Abstract 109: Gamma-adducin Effects on Microvascular Function- a Common Link of Hypertension Induced Chronic Kidney Disease and Cognitive Impairments

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Fan Fan ◽  
Shaoxun Wang ◽  
Paige N Mims ◽  
Chao Zhang ◽  
Richard J Roman
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Genetic Model ◽  
Cognitive Impairments ◽  
Microvascular Dysfunction ◽  
Small Region ◽  
Glomerular Injury ◽  
Flow Pressure ◽  
Underlying Mechanisms ◽  
Stop Flow

Chronic kidney disease (CKD) and cognitive impairments are common complications of hypertension. Increasing evidence suggests that the cognitive impairments associated with CKD may be related to microvascular dysfunction, however, the underlying mechanisms remain to be elucidated. FHH is a genetic model of hypertension-induced nephropathy. We found that the myogenic response and autoregulation of the renal and cerebral circulation is impaired in FHH rats, and was restored in a FHH.1 BN congenic strain in which a small region of Chr. 1 containing 15 genes, including Add3, from BN rats was transferred into the FHH background. The present study examined whether Add3 contributes to hypertension related CKD, and is associated with the development of cognitive impairments due to microvascular dysfunction. FHH rats exhibited impaired autoregulation of RBF in comparison with FHH.1 BN rats. Pgc estimated from the stop flow pressure increased by 20 mmHg in FHH rats when RPP was increased from 100 to 140 mmHg versus only 4 mmHg in FHH.1 BN . FHH rats developed severe renal injury, and proteinuria rose from 37 ± 2 to 260 ± 32 mg/day as they aged from 12 to 21 weeks, but rose by a significant lesser extent in FHH.1 BN and FHH.Add3 rats. Glomerular injury scores were 3.31 ± 0.01, 2.54 ± 0.01 and 2.50 ± 0.03, and areas of fibrosis in renal cortex were 23.57 ± 1.04%, 8.28 ± 0.33 and 4.71 ± 0.3 in DOCA/salt induced hypertensive FHH, FHH.1 BN and FHH.Add3 rats, respectively. CBF rose by 99 ± 7%, 64 ± 5% and 42 ± 4% in FHH, FHH.1 BN and FHH.Add3 rats, respectively, when MAP was increased from 100 to 190 mmHg, demonstrating impaired autoregulation of CBF in FHH rats was partially rescued with the replacement of wildtype Add3. BBB leakage was greater in FHH rats than in FHH.1 BN and FHH.Add3 rats, and hypertensive FHH rats exhibited marked neurodegeneration and vascular remodeling of the neocortex and hippocampus. The hypertensive FHH rats took 2.5 times longer time to escape from an eight-arm water maze in comparison to FHH.1 BN rats suggesting cognitive deficit. These results indicate that Add3 may play a role in the development of hypertension related CKD and cognitive impairments in FHH rats associated with microvascular dysfunction.

Does Vitamin K Intake Influence High Phosphate Induced Vascular Pseudo-ossification: An Underappreciated Therapeutic Prospect in General Population?

2019 ◽  
Vol 20 (4) ◽  
pp. 421-430
Author(s):  
Zar Chi Thent ◽  
Gabriele R.A. Froemming ◽  
Suhaila Abd Muid
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Vascular Calcification ◽  
Vitamin K ◽  
Prolonged Exposure ◽  
Vascular Complication ◽  
Key Factors ◽  
The Matrix ◽  
Underlying Mechanisms ◽  
High Phosphate

Increasing interest in vascular pseudo-ossification has alarmed the modern atherosclerotic society. High phosphate is one of the key factors in vascular pseudo ossification, also known as vascular calcification. The active process of deposition of the phosphate crystals in vascular tissues results in arterial stiffness. High phosphate condition is mainly observed in chronic kidney disease patients. However, prolonged exposure with high phosphate enriched foods such as canned drinks, dietary foods, etc. can be considered as modifiable risk factors for vascular complication in a population regardless of chronic kidney disease. High intake of vitamin K regulates the vascular calcification by exerting its anti-calcification effect. The changes in serum phosphate and vitamin K levels in a normal individual with high phosphate intake are not well investigated. This review summarised the underlying mechanisms of high phosphate induced vascular pseudo ossification such as vascular transdifferentiation, vascular apoptosis and phosphate uptake by sodium-dependent co-transporters. Pubmed, Science Direct, Scopus, ISI Web of Knowledge and Google Scholar were searched using the terms ‘vitamin K’, ‘vascular calcification, ‘phosphate’, ‘transdifferentiation’ and ‘vascular pseudoossification’. Vitamin K certainly activates the matrix GIA protein and inhibits vascular transition and apoptosis in vascular pseudo-ossification. The present view highlighted the possible therapeutic linkage between vitamin K and the disease. Understanding the role of vitamin K will be considered as potent prophylaxis agent against the vascular disease in near future.

