Renal ischemia/reperfusion injury (IRI) is a significant challenge in perioperative medicine and is related to oxidative programmed cell death. However, the role of ferroptosis, a newly discovered form of oxidative cell death, has not been evaluated widely. Pannexin 1 (PANX1), an ATP-releasing pathway family protein, has pro-apoptotic effects during kidney injury. Here, we demonstrate that PANX1 deletion protects against renal IRI by regulating ferroptotic cell death. Panx1 knockout mice subjected to renal IRI had decreased plasma creatinine, malondialdehyde (MDA) levels in kidney tissues, and tubular cell death (visible as decreased TUNEL-positive renal tubular cells) compared with WT mice. In cultured human kidney 2 (HK-2) cells, silenced Panx1 expression significantly attenuated ferroptotic lipid peroxidation and iron accumulation induced by the ferroptosis inducer erastin. Moreover, the Panx1 silencing significantly modulated ferroptosis-related protein expression. Furthermore, Panx1 deletion induced the expression of a cytoprotective chaperone, heme oxygenase-1 (HO-1), and inhibited ferroptinophagy via the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. In summary, Panx1 deletion protects against renal IRI by attenuating MAPK/ERK activation in a ferroptotic pathway. Our findings provide critical insights into the role of PANX1 in ferroptotic cell death and highlight a potential therapeutic target for the management of acute kidney injury (AKI) during the perioperative period.Acute kidney injury (AKI) 2 is a frequent complication after cardiac surgery, which contributes to increased mortality, and
AIM:To evaluate the impact of pharmaceutical care on the clinical outcomes of patients enrolled in a pharmacist-coordinated diabetes management program in a rural health setup.SETTINGS AND DESIGN:Patients were registered into ‘control’ and ‘intervention’ groups by randomization at three primary health centers. The study was an open-label parallel study.MATERIALS AND METHODS:Medical records were prospectively reviewed. Capillary blood glucose level, blood pressure and demographic data were collected at baseline and at the follow-up visits. Pharmacists gave counseling to the intervention group during every visit and their health-related quality of life (HRQoL) was assessed with the Ferrans and Powers questionnaire.STATISTICAL ANALYSIS:Single factor ANOVA and the t-test were used to compare the results using SPSS version 0.9 software and MS Excel worksheets.RESULTS:The intervention group (n = 104) showed well-controlled BMI, whereas the control group (n = 50) showed significant increase in the BMI. Mean blood glucose level in the intervention group reduced to 25 units from baseline (P = 0.0001) but was significantly increased in the control group (P = 0.0001). ANOVA showed that from the second follow-up onward there was significant decrease in blood glucose levels. Overall, the HRQoL scores increased by 45% in the intervention group and decreased by 2% in the control group.CONCLUSIONS:The pharmaceutical care program was effective in improving the clinical outcome and HRQoL of diabetes patients in rural India. Such ‘pharmaceutical care’ models should be fine-tuned and implemented widely.
Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently not available. To address this, we characterize five candidate biomarkers of kidney fibrosis: Cadherin-11 (CDH11), Sparc-related modular calcium binding protein-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-Gla protein, and Thrombospondin-2. Gene expression profiles in single-cell and single-nucleus RNA-sequencing (sc/snRNA-seq) datasets from rodent models of fibrosis and human chronic kidney disease (CKD) were explored, and Luminex-based assays for each biomarker were developed. Plasma and urine biomarker levels were measured using independent prospective cohorts of CKD: the Boston Kidney Biopsy Cohort, a cohort of individuals with biopsyconfirmed semiquantitative assessment of kidney fibrosis, and the Seattle Kidney Study, a cohort of patients with common forms of CKD. Ordinal logistic regression and Cox proportional hazards regression models were used to test associations of biomarkers with interstitial fibrosis and tubular atrophy and progression to end-stage kidney disease and death, respectively. Sc/snRNA-seq data confirmed cell-specific expression of biomarker genes in fibroblasts. After multivariable adjustment, higher levels of plasma CDH11, SMOC2, and PEDF and urinary CDH11 and PEDF were significantly associated with increasing severity of interstitial fibrosis and tubular atrophy in the Boston Kidney Biopsy Cohort. In both cohorts, higher levels of plasma and urinary SMOC2 and urinary CDH11 were independently associated with progression to end-stage kidney disease. Higher levels of urinary PEDF associated with end-stage kidney disease in the Seattle Kidney Study, with a similar signal in the Boston Kidney Biopsy Cohort, although the latter narrowly missed statistical significance. Thus, we identified CDH11, SMOC2, and PEDF as promising non-invasive biomarkers of kidney fibrosis.
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