ureter obstruction
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2021 ◽  
Author(s):  
Bo Wang ◽  
Chenguang Ding ◽  
Xiaoming Ding ◽  
Greg H Tesch ◽  
Jin Zheng ◽  
...  

Inflammation is a pathological feature of kidney injury and its progression correlates with the development of kidney fibrosis which can lead to kidney function impairment. This project investigated the regulatory function of WNT1-inducible-signaling pathway protein 1 (WISP1) in kidney inflammation. Administration of recombinant WISP1 protein to healthy mice induced kidney inflammation (macrophage accrual and production of TNFα, CCL2 and IL-6), which could be prevented by inhibition of NF-κB. Furthermore, inhibition of WISP1, by gene knockdown or neutralising antibody, could inhibit cultured macrophages producing inflammatory cytokines following stimulation with lipopolysaccharides (LPS) and kidney fibroblasts proliferating in response to TNFα, which both involved NF-κB signalling.  Kidney expression of WISP1 was found to be increased in mouse models of progressive kidney inflammation- unilateral ureter obstruction (UUO) and streptozotocin-induced diabetic nephropathy. Treatment of UUO mice with WISP1 antibody reduced the kidney inflammation in these mice. Therefore, pharmacological blockade of WISP1 exhibits potential as a novel therapy for inhibiting inflammation in kidney disease.


2021 ◽  
Vol 2021 (11) ◽  
Author(s):  
Toshio Arai ◽  
Yuichiro Mori ◽  
Saori Yoshizaki ◽  
Ryo Ando ◽  
Shunsuke Natori ◽  
...  

ABSTRACT Sepsis has a high mortality rate; thus, in the intensive care unit, early diagnosis and adjunctive treatments are crucial. However, generally, most patients with sepsis from rural area initially visit the emergency department at a rural hospital and are managed in general medical wards in Japan. Here we report on an 81-year-old Japanese female manifesting septic shock caused by the upper urinary tract infection of extended-spectrum beta-lactamase-producing Escherichia coli secondary to the left ureter obstruction by the urothelial carcinoma. Broad-spectrum antibiotics were administered. Although critical for the source control of infection, drainage of the ureteropelvic junction could not be performed immediately because of catecholamine-resistant hypotension. Hence, we administered polymyxin B-immobilized fiber column direct hemoperfusion, followed by low-dose hydrocortisone administration. After 8 hours of infusion, she recovered from the septic shock and successfully underwent emergency percutaneous nephrostomy. This presented strategy may provide a new resolution of catecholamine-resistant patients in urosepsis.


2021 ◽  
pp. 1-15
Author(s):  
Lu Zhou ◽  
Xian Xue ◽  
Qing Hou ◽  
Chunsun Dai

<b><i>Background:</i></b> Ferroptosis, an iron-dependent form of regulated necrosis mediated by lipid peroxidation, predominantly polyunsaturated fatty acids, is involved in postischemic and toxic kidney injury. However, the role and mechanisms for tubular epithelial cell (TEC) ferroptosis in kidney fibrosis remain largely unknown. <b><i>Objectives:</i></b> The aim of the study was to decipher the role and mechanisms for TEC ferroptosis in kidney fibrosis. <b><i>Methods:</i></b> Mouse models with unilateral ureter obstruction (UUO) or ischemia/reperfusion injury (IRI) were generated. <b><i>Results:</i></b> We found that TEC ferroptosis exhibited as reduced glutathione peroxidase 4 (GPX4) expression and increased 4-hydroxynonenal abundance was appeared in kidneys from chronic kidney disease (CKD) patients and mouse models with UUO or IRI. Inhibition of ferroptosis could largely mitigate kidney injury, interstitial fibrosis, and inflammatory cell accumulation in mice after UUO or IRI. Additionally, treatment of TECs with (1S,3R)-RSL-3, an inhibitor of GPX4, could enhance cell ferroptosis and recruit macrophages. Furthermore, inhibiting TEC ferroptosis reduced monocyte chemotactic protein 1 (MCP-1) secretion and macrophage chemotaxis. <b><i>Conclusions:</i></b> This study uncovers that TEC ferroptosis may promote interstitial fibrosis and inflammation, and targeting ferroptosis may shine a light on protecting against kidney fibrosis in patients with CKDs.


2021 ◽  
Author(s):  
Michael A Ortega ◽  
Ross K Villiger ◽  
Malia Harrison-Chau ◽  
Suzanna Lieu ◽  
Kadee-Kalia Tamashiro ◽  
...  