scholarly journals NLRP3 Deficiency Attenuates Renal Fibrosis and Ameliorates Mitochondrial Dysfunction in a Mouse Unilateral Ureteral Obstruction Model of Chronic Kidney Disease

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Honglei Guo ◽  
Xiao Bi ◽  
Ping Zhou ◽  
Shijian Zhu ◽  
Wei Ding
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Mitochondrial Dysfunction ◽  
Ureteral Obstruction ◽  
Renal Fibrosis ◽  
Unilateral Ureteral Obstruction ◽  
Tubulointerstitial Fibrosis ◽  
Mitochondrial Morphology ◽  
Glomerular Injury ◽  
Matrix Deposition

Background and Aims. The nucleotide-binding domain and leucine-rich repeat containing PYD-3 (NLRP3) inflammasome has been implicated in the pathogenesis of chronic kidney disease (CKD); however, its exact role in glomerular injury and tubulointerstitial fibrosis is still undefined. The present study was performed to identify the function of NLRP3 in modulating renal injury and fibrosis and the potential involvement of mitochondrial dysfunction in the murine unilateral ureteral obstruction (UUO) model of CKD. Methods. Employing wild-type (WT) and NLRP3−/− mice with or without UUO, we evaluated renal structure, tissue injury, and mitochondrial ultrastructure, as well as expression of some vital molecules involved in the progression of fibrosis, apoptosis, inflammation, and mitochondrial dysfunction. Results. The severe glomerular injury and tubulointerstitial fibrosis induced in WT mice by UUO was markedly attenuated in NLRP3−/− mice as evidenced by blockade of extracellular matrix deposition, decreased cell apoptosis, and phenotypic alterations. Moreover, NLRP3 deletion reversed UUO-induced impairment of mitochondrial morphology and function. Conclusions. NLRP3 deletion ameliorates mitochondrial dysfunction and alleviates renal fibrosis in a murine UUO model of CKD.

scholarly journals Role of mitochondria-derived reactive oxygen species in microvascular dysfunction in chronic kidney disease

2018 ◽  
Vol 314 (3) ◽  
pp. F423-F429 ◽  
Author(s):  
Danielle L. Kirkman ◽  
Bryce J. Muth ◽  
Meghan G. Ramick ◽  
Raymond R. Townsend ◽  
David G. Edwards
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Local Heating ◽  
Reactive Oxygen ◽  
Microvascular Dysfunction ◽  
Healthy Controls ◽  
Oxygen Species ◽  
Cutaneous Vasodilation

Cardiovascular disease is the leading cause of mortality in chronic kidney disease (CKD). Mitochondrial dysfunction secondary to CKD is a potential source of oxidative stress that may impair vascular function. This study sought to determine if mitochondria-derived reactive oxygen species contribute to microvascular dysfunction in stage 3–5 CKD. Cutaneous vasodilation in response to local heating was assessed in 20 CKD patients [60 ± 13 yr; estimated glomerular filtration rate (eGFR) 46 ± 13 ml·kg−1·1.73 m−2] and 11 matched healthy participants (58 ± 2 yr; eGFR >90 ml·kg−1·1.73 m−2). Participants were instrumented with two microdialysis fibers for the delivery of 1) Ringer solution, and 2) the mitochondria- specific superoxide scavenger MitoTempo. Skin blood flow was measured via laser Doppler flowmetry during standardized local heating (42°C). Cutaneous vascular conductance (CVC) was calculated as a percentage of the maximum conductance achieved with sodium nitroprusside infusion at 43°C. Urinary isofuran/F2-isoprostane ratios were assessed by gas-chromatography mass spectroscopy. Isofuran-to-F2-isoprostane ratios were increased in CKD patients (3.08 ± 0.32 vs. 1.69 ± 0.12 arbitrary units; P < 0.01) indicative of mitochondria-derived oxidative stress. Cutaneous vasodilation was impaired in CKD compared with healthy controls (87 ± 1 vs. 92 ± 1%CVCmax; P < 0.01). Infusion of MitoTempo significantly increased the plateau phase CVC in CKD patients (CKD Ringer vs. CKD MitoTempo: 87 ± 1 vs. 93 ± 1%CVCmax; P < 0.01) to similar levels observed in healthy controls ( P = 0.9). These data provide in vivo evidence that mitochondria-derived reactive oxygen species contribute to microvascular dysfunction in CKD and suggest that mitochondrial dysfunction may be a potential therapeutic target to improve CKD-related vascular dysfunction.

