyword(s):  
Critical Role ◽  
Tnf Alpha ◽  
Ureteric Obstruction ◽  
Wild Type ◽  
Glomerular Filtration Barrier ◽  
Filtration Barrier ◽  
Inflammatory Chemokines ◽  
Cc Chemokines ◽  
Histopathologic Analysis ◽  
Unilateral Ureteric Obstruction

Abstract Background and Aims Kruppel-like factors (KLFs) comprise a family of zinc-finger transcription factors that play a critical role in development, proliferation, and regeneration following injury. There are over 17 members of this family; recent studies have shown that KLF family members regulate podocyte differentiation, preservation of the glomerular filtration barrier, and regulation of mitochondrial function. However, a role for KLF11 in renal pathophysiology has not been previously established. Method Wild-type (WT) and KLF11 knockout (KO) mice were subjected to unilateral ureteric obstruction (UUO), a well-established model of renal inflammation and fibrosis; controls included mice subjected to manipulation of the ureter without ligation. Kidneys were harvested after 9 days (n=8 animals per group). Semiquantitative histopathologic analysis of renal atrophy, fibrosis, and inflammation was performed in a blinded fashion. Gene expression analysis was performed on renal cortex employing the Pathway Detect RNA array and RNASeq. Results In UUO, renal atrophy was more severe in KLF11 KO mice than WT mice (p<0.001). Deposition of collagen, as assessed by quantitative analysis of Sirus Red stained sections, was greater in KLF11 KO mice, compared to WT mice subjected to UUO; COL3A1 expression was also increased (p<0.05). Atrophy was associated with an increase in F4/80+ (p<0.01) and CD206+ macrophages (p<0.05), but not CD3+ T cells in KLF11 KO vs. WT mice. Induction of CC chemokines, including CCL2, CCL5, CCL7, CCL12, and CCL2 as well as CCR2 was significantly higher in KLF11 KO versus WT mice subjected to UUO (all p<0.001). Expression of NF-kB (p<0.01) and TNF alpha (p<0.01), but not IL-1 beta, IL-6, or IL-10 were significantly higher in KLF11 KO than WT mice with UUO. Expression of TGF-beta 1, Smad2, and Smad3 were also higher in KLF11 KO mice than WT mice with UUO (p<0.05). Conclusion Renal injury in UUO is exacerbated in KLF11 KO mice, compared to WT mice. Injury is associated with increased macrophage influx and production of pro-inflammatory chemokines. Future studies will determine how KLF11 deficiency directs transcription of pro-inflammatory and pro-fibrotic genes.

scholarly journals The critical role of Krüppel-like factors in kidney disease

2017 ◽  
Vol 312 (2) ◽  
pp. F259-F265 ◽  
Author(s):  
Sandeep K. Mallipattu ◽  
Chelsea C. Estrada ◽  
John C. He
Keyword(s):  
Current Knowledge ◽  
Critical Role ◽  
Vital Role ◽  
Glomerular Filtration Barrier ◽  
Kidney Fibrosis ◽  
Physiological Processes ◽  
Filtration Barrier ◽  
And Function ◽  
Mammalian Embryonic Development

Krüppel-like factors (KLFs) are a family of zinc-finger transcription factors critical to mammalian embryonic development, regeneration, and human disease. There is emerging evidence that KLFs play a vital role in key physiological processes in the kidney, ranging from maintenance of glomerular filtration barrier to tubulointerstitial inflammation to progression of kidney fibrosis. Seventeen members of the KLF family have been identified, and several have been well characterized in the kidney. Although they may share some overlap in their downstream targets, their structure and function remain distinct. This review highlights our current knowledge of KLFs in the kidney, which includes their pattern of expression and their function in regulating key biological processes. We will also critically examine the currently available literature on KLFs in the kidney and offer some key areas in need of further investigation.

scholarly journals Podocyte endocytosis in the regulation of the glomerular filtration barrier

2015 ◽  
Vol 309 (5) ◽  
pp. F398-F405 ◽  
Author(s):  
Kazunori Inoue ◽  
Shuta Ishibe
Keyword(s):  
Glomerular Filtration ◽  
Critical Role ◽  
Vital Role ◽  
Glomerular Filtration Barrier ◽  
Filtration Barrier ◽  
Endocytic Machinery ◽  
Health And Disease ◽  
Models Of Disease ◽  
Genetic Mouse Models

Severe defects in the glomerular filtration barrier result in nephrotic syndrome, which is characterized by massive proteinuria. The podocyte, a specialized epithelial cell with interdigitating foot processes separated by a slit diaphragm, plays a vital role in regulating the passage of proteins from the capillary lumen to Bowman's space. Recent findings suggest a critical role for endocytosis in podocyte biology as highlighted by genetic mouse models of disease and human genetic mutations that result in the loss of the integrity of the glomerular filtration barrier. In vitro podocyte studies have also unraveled a plethora of constituents that are differentially internalized to maintain homeostasis. These observations provide a framework and impetus for understanding the precise regulation of podocyte endocytic machinery in both health and disease.

scholarly journals Fn14 Deficiency Ameliorates Anti-dsDNA IgG-Induced Glomerular Damage in SCID Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Jiawen Wu ◽  
Xiaoyun Min ◽  
Li Wang ◽  
Jie Yang ◽  
Ping Wang ◽  
...  
Keyword(s):  
Inflammatory Cell ◽  
Severe Combined Immunodeficiency ◽  
Kidney Tissue ◽  
Scid Mice ◽  
Hybridoma Cells ◽  
Wild Type ◽  
Glomerular Filtration Barrier ◽  
Tissue Samples ◽  
Filtration Barrier ◽  
Glomerular Damage

Many studies have demonstrated that anti-dsDNA IgG is closely associated with lupus nephritis. Recently, it was found that activation of the fibroblast growth factor-inducible 14 (Fn14) signaling pathway damages glomerular filtration barrier in MRL/lpr lupus-prone mice. However, MRL/lpr mice have high titers of serum autoantibodies other than anti-dsDNA IgG. The aim of this study was to further explore the effect of Fn14 deficiency on anti-dsDNA IgG-induced glomerular damage in severe combined immunodeficiency (SCID) mice that have no endogenous IgG. Fn14 deficiency was generated in SCID mice. The murine hybridoma cells producing control IgG or anti-dsDNA IgG were intraperitoneally injected into mice. In two weeks, the urine, serum, and kidney tissue samples were harvested from mice at sacrifice. It showed that the injection of anti-dsDNA IgG, but not control IgG hybridoma cells, induced proteinuria and glomerular damage in SCID mice. Between the wild-type (WT) and knockout (KO) mice injected with anti-dsDNA IgG hybridoma cells, the latter showed a decrease in both proteinuria and glomerular IgG deposition. The histopathological changes, inflammatory cell infiltration, and proinflammatory cytokine production were also attenuated in the kidneys of the Fn14-KO mice upon anti-dsDNA IgG injection. Therefore, Fn14 deficiency effectively protects SCID mice from anti-dsDNA IgG-induced glomerular damage.

scholarly journals Klotho Deficiency Aggravated Diabetes-induced Podocyte injury

2020 ◽  
Author(s):  
Zhi Chen ◽  
Qing Zhou ◽  
Cong Liu ◽  
Yiping Zeng ◽  
Shaolong Yuan
Keyword(s):  
Dna Damage ◽  
Progressive Disease ◽  
Oxygen Species ◽  
Wild Type ◽  
Glomerular Filtration Barrier ◽  
Podocyte Injury ◽  
Albumin Creatinine Ratio ◽  
Filtration Barrier

Abstract Background: Diabetic nephropathy (DN) is a progressive disease, the main pathogeny of which is podocyte injury inducing glomerular filtration barrier and proteinuria. The occurrence and development of DN could be partly attributed to the reactive oxygen species (ROS) generated by mitochondria. However, researches on how mitochondrial dysfunction (MtD) ultimately causes DNA damage is poor.Methods: We generated streptozotocin (STZ)-induced diabetic mice with wild-type(C57BL/6J) or Klotho deficiency mice (KL+/-) and treated podocytes with high glucose (HG) to investigated the function of Klotho on HG-induced podocyte injury in vivo and in vitro.Results: The absence of Klotho aggravated diabetic phenotypes indicated by podocyte injury accompanied by elevated urea albumin creatinine ratio (UACR), creatinine, urea nitrogen. Then, Klotho deficiency could significantly aggravate DNA damage by increasing 8-OHdG and reducing OGG1. Finally, Klotho deficiency may promote MtD to promote 8-OHdG-induced podocyte injury.Conclusions: Klotho deficiency may promote diabetes-induced podocytic MtD and aggravate 8-OHdG-induced DNA damage by affecting OOG1.

scholarly journals Insulin directly stimulates VEGF-A production in the glomerular podocyte

2013 ◽  
Vol 305 (2) ◽  
pp. F182-F188 ◽  
Author(s):  
L. J. Hale ◽  
J. Hurcombe ◽  
A. Lay ◽  
B. Santamaría ◽  
A. M. Valverde ◽  
...  
Keyword(s):  
Mrna Levels ◽  
Wild Type ◽  
Hairpin Rna ◽  
Glomerular Filtration Barrier ◽  
Insulin Resistant ◽  
Filtration Barrier ◽  
Resistance Modulation ◽  
Rna Knockdown

Podocytes are critically important for maintaining the integrity of the glomerular filtration barrier and preventing albuminuria. Recently, it has become clear that to achieve this, they need to be insulin sensitive and produce an optimal amount of VEGF-A. In other tissues, insulin has been shown to regulate VEGF-A release, but this has not been previously examined in the podocyte. Using in vitro and in vivo approaches, in the present study, we now show that insulin regulates VEGF-A in the podocyte in both mice and humans via the insulin receptor (IR). Insulin directly increased VEGF-A mRNA levels and protein production in conditionally immortalized wild-type human and murine podocytes. Furthermore, when podocytes were rendered insulin resistant in vitro (using stable short hairpin RNA knockdown of the IR) or in vivo (using transgenic podocyte-specific IR knockout mice), podocyte VEGF-A production was impaired. Importantly, in vivo, this occurs before the development of any podocyte damage due to podocyte insulin resistance. Modulation of VEGF-A by insulin in the podocyte may be another important factor in the development of glomerular disease associated with conditions in which insulin signaling to the podocyte is deranged.

The lymphatic system controls intestinal inflammation and inflammation-associated colon cancer through the chemokine decoy receptor D6

Gut ◽  
2009 ◽  
Vol 59 (2) ◽  
pp. 197-206 ◽  
Author(s):  
Stefania Vetrano ◽  
Elena M Borroni ◽  
Adelaida Sarukhan ◽  
Benedetta Savino ◽  
Raffaella Bonecchi ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Lymphatic System ◽  
Intestinal Inflammation ◽  
Lymphatic Vessels ◽  
Experimental Colitis ◽  
Distal Segment ◽  
Wild Type ◽  
Decoy Receptor ◽  
Inflammatory Chemokines ◽  
Cc Chemokines

Background and aimsInflammatory CC chemokines have long been associated with cancer, but unequivocal evidence of a role in clinically relevant models of carcinogenesis is lacking. D6, a promiscuous decoy receptor that scavenges inflammatory CC chemokines, plays a non-redundant role in reducing the inflammatory response in various organs. As inflammation is a key player in the development of inflammatory bowel disease (IBD) and IBD-associated colorectal cancer, we investigated D6 expression in human colitis and colon cancer, and its role in experimental colitis and inflammation-associated colon cancer.ResultsIn humans, D6 was mainly expressed by lymphatic vessels and leukocytes in the mucosa of individuals with IBD and colon cancer, as well as the mucosa of control individuals. Mice lacking expression of D6 were significantly more susceptible to experimental colitis than wild-type mice and failed to resolve colitis, with significantly higher levels of several pro-inflammatory chemokines. In bone marrow chimeric mice, the ability of D6 to regulate colitis was tracked to the stromal/lymphatic compartment, with no contribution of haemopoietic cells. Finally, after administration of the carcinogen azoxymethane, D6−/− mice showed increased susceptibility to colitis-associated cancer in the distal segment of the colon compared with wild-type mice.ConclusionsD6 expressed on lymphatic vessels plays a key role in the control of intestinal inflammation and the development of inflammation-associated colon cancer. Our results reveal a new unexpected role for the lymphatic system in the pathogenesis of IBD and intestinal cancer, and candidate chemokines as novel players in tumour promotion and progression.

scholarly journals Sodium-Glucose Cotransporter-2 Inhibitors in Patients with Hereditary Podocytopathies, Alport Syndrome, and FSGS: A Case Series to Better Plan a Large-Scale Study

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1815
Author(s):  
Jan Boeckhaus ◽  
Oliver Gross
Keyword(s):  
Glomerular Filtration ◽  
Alport Syndrome ◽  
Large Scale ◽  
Case Series ◽  
Hereditary Diseases ◽  
Glomerular Filtration Barrier ◽  
Early Effect ◽  
Filtration Barrier ◽  
First Case ◽  
Sodium Glucose Cotransporter

Hereditary diseases of the glomerular filtration barrier are characterized by a more vulnerable glomerular basement membrane and dysfunctional podocytes. Recent clinical trials have demonstrated the nephroprotective effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in chronic kidney disease (CKD). SGLT2-mediated afferent arteriole vasoconstriction is hypothesized to correct the hemodynamic overload of the glomerular filtration barrier in hereditary podocytopathies. To test this hypothesis, we report data in a case series of patients with Alport syndrome and focal segmental glomerulosclerosis (FSGS) with respect of the early effect of SGLT2i on the kidney function. Mean duration of treatment was 4.5 (±2.9) months. Mean serum creatinine before and after SGLT-2i initiation was 1.46 (±0.42) and 1.58 (±0.55) mg/dL, respectively, with a median estimated glomerular filtration rate of 64 (±27) before and 64 (±32) mL/min/1.73 m2 after initiation of SGLT2i. Mean urinary albumin-creatinine ratio in mg/g creatinine before SGLT-2i initiation was 1827 (±1560) and decreased by almost 40% to 1127 (±854) after SGLT2i initiation. To our knowledge, this is the first case series on the effect and safety of SGLT2i in patients with hereditary podocytopathies. Specific large-scale trials in podocytopathies are needed to confirm our findings in this population with a tremendous unmet medical need for more effective, early on, and safe nephroprotective therapies.

scholarly journals Thrombomodulin is upregulated in the kidneys of women with pre-eclampsia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Cleo C. L. van Aanhold ◽  
Manon Bos ◽  
Katrina M. Mirabito Colafella ◽  
Marie-Louise P. van der Hoorn ◽  
Ron Wolterbeek ◽  
...  
Keyword(s):  
Glomerular Filtration ◽  
Early Stage ◽  
Vascular Inflammation ◽  
Angiogenesis Inhibitor ◽  
Serum Levels ◽  
Dependent Manner ◽  
Glomerular Filtration Barrier ◽  
Soluble Thrombomodulin ◽  
Filtration Barrier ◽  
Glomerular Endothelium

AbstractThe endothelial glycoprotein thrombomodulin regulates coagulation, vascular inflammation and apoptosis. In the kidney, thrombomodulin protects the glomerular filtration barrier by eliciting crosstalk between the glomerular endothelium and podocytes. Several glomerular pathologies are characterized by a loss of glomerular thrombomodulin. In women with pre-eclampsia, serum levels of soluble thrombomodulin are increased, possibly reflecting a loss from the glomerular endothelium. We set out to investigate whether thrombomodulin expression is decreased in the kidneys of women with pre-eclampsia and rats exposed to an angiogenesis inhibitor. Thrombomodulin expression was examined using immunohistochemistry and qPCR in renal autopsy tissues collected from 11 pre-eclamptic women, 22 pregnant controls and 11 hypertensive non-pregnant women. Further, kidneys from rats treated with increasing doses of sunitinib or sunitinib in combination with endothelin receptor antagonists were studied. Glomerular thrombomodulin protein levels were increased in the kidneys of women with pre-eclampsia. In parallel, in rats exposed to sunitinib, glomerular thrombomodulin was upregulated in a dose-dependent manner, and the upregulation of glomerular thrombomodulin preceded the onset of histopathological changes. Selective ETAR blockade, but not dual ETA/BR blockade, normalised the sunitinib-induced increase in thrombomodulin expression and albuminuria. We propose that glomerular thrombomodulin expression increases at an early stage of renal damage induced by antiangiogenic conditions. The upregulation of this nephroprotective protein in glomerular endothelial cells might serve as a mechanism to protect the glomerular filtration barrier in pre-eclampsia.

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