Psychiatric use of lithium has been associated with hypoglycemic effects, but its effect on type 1 diabetes mellitus (T1D) is unknown. In streptozotocin (STZ) induced murine models of T1D, microdose ...lithium therapy improved hyperglycemia, attenuated body weight loss and prevented early signs of diabetic kidney injury. This beneficial effect was associated with preservation of pancreatic islet histology and β-cell production of insulin as well as mitigated oxidative damage of islets. Mechanistically, lithium in islets cells induced inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β), the major molecular target of lithium that has been recently implicated in non-canonical regulation of Nrf2 activity. In turn, Nrf2 antioxidant response was potentiated in islets, marked by nuclear translocation of Nrf2 and augmented expression of its target antioxidant enzyme heme oxygenase 1 (HO-1). Conversely, cotreatment with trigonelline, a selective blockade of Nrf2, offset the lithium enhanced Nrf2 antioxidant response in islets, blunted the protective effect of lithium on pancreatic islets and β-cells, and abolished the hypoglycemic activity of lithium in STZ-injured mice. Collectively, our findings suggest that microdose lithium confers a protective effect on islet β-cells via targeting the GSK3β-regulated Nrf2 antioxidant response and thereby ameliorates T1D and its related kidney impairment.
Renal artery stenosis (RAS) is known to co-exist with heart failure (HF), however the impact of RAS on rates of acute kidney injury during an acute HF hospitalization, and adverse events after acute ...HF hospitalizations has not been well studied.
We performed a retrospective cohort study of subjects hospitalized for acute HF at a tertiary academic care center. We identified subjects who had a renal artery duplex ultrasound or other diagnostic study for RAS to categorize heart failure subjects as RAS+ or RAS-. AKI was defined as a rise from admission to peak creatinine of >0.3 mg/dL or >1.5 fold. In-hospital outcomes including rates of AKI were ascertained. Adverse outcomes over a two-year follow up period were also ascertained.
A total of 93 subjects with acute HF hospitalization met the inclusion criteria and were enrolled in this study; 27 (29%) were identified as RAS+. At admission, subjects with RAS had higher rates of diabetes and prior PCI. During the HF hospitalization, subjects with RAS were more likely to develop AKI. No significant differences were identified in baseline or hospital medication use among subjects with versus without RAS. Importantly, the rate of ACE-I/ARB use was low in both groups and no significant difference in ACE-I/ARB use was demonstrated. Subjects with RAS had higher rates of recurrent HF hospitalization during the follow-up period.
RAS is prevalent among subjects with acute HF, associated with higher rates of AKI during HF hospitalization, and associated with higher rates of recurrent HF hospitalization during follow-up.
Clinical use of nonsteroidal anti-inflammatory drugs (NSAIDs) like diclofenac (DCLF) is limited by multiple adverse effects, including renal toxicity leading to acute kidney injury. In mice with ...DCLF-induced nephrotoxicity, TDZD-8, a selective glycogen synthase kinase (GSK)3β inhibitor, improved acute kidney dysfunction and ameliorated tubular necrosis and apoptosis associated with induced cortical expression of cyclooxygenase-2 (COX-2) and prostaglandin E2. This renoprotective effect was blunted but still largely preserved in COX-2-null mice, suggesting that other GSK3β targets beyond COX-2 functioned in renal protection. Indeed, TDZD-8 diminished the mitochondrial permeability transition in DCLF-injured kidneys. In vitro, GSK3β inhibition reinstated viability and suppressed necrosis and apoptosis in DCLF-stimulated tubular epithelial cells. DCLF elicited oxidative stress, enhanced the activity of the redox-sensitive GSK3β, and promoted a mitochondrial permeability transition by interacting with cyclophilin D, a key component of the mitochondrial permeability transition pore. TDZD-8 blocked GSK3β activity and prevented GSK3β-mediated cyclophilin D phosphorylation and the ensuing mitochondrial permeability transition, concomitant with normalization of intracellular ATP. Conversely, ectopic expression of a constitutively active GSK3β abolished the effects of TDZD-8. Hence, inhibition of GSK3β ameliorates NSAID-induced acute kidney injury by induction of renal cortical COX-2 and direct inhibition of the mitochondrial permeability transition.