scholarly journals Insulinoma and Chronic Kidney Disease: An Uncommon Conundrum Not to Be Overlooked

2017 ◽  
Vol 10 ◽  
pp. 117955141774262 ◽  
Author(s):  
Luca Foppiani ◽  
Serena Panarello ◽  
Marco Filauro ◽  
Maria Concetta Scirocco ◽  
Stefano Cappato ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Pancreatic Head ◽  
Small Region ◽  
Uncinate Process ◽  
Positron Emission ◽  
Long Term Follow Up ◽  
Histology And Immunohistochemistry

A hypertensive man with chronic kidney disease (CKD) secondary to polycystic disease was hospitalized for symptoms related to hypoglycemia. Fasting test elicited symptomatic hypoglycemia after 12 hours, which was associated with inappropriately unsuppressed normal insulin and C-peptide levels. Neither ultrasonography (US) nor magnetic resonance imaging detected any pancreatic tumor. Endoscopic ultrasonography (EUS) showed a small isoechogenic nodule suspect for neuroendocrine tumor in the pancreatic head. 68Gallium-DOTA-Tyr3-octreotide positron emission tomography/computed tomography revealed intense uptake by a small region in the pancreatic head. Surgical exploration together with intraoperative US confirmed the nodule in the pancreatic head and evidenced another hypoechogenic one in the uncinate process. Both nodules were enucleated, but only the latter, which had not been previously detected by EUS, proved compatible with insulinoma on combined histology and immunohistochemistry. After nodule enucleation, hypoglycemia resolved and did not relapse. Insulinoma, as a major cause of unexplained hypoglycemia, requires careful hormonal and instrumental workup. In patients with CKD, the interpretation of biochemical criteria for the diagnosis of insulinoma can be challenging. Localization techniques may display pitfalls. Surgery is curative in most patients but long-term follow-up is required.

Immunity

2015 ◽  
Author(s):  
Behdad Afzali ◽  
Claudia Kemper
Keyword(s):  
Chronic Kidney Disease ◽  
Immune System ◽  
Kidney Disease ◽  
Causes Of Death ◽  
Immune Responsiveness ◽  
Pregnancy Failure ◽  
Acquired Immunodeficiency ◽  
Underlying Mechanisms ◽  
Almost All ◽  
Fetal Antigens

Immunological health relies on a balance between immune responsiveness to foreign pathogens and tolerance to self-components, commensals, food-derived components, and semi-allogeneic fetal antigens. Disruptions of this balance are hallmarks of immunodeficiency diseases, autoimmune diseases, and pregnancy failure. Patients with chronic kidney disease are immunologically unique in demonstrating features of both chronic inflammation and acquired immunodeficiency—predisposing these individuals to the two commonest causes of death, namely cardiovascular disease and sepsis. Defects and abnormalities in almost all components of the immune system can be observed, although it is difficult to say whether the observations denote mechanism or effect. This chapter reviews, briefly, measurable immune system abnormalities in chronic kidney disease and some of the potential underlying mechanisms.

scholarly journals Nicorandil, a Katp channel opener, alleviates chronic renal injury by targeting podocytes and macrophages

2012 ◽  
Vol 303 (3) ◽  
pp. F339-F349 ◽  
Author(s):  
Yoshifuru Tamura ◽  
Katsuyuki Tanabe ◽  
Wataru Kitagawa ◽  
Shunya Uchida ◽  
George F. Schreiner ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Xanthine Oxidase ◽  
Renal Injury ◽  
Vascular System ◽  
K Channel ◽  
Sulfonylurea Receptor ◽  
Glomerular Injury ◽  
Tubulointerstitial Injury

Nicorandil exhibits a protective effect in the vascular system, which is thought to be due to vasodilatation from opening ATP-dependent potassium channels and donation of nitric oxide. Recently, nicorandil was shown to be renoprotective in models of acute kidney injury and glomerulonephritis. However, the specific mechanisms of renoprotection are unclear. We evaluated the effect of nicorandil on the rat remnant kidney model of chronic kidney disease. Blood pressure was unchanged by a 10-wk course of nicorandil, while albuminuria was significantly reduced. Glomerular injury and tubulointerstitial injury were also ameliorated by nicorandil. Oