Background: Excessive immune activation leads to secondary injury and impedes injured brain recovery after ischemic stroke. However, few effective methods are currently used for equilibrating immune balance. CD3 + NK1.1 - TCR β + CD4 – CD8 – double-negative T (DNT) cells which do not express NK cell surface markers are unique regulatory cells that maintain homeostasis in several immune-related diseases. However, the therapeutic potential and regulatory mechanism of DNT cells in ischemic stroke are still unknown. Methods: Mouse ischemic stroke is induced by occlusion of the distal branches of the middle cerebral artery (dMCAO). DNT cells were adoptively transferred intravenously into ischemic stroke mice. Neural recovery was evaluated by TTC staining and behavioral analysis. Using immunofluorescence, flow cytometry, and RNA sequencing, the immune regulatory function of DNT cells was investigated at different time points post ischemic stroke. Results: Adoptive transfer of DNT cells significantly reduces infarct volume and improves sensorimotor function after ischemic stroke. DNT cells suppress peripheral Trem1 + myeloid cell differentiation during the acute phase. Furthermore, they infiltrate the ischemic tissue via CCR5 and equilibrate the local immune balance during the subacute phase. During the chronic phase, DNT cells enhance Treg cell recruitment through CCL5, eventually developing an immune homeostatic milieu for neuronal recovery. Conclusions: DNT cell treatment renders the comprehensive anti-inflammatory roles in specific phases of ischemic stroke. Our study suggests that the adoptive transfer of regulatory DNT cells may be a potential cell-based therapy for ischemic stroke.

Theranostics: MRI-Visualized, Dual-Targeting, Combined Tumor Therapy Using Magnetic Graphene-Based Mesoporous Silica (Small 1/2014)

Abstract The mechanism underlying acute kidney injury (AKI) and AKI-to-Chronic kidney disease (CKD) transition remains unclear, but mitochondrial dysfunction may be a key driving factor. Literature reports suggest that dual-specificity phosphatase 1 (DUSP1) plays a critical role in maintaining mitochondrial function and structural integrity. In this study, ischemic Acute Kidney Injury (AKI) and post-ischemic fibrosis models were established by clamping the renal pedicle with different reperfusion times. To investigate the role of DUSP1, constitutional Dusp1 knockout mice and tubular-specific Sting knockout mice were used. Mitochondrial damage was assessed through electron microscopy observation, measurements of mitochondrial membrane potential, mtDNA release, and BAX translocation. We found that Dusp1 expression was significantly upregulated in human transplant kidney tissue and mouse AKI tissue. Dusp1 gene deletion exacerbated acute ischemic injury, post-ischemic renal fibrosis, and tubular mitochondrial dysfunction in mice. Mechanistically, DUSP1 could directly bind to JNK, and DUSP1 deficiency could lead to aberrant phosphorylation of JNK and BAX mitochondria translocation. BAX translocation promoted mitochondrial DNA (mtDNA) leakage and activated the cGAS-STING pathway. Inhibition of JNK or BAX could inhibit mtDNA leakage. Furthermore, STING knockout or JNK inhibition could significantly mitigate the adverse effects of DUSP1 deficiency in ischemic AKI model. Collectively, our findings suggest that DUSP1 is a regulator for the protective response during AKI. DUSP1 protects against AKI by preventing BAX-induced mtDNA leakage and blocking excessive activation of the cGAS-STING signaling axis through JNK dephosphorylation. 

DUSP1 protects against ischemic acute kidney injury through stabilizing mtDNA via interaction with JNK

Abstract The kidney is a vital organ with diverse biological effects and the burden of kidney function impairment is increasing in modern medicine. As the effects from kidney function on diverse biochemical parameters are yet fully understood, additional investigation to reveal the causal effects is warranted. Here we show the causal estimates from kidney function parameter, estimated glomerular filtration rate (eGFR), on 60 biochemical parameters by performing two-sample Mendelian randomization (MR) study in 337,138 white British UK Biobank participants. A higher genetically predicted eGFR was significantly associated with higher lymphocyte percentage, HDL cholesterol, and alanine aminotransferase. The causal estimates indicated that a higher genetically predicted eGFR was associated with lower urea, urate, insulin growth factor-1, and triglycerides levels. The parameters with significant but non-linear causal estimates were hemoglobin concentration, calcium, vitamin D, and urine creatinine values, identified by non-linear MR. Healthcare providers should understand that changes in eGFR may affect the identified biochemical parameters in diverse patterns. Future study is warranted to expand the knowledge of the mechanisms and clinical implications of the causal effects of eGFR on various biochemical parameters. 