Viral entry mechanisms for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are an important aspect of virulence. Proposed mechanisms involve host cell membrane-bound ...angiotensin-converting enzyme 2 (ACE2), type II transmembrane serine proteases (TTSPs), such as transmembrane serine protease isoform 2 (TMPRSS2), lysosomal endopeptidase Cathepsin L (CTSL), subtilisin-like proprotein peptidase furin (FURIN), and even potentially membrane bound heparan sulfate proteoglycans. The distribution and expression of many of these genes across cell types representing multiple organ systems in healthy individuals has recently been demonstrated. However, comorbidities such as diabetes and cardiovascular disease are highly prevalent in patients with Coronavirus Disease 2019 (COVID-19) and are associated with worse outcomes. Whether these conditions contribute directly to SARS-CoV-2 virulence remains unclear. Here, we show that the expression levels of ACE2, TMPRSS2 and other viral entry-related genes, as well as potential downstream effector genes such as bradykinin receptors, are modulated in the target organs of select disease states. In tissues, such as the heart, which normally express ACE2 but minimal TMPRSS2, we found that TMPRSS2 as well as other TTSPs are elevated in individuals with comorbidities compared to healthy individuals. Additionally, we found the increased expression of viral entry-related genes in the settings of hypertension, cancer, or smoking across target organ systems. Our results demonstrate that common comorbidities may contribute directly to SARS-CoV-2 virulence and we suggest new therapeutic targets to improve outcomes in vulnerable patient populations.
Reactive oxygen species are thought to be critical inducers of renal inflammation and destruction. We examined the effects of candesartan, a highly selective angiotensin II type I receptor (AT1R) ...blocker, on renal inflammation and oxidative stress. Candesartan suppressed TNF-induced chemokine expression and NFκB activation independent of AT1R blockade in cultured renal tubular epithelial cells. This receptor blocker decreased reactive oxygen generation elicited by either TNF or the pro-oxidant hydrogen peroxide and reinstated redox homeostasis, suggesting a direct antioxidant effect. This result was unique to candesartan among several angiotensin II receptor blockers and occurred in cells lacking the AT1R. A dose 5 times the standard therapeutic dose lessened renal inflammation and suppressed tubular NFκB activation in spontaneously hypertensive rats. An ultrahigh dose (15 times standard) produced an even greater beneficial effect. Angiotensin II infusion did not cause any hemodynamic changes at either candesartan dose denoting a complete blockade of systemic and renal AT1R. There was, however, a dose-dependent improvement of renal redox homeostasis. Our study suggests that candesartan suppresses redox-sensitive NFκB-mediated renal inflammation by a direct antioxidant effect independent of AT1R blockade.
Soluble CD40 ligand (sCD40L) has been implicated in the development of renal injury. The CD40 receptor exists in a soluble form, sCD40R, and has been shown to function as a competitive antagonist ...against CD40 activation. We analyzed whether plasma levels of sCD40L and sCD40R predict changes in renal function in an all-cause chronic kidney disease (CKD) cohort. Stratification of subjects based on sCD40L and sCD40R individually, as well as in combination, demonstrated that sCD40L was directly associated with declines in estimated glomerular filtration rate (eGFR). sCD40R was negatively associated with declines in eGFR. Baseline characteristics following stratification, including systolic blood pressure, history of diabetes mellitus or peripheral vascular disease, primary renal disease classification, and angiotensin converting enzyme inhibitor or angiotensin receptor blocker usage were not significantly different. High sCD40L and low sCD40R were both found to be independent predictors of a decline in eGFR at 1-year follow-up (-7.57%, p = 0.014; -6.39%, p = 0.044). Our data suggest that circulating levels of sCD40L and sCD40R are associated with changes in renal function in patients with CKD. The CD40 decoy receptor, sCD40R, may serve as a potential therapeutic target to attenuate renal function decline.
Randomized clinical trials have not shown an additional clinical benefit of renal artery stent placement over optimal medical therapy alone. However, studies of renal artery stent placement have not ...examined the relationship of albuminuria and treatment group outcomes. The CORAL study (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) is a prospective clinical trial of 947 participants with atherosclerotic renal artery stenosis randomized to optimal medical therapy with or without renal artery stent which showed no treatment differences (3(5.8% and 35.1% event rate at mean 43-month follow-up). In a post hoc analysis, the study population was stratified by the median baseline urine albumin/creatinine ratio (n=826) and analyzed for the 5-year incidence of the primary end point (myocardial infarction, hospitalization for congestive heart failure, stroke, renal replacement therapy, progressive renal insufficiency, or cardiovascular disease- or kidney disease-related death), for each component of the primary end point, and overall survival. When baseline urine albumin/creatinine ratio was ≤ median (22.5 mg/g, n=413), renal artery stenting was associated with significantly better event-free survival from the primary composite end point (73% versus 59% at 5 years; P=0.02), cardiovascular disease-related death (93% versus 85%; P≤ 0.01), progressive renal insufficiency (91% versus 77%; P=0.03), and overall survival (89% versus 76%; P≤0.01), but not when baseline urine albumin/creatinine ratio was greater than median (n=413). These data suggest that low albuminuria may indicate a potentially large subgroup of those with renal artery stenosis that could experience improved event-free and overall-survival after renal artery stent placement plus optimal medical therapy compared with optimal medical therapy alone. Further research is needed to confirm these preliminary observations.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT00081731.
Atherosclerotic renal artery stenosis may cause kidney function loss, but effects of stenting on eGFR and clinical events associated with CKD are uncertain. Our study objectives were to determine ...effects of stenting on eGFR and predictors of clinical events.
Participants (n=931) in the Cardiovascular Outcomes in Renal Artery Stenosis Trial (from May of 2005 to September of 2012) had >60% atherosclerotic renal artery stenosis and systolic hypertension on two or more antihypertensive drugs and/or stage ≥3 CKD. The intervention was stenting versus no stenting on a background of risk factor management: renin-angiotensin system inhibition, statin, antiplatelet therapy, and smoking cessation education. The effect of stenting on eGFR by the serum creatinine-cystatin C Chronic Kidney Disease Epidemiology Collaboration equation was the prespecified analysis of kidney function. Predictors of eGFR and CKD outcomes (≥30% eGFR loss, ESRD, and death) and cardiovascular disease outcomes (stroke, myocardial infarction, heart failure, and death) controlling for eGFR and albuminuria were also determined.
eGFR was 59±24 ml/min per 1.73 m(2) (mean±SD) at baseline. Over 3 years, eGFR change, assessed by generalized estimating equations, was -1.5±7.0 ml/min per 1.73 m(2) per year in the stent group versus -2.3±6.3 ml/min per 1.73 m(2) per year in the medical therapy only group (P=0.18). eGFR predictors (multiple variable generalized estimating equations) were age, albuminuria, systolic BP, and diabetes (inverse associations) as well as men, total cholesterol, and HDL cholesterol (positive associations). CKD outcomes events occurred in 19% (175 of 931), and predictors (Cox proportional hazards models) included albuminuria (positive association), systolic BP (positive association), and HDL cholesterol (inverse association). Cardiovascular disease outcomes events occurred in 22% (207 of 931), and predictors included age, albuminuria, total cholesterol, prior cardiovascular disease, and bilateral atherosclerotic renal artery stenosis (positive associations).
Stenting did not influence eGFR in participants with atherosclerotic renal artery stenosis receiving renin-angiotensin system inhibition-based therapy. Predictors of clinical events were traditional risk factors for CKD and cardiovascular disease.
Multiple randomized clinical trials comparing renal artery stent placement plus medical therapy with medical therapy alone have not shown any benefit of stent placement. However, debate continues ...whether patients with extreme pressure gradients, stenosis severity, or baseline blood pressure benefit from stent revascularization.
The study sought to test the hypothesis that pressure gradients, stenosis severity, and/or baseline blood pressure affects outcomes after renal artery stent placement.
Using data from 947 patients with a history of hypertension or chronic kidney disease from the largest randomized trial of renal artery stent placement, the CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) study, we performed exploratory analyses to determine if subsets of patients experienced better outcomes after stent placement than the overall cohort. We examined baseline stenosis severity, systolic blood pressure, and translesion pressure gradient (peak systolic and mean) and performed interaction tests and Cox proportional hazards analyses for the occurrence of the primary endpoint through all follow-up, to examine the effect of these variables on outcomes by treatment group.
There were no statistically significant differences in outcomes based on the examined variables nor were there any consistent nonsignificant trends.
Based on data from the CORAL randomized trial, there is no evidence of a significant treatment effect of the renal artery stent procedure compared with medical therapy alone based on stenosis severity, level of systolic blood pressure elevation, or according to the magnitude of the trans-stenotic pressure gradient. (Benefits of Medical Therapy Plus Stenting for Renal Atherosclerotic Lesions CORAL; NCT00081731).
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