TREM1/3 deficiency impairs tissue repair after acute kidney injury and mitochondrial metabolic flexibility in tubular epithelial cells

Long-term sequelae of acute kidney injury (AKI) are associated with incomplete recovery of renal function and the development of chronic kidney disease (CKD), which can be mediated by aberrant innate immune activation, mitochondrial pathology, and accumulation of senescent tubular epithelial cells (TECs). Herein, we show that the innate immune receptor Triggering receptor expressed on myeloid cells-1 (TREM-1) links mitochondrial metabolism to tubular epithelial senescence. TREM-1 is expressed by inflammatory and epithelial cells, both players in renal repair after ischemia/reperfusion (IR)-induced AKI. Hence, we subjected WT and TREM1/3 KO mice to different models of renal IR. TREM1/3 KO mice displayed no major differences during the acute phase of injury, but increased mortality was observed in the recovery phase. This detrimental effect was associated with maladaptive repair, characterized by persistent tubular damage, inflammation, fibrosis, and TEC senescence. In vitro, we observed an altered mitochondrial homeostasis and cellular metabolism in TREM1/3 KO primary TECs. This was associated with G2/M arrest and increased ROS accumulation. Further exposure of cells to ROS-generating triggers drove the cells into a stress-induced senescent state, resulting in decreased wound healing capacity. Treatment with a mitochondria anti-oxidant partly prevented the senescent phenotype, suggesting a role for mitochondria herein. In summary, we have unraveled a novel (metabolic) mechanism by which TREM1/3 deficiency drives senescence in TECs. This involves redox imbalance, mitochondrial dysfunction and a decline in cellular metabolic activities. These finding suggest a novel role for TREM-1 in maintaining tubular homeostasis through regulation of mitochondrial metabolic flexibility

RAGE does not contribute to renal injury and damage upon ischemia/reperfusion-induced injury.

Item does not contain fulltextThe receptor for advanced glycation end products (RAGE) mediates a variety of inflammatory responses in renal diseases, but its role in renal ischemia/reperfusion (I/R) injury is unknown. We showed that during renal I/R, RAGE ligands HMGB1 and S100B are expressed. However, RAGE deficiency does not affect renal injury and function upon I/R-induced injury

Toll-Like Receptor Family Polymorphisms Are Associated with Primary Renal Diseases but Not with Renal Outcomes Following Kidney Transplantation

Toll-like receptors (TLRs) play a crucial role in innate- and adaptive immunity. The TLR pathways were shown to play key functional roles in experimental acute and chronic kidney injury, including the allo-immune response after experimental renal transplantation. Data about the precise impact of TLRs and their negative regulators on human renal transplant outcomes however are limited and contradictory. We studied twelve non-synonymous single nucleotide polymorphisms (SNPs) of which eleven in TLR1-8 and one in SIGIRR in a final cohort comprising 1116 matching donors and recipients. TLR3 p.Leu412Phe and SIGIRR p.Gln312Arg significantly deviated from Hardy-Weinberg equilibrium and were excluded. The frequency distribution of the minor alleles of the remaining 10 TLR variants were compared between patients with end-stage renal disease (recipients) and controls (kidney donors) in a case-control study. Secondly, the associations between the minor allele frequency of the TLR variants and delayed graft function, biopsy-proven acute rejection and death-censored graft failure after transplantation were investigated with Cox regression. Carrier frequencies of the minor alleles of TLR1 p.His305Leu (OR = 4.79, 95% CI = 2.35-9.75, P = 0.0002), TLR1 p.Asn248Ser (OR = 1.26, 95% CI = 1.07-1.47, P = 0.04) and TLR8 p.Met1Val (OR = 1.37, 95% CI = 1.14-1.64, P = 0.008) were significantly higher in patients with ESRD, with little specificity for the underlying renal disease entity (adjusted for age, gender and donor-recipient relatedness). The minor allele frequency of none of the TLR variants significantly associated with the surrogate and definite outcomes, even when multivariable models were created that could account for TLR gene redundancy. In conclusion, genetic variants in TLR genes were associated with the prevalence of ESRD but not renal transplant outcomes. Therefore, our data suggests that specific TLR signaling routes might play a role in the final common pathway of primary renal injury. A role for TLR signaling in the context of renal transplantation is probably limited

S100A8/A9 Is Not Involved in Host Defense against Murine Urinary Tract Infection

Background: Inflammation is commonly followed by the release of endogenous proteins called danger associated molecular patterns (DAMPs) that are able to warn the host for eminent danger. S100A8/A9 subunits are DAMPs that belong to the S100 family of calcium binding proteins. S100A8/A9 complexes induce an inflammatory response and their expression correlates with disease severity in several inflammatory disorders. S100A8/A9 promote endotoxin-and Escherichia (E.) coli-induced sepsis showing its contribution in systemic infection. The role of S100A8/A9 during a local infection of the urinary tract system caused by E. coli remains unknown. Methodology/Principal Findings: We investigated the contribution of S100A8/A9 in acute urinary tract infection (UTI) by instilling 2 different doses of uropathogenic E. coli transurethrally in wild type (WT) and S100A9 knockout (KO) mice. Subsequently, we determined bacterial outgrowth, neutrophilic infiltrate and inflammatory mediators in bladder and kidney 24 and 48 hours later. UTI resulted in a substantial increase of S100A8/A9 protein in bladder and kidney tissue of WT mice. S100A9 KO mice displayed similar bacterial load in bladder or kidney homogenate compared to WT mice using 2 different doses at 2 different time points. S100A9 deficiency had little effect on the inflammatory responses to E. Coli-induced UTI infection, as assessed by myeloperoxidase activity in bladder and kidneys, histopathologic analysis, and renal and bladder cytokine concentrations. Conclusions: We show that despite high S100A8/A9 expression in bladder and kidney tissue upon UTI, S100A8/A9 does not contribute to an effective host response against E. Coli in the urinary tract syste

The Role of Toll-Like Receptor 2 in Inflammation and Fibrosis during Progressive Renal Injury

Tissue fibrosis and chronic inflammation are common causes of progressive organ damage, including progressive renal disease, leading to loss of physiological functions. Recently, it was shown that Toll-like receptor 2 (TLR2) is expressed in the kidney and activated by endogenous danger signals. The expression and function of TLR2 during renal fibrosis and chronic inflammation has however not yet been elucidated. Therefore, we studied TLR2 expression in human and murine progressive renal diseases and explored its role by inducing obstructive nephropathy in TLR2−/− or TLR2+/+ mice. We found that TLR2 is markedly upregulated on tubular and tubulointerstitial cells in patients with chronic renal injury. In mice with obstructive nephropathy, renal injury was associated with a marked upregulation and change in distribution of TLR2 and upregulation of murine TLR2 danger ligands Gp96, biglycan, and HMGB1. Notably, TLR2 enhanced inflammation as reflected by a significantly reduced influx of neutrophils and production of chemokines and TGF-β in kidneys of TLR2−/− mice compared with TLR2+/+ animals. Although, the obstructed kidneys of TLR2−/− mice had less interstitial myofibroblasts in the later phase of obstructive nephropathy, tubular injury and renal matrix accumulation was similar in both mouse strains. Together, these data demonstrate that TLR2 can initiate renal inflammation during progressive renal injury and that the absence of TLR2 does not affect the development of chronic renal injury and fibrosis

An Overview of Pathways of Regulated Necrosis in Acute Kidney Injury

Necrosis is the predominant form of regulated cell death in acute kidney injury (AKI) and represents results in the formation of casts that appear in the urine sedimentation, referred to as muddy brown casts, which are part of the diagnosis of AKI. Pathologists referred to this typical feature as acute tubular necrosis. We are only beginning to understand the dynamics and the molecular pathways that underlie such typical necrotic morphology. In this review, we provide an overview of candidate pathways and summarize the emerging evidence for the relative contribution of these pathways of regulated necrosis, such as necroptosis, ferroptosis, mitochondrial permeability transition-mediated regulated necrosis, parthanatos, and pyroptosis. Inhibitors of each of these pathways are available, and clinical trials may be started after the detection of the most promising drug targets, which will be discussed here. With the global burden of AKI in mind, inhibitiors of regulated necrosis represent promising means to prevent this diseas

Sensing damage by the NLRP3 inflammasome

The NLRP3 inflammasome is activated in response to a variety of signals that are indicative of damage to the host including tissue damage, metabolic stress, and infection. Upon activation, the NLRP3 inflammasome serves as a platform for activation of the cysteine protease caspase-1, which leads to the processing and secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. Dysregulated NLRP3 inflammasome activation is associated with both heritable and acquired inflammatory diseases. Here, we review new insights into the mechanism of NLRP3 inflammasome activation and its role in disease pathogenesi

Pattern recognition receptors and the inflammasome in kidney disease

Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain receptors (NLRs) are families of pattern recognition receptors that, together with inflammasomes, sense and respond to highly conserved pathogen motifs and endogenous molecules released upon cell damage or stress. Evidence suggests that TLRs, NLRs and the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome have important roles in kidney diseases through regulation of inflammatory and tissue-repair responses to infection and injury. In this Review, we discuss the pathological mechanisms that are related to TLRs, NLRs and NLRP3 in various kidney diseases. In general, these receptors are protective in the host defence against urinary tract infection, but can sustain and self-perpetuate tissue damage in sterile inflammatory and immune-mediated kidney diseases. TLRs, NLRs and NLRP3, therefore, have become promising drug targets to enable specific modulation of kidney inflammation and suppression of immunopathology in kidney diseas

Hematopoietic stem cell mobilization therapy accelerates recovery of renal function independent of stem cell contribution

Acute renal failure and tubular cell loss as a result of ischemia constitute major challenges in renal pathophysiology. Increasing evidence suggests important roles for bone marrow stem cells in the regeneration of renal tissue after injury. This study investigated whether the enhanced availability of hematopoietic stem cells, induced by stem cell factor and granulocyte colony-stimulating factor, to the injured kidney provides an adequate strategy for stem cell-based therapy to counteract renal ischemia/reperfusion injury. It is interesting that cytokine treatment before injury resulted in significant enhancement of function recovery of the kidney. This, however, was not due to increased incorporation of tubular epithelial cells from bone marrow origin. Importantly, cytokine treatment resulted in impaired influx of granulocytes into the injured kidney. Although cytokine treatment improved renal function rapidly after ischemic injury, the results show that the underlying mechanism likely is not based on stem cell transdifferentiation but rather on altered inflammatory kinetic

The ISTH-BAT score and outcomes after endometrial ablation in women with heavy menstrual bleeding

BACKGROUND: The International Society on Thrombosis and Haemostasis bleeding assessment tool (ISTH-BAT), is used during the diagnostic workup of bleeding disorders. Data on ISTH-BAT scores in women with heavy menstrual bleeding (HMB) undergoing endometrial ablation (EA) could be essential in optimizing HMB counselling. OBJECTIVE: To investigate the postsurgical incidence of amenorrhea, dysmenorrhea, quality of life, re-intervention after EA, and ISTH-BAT score. METHODS: This study included women who have undergone EA because of HMB. During a follow-up of 2 to 5 years, ISTH-BAT, pictorial blood assessment chart (PBAC), and Short Form-36 survey (SF-36) were administered. At 10 years of follow-up surgical re-interventions were evaluated. RESULTS: Seventy-one women were included of whom 77% (n = 55) had an ISTH-BAT score < 6, versus 23% (n = 16) ISTH-BAT score =6 (mean age 46.3 versus 42.3, p = 0.004). In the ISTH-BAT =6 group versus < 6 group, amenorrhea occurred in 63% (10/16) versus 82% (45/55) (p = 0.111), dysmenorrhea in 38% (6/16) versus 18% (10/55) (p = 0.111), and surgical re-intervention in 19% (3/16) versus 25% (14/55) (p = 0.582). SF-36 item (Bodily) pain was lower in the ISTH-BAT =6 group versus < 6 (median score 58.7 vs. 80.0, p = 0.104). CONCLUSIONS: An ISTH-BAT score =6 may be related to a lower amenorrhea incidence and higher dysmenorrhea rate after EA