/pdf/mendelian-randomization-reveals-causal-effects-of-kidney-35tv0hbp.pdf

Mendelian randomization reveals causal effects of kidney function on various biochemical parameters

Transcriptome profiling of tubulointerstitial tissue in glomerulonephritis may reveal a potential tubulointerstitial injury‐related biomarker. We profiled manually microdissected tubulointerstitial tissue from biopsy cores of 65 glomerulonephritis cases, including 43 patients with IgA nephropathy, 3 with diabetes mellitus nephropathy, 3 with focal segmental glomerulosclerosis, 3 with lupus nephritis, 4 with membranous nephropathy and 9 with minimal change disease, and additional 22 nephrectomy controls by RNA sequencing. A potential biomarker was selected based on the false discovery rate, and experiments were performed in TNF‐α‐stimulated primary cultured human tubular epithelial cells (hTECs). We identified 3037 genes with low expression and 2852 genes with high expression in the disease samples compared to the controls. Dual‐specificity phosphatase 1 (DUSP1) exhibited universal low expression in various diseases (log2 fold change, −3.87), with the lowest false discovery rate (7.03E‐132). In further experimental validation study, DUSP1 overexpression ameliorated inflammatory markers related to MAP kinase pathways in hTECs, while pharmacologic inhibition of DUSP1 increased these markers. The combination of DUSP1 overexpression with low‐concentration corticosteroid treatment resulted in more potent suppression of inflammation than high‐concentration corticosteroid treatment alone. The profiled transcriptomes provide insights into the pathophysiology of tubulointerstitial injury in kidney diseases and may reveal a potential therapeutic biomarker.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/jcmm.17340

RNA‐seq profiling of tubulointerstitial tissue reveals a potential therapeutic role of dual anti‐phosphatase 1 in glomerulonephritis

BACKGROUND
Observational studies investigating the role of vitamin D in renal function have yielded inconsistent results. We tested whether 25-hydroxyvitamin D [25(OH)D] serum levels are associated with renal function, and inversely, whether altered renal function causes changes in 25(OH)D, using Mendelian randomization (MR).


METHODS
In this two-sample MR study, we used single nucleotide polymorphisms (SNP) associated with 25(OH)D in 443,734 Europeans, and their effects on eGFR, Blood Urea Nitrogen [BUN], chronic kidney disease [CKD] risk and progression in genome-wide association studies totaling over 1 million Europeans. To control for pleiotropy, we also used SNPs solely in DHCR7, CYP2R1, GC, all genes with known roles in vitamin D metabolism. We performed a reverse MR, using SNPs for the above indices of renal function to study causal effects on 25(OH)D levels.


RESULTS
We did not find robust evidence supporting effects of 25(OH)D on eGFR, BUN, and CKD or its progression. Our inverse variance weighted MR demonstrated a 0.56 decrease in standardized log-transformed 25(OH)D (95% CI = -0.73, -0.41 P = 2.89 x10-12) per unit increase in log-transformed eGFR. Increased BUN was associated with increased 25(OH)D (β = 0.25, 95% CI = 0.15, 0.36, P = 4.12 × 10-6 per unit increase in log-transformed BUN). Finally, genetically predicted CKD conferred a 0.05 increase in standardized log-transformed 25(OH)D level (95% CI = 0.04,0.06, P = 1.06 x10-13). Other MR methods confirmed the findings of the main analyses.


CONCLUSIONS
Genetically predicted CKD, increased BUN and decreased eGFR are associated with increased 25(OH)D levels, but we found no causal effect of 25(OH)D on renal function in Europeans.

Effects of 25 hydroxyvitamin D levels on renal function: a bidirectional Mendelian randomization study.

Previous observational studies suggested that a reduction in estimated glomerular filtration rate (eGFR) or a supranormal eGFR value was associated with adverse cardiovascular risks. However, a previous Mendelian randomization (MR) study under the linearity assumption reported null causal effects from eGFR on myocardial infarction (MI) risks. Further investigation of the nonlinear causal effect of kidney function assessed by eGFR on the risk of MI by nonlinear MR analysis is warranted.In this MR study, genetic instruments for log-eGFR based on serum creatinine were developed from European samples included in the CKDGen genome-wide association study (GWAS) meta-analysis (N=567,460). Alternate instruments for log-eGFR based on cystatin C were developed from a GWAS of European individuals that included the CKDGen and UK Biobank data (N=460,826). Nonlinear MR analysis for the risk of MI was performed using the fractional polynomial method and the piecewise linear method on data from individuals of white British ancestry in the UK Biobank (N=321,024, with 12,205 MI cases).Nonlinear MR analysis demonstrated a U-shaped (quadratic P value < 0.001) association between MI risk and genetically predicted eGFR (creatinine) values, as MI risk increased as eGFR declined in the low eGFR range and the risk increased as eGFR increased in the high eGFR range. The results were similar even after adjustment for clinical covariates, such as blood pressure, diabetes mellitus, dyslipidemia, or urine microalbumin levels, or when genetically predicted eGFR (cystatin C) was included as the exposure.Genetically predicted eGFR is significantly associated with the risk of MI with a parabolic shape, suggesting that kidney function impairment, either by reduced or supranormal eGFR, may be causally linked to a higher MI risk. 

/pdf/nonlinear-causal-effects-of-estimated-glomerular-filtration-18fdh6g2.pdf

Nonlinear causal effects of estimated glomerular filtration rate on myocardial infarction risks: Mendelian randomization study

ABSTRACT Background The association between visit-to-visit blood pressure (BP) variability and dementia risk in chronic kidney disease (CKD) patients has rarely been studied. Methods In this retrospective observational study, individuals who received three or more general health screenings were identified in the nationwide database of Korea. Those with persistent non-dialysis-dependent CKD [estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or dipstick albuminuria ≥1+] were included. The study exposure was systolic or diastolic BP variability, calculated as the variation independent of the mean and categorized into quartiles (Q4: the highest quartile; Q1: the lowest quartile). The risks of all-cause dementia, including Alzheimer's disease and vascular dementia, were analyzed by Cox regression adjusted for various clinical characteristics, including baseline BP and eGFR values. Results We included 103 139 CKD patients and identified 7574 (7%) dementia events, including 5911 (6%) Alzheimer's disease cases, 886 (1%) vascular dementia events and 777 (1%) cases categorized as other types of dementia. Higher systolic BP variability was significantly associated with higher risks of all-cause dementia {[Q4 versus Q1], hazard ratio [HR] 1.173 [95% confidence interval (CI) 1.102–1.249], P for trend < .001}. The results were also significant for the risk of Alzheimer's disease [HR 1.162 (95% CI 1.083–1.248), P < .001] and vascular dementia [HR 1.282 (95% CI 1.064–1.545), P = .039]. The results were similar when diastolic BP variability was the exposure, as high diastolic BP variability was significantly associated with higher risks of all-cause dementia [HR 1.191 (95% CI 1.117,1.270), P < .001]. Conclusions Higher visit-to-visit BP variability is significantly associated with a higher risk of dementia in CKD patients.

/pdf/association-between-visit-to-visit-blood-pressure-3qt4yed5.pdf

Association between visit-to-visit blood pressure variability and risks of dementia in CKD patients: a nationwide observational cohort study

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Papers

Nonlinear causal effects of estimated glomerular filtration rate on myocardial infarction risks: Mendelian randomization study

Mendelian randomization reveals causal effects of kidney function on various biochemical parameters

RNA‐seq profiling of tubulointerstitial tissue reveals a potential therapeutic role of dual anti‐phosphatase 1 in glomerulonephritis

Association between visit-to-visit blood pressure variability and risks of dementia in CKD patients: a nationwide observational cohort study