Ureter obstruction is a highly prevalent event during embryonic development and is a major cause of pediatric kidney disease. We have reported that ureteric bud specific ablation of the exocyst Exoc5 subunit in late murine gestation results in failure of urothelial stratification, cell death, and complete ureter obstruction. However, the mechanistic connection between disrupted exocyst activity, urothelial cell death, and subsequent ureter obstruction was unclear. Here, we report that inhibited urothelial stratification does not drive cell death during ureter development. Instead, we demonstrate that the exocyst plays a critical role in autophagy in urothelial cells, and that disruption of autophagy activates a urothelial NF-κB stress response. Impaired autophagy first provokes canonical NF κB activity which is progressively followed by increasing non-canonical NF-κB activity and cell death if the stress remains unresolved. Furthermore, we demonstrate that ureter obstructions can be completely rescued in Exoc5 conditional knockout mice by administering a single dose of pan-caspase inhibitor z VAD-FMK at E16.5 prior to urothelial cell death. Taken together, ablation of Exoc5 disrupts autophagic stress response and activates progressive NF-κB signaling which promotes obstructive uropathy.


2021 ◽  
Author(s):  
Feng Wang ◽  
Tadashi Otsuka ◽  
Keiko Takahashi ◽  
Chikage Narui ◽  
Daniel C. Colvin ◽  
...  

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Gunsmaa Nyamsuren ◽  
Gregor Christof Rapp ◽  
Björn Tampe ◽  
Michael Zeisberg

Abstract Background and Aims Aryl hydrocarbon receptor nuclear translocator (ARNT) mediates anti-fibrotic activity in kidney and liver through induction of ALK3-receptor expression and subsequently increased Smad1/5/8 signaling. While expression of ARNT can be pharmacologically induced by sub-immunosuppressive doses of FK506 or by GPI1046, its anti-fibrotic activity is only realized when ARNT-ARNT homodimers form, as opposed to formation of ARNT-AHR or ARNT-HIF1α heterodimers. Mechanisms underlying ARNTs dimerization decision to specifically form ARNT-ARNT homodimers and possible cues to specifically induce ARNT homodimerization have been previously unknown. We here aimed to elucidate the molecular mechanisms underlying control of ARNT dimerization decision and to explore its therapeutic potential. Method We analyzed dimerization of recombinant and native ARNT by immunoprecipitation, MALDI-TOF mass spectrometry, and LS-MS/MS analysis and proximity ligation assay. Phosphorylation sites were mapped through generation of phosphorylation site mutants and through pharmacological inhibition. For in vivo analysis we challenged mice with model of unilateral ureter obstruction and carbon tetrachloride to induce fibrosis in kidney and liver. Results Here we report that inhibition of PP2A phosphatase activity increases intracellular accumulation of ARNT-ARNT homodimers. This effect is dependent on enhanced ARNT-ARNT homodimerization and decreased ARNT proteolytic degradation, but independent of ARNT transcription (which remains unchanged upon PP2A inhibition). We further identify that Ser77 phosphorylation plays a critical role in ARNT homodimerization, as ARNT-ARNT homodimers do not form with Ser77/Asp-mutant ARNT proteins. In light of previous studies which identified anti-fibrotic activity upon increased ARNT expression, we further demonstrate attenuated fibrosis upon monotherapy with the PP2A inhibitor LB100, and additive anti-fibrotic activities upon combination with pharmacological inducers of ARNT expression FK506 or GPI1046 in murine models of kidney and liver fibrosis. Conclusion Our study provides additional evidence for the anti-fibrotic activity of ARNT and reveals Ser77 phosphorylation as a novel pharmacological target to realize the therapeutic potential of increased ARNT transactivation activity.


Author(s):  
Yan Liang ◽  
Xiaoli Sun ◽  
Mingjie Wang ◽  
Qingmiao Lu ◽  
Mengru Gu ◽  
...  

AbstractMacrophage accumulation and activation play an essential role in kidney fibrosis; however, the underlying mechanisms remain to be explored. By analyzing the kidney tissues from patients and animal models with kidney fibrosis, we found a large induction of PP2Acα in macrophages. We then generated a mouse model with inducible macrophage ablation of PP2Acα. The knockouts developed less renal fibrosis, macrophage accumulation, or tubular cell death after unilateral ureter obstruction or ischemic reperfusion injury compared to control littermates. In cultured macrophages, PP2Acα deficiency resulted in decreased cell motility by inhibiting Rap1 activity. Moreover, co-culture of PP2Acα−/− macrophages with tubular cells resulted in less tubular cell death attributed to downregulated Stat6-mediated tumor necrosis factor α (TNFα) production in macrophages. Together, this study demonstrates that PP2Acα promotes macrophage accumulation and activation, hence accelerates tubular cell death and kidney fibrosis through regulating Rap1 activation and TNFα production.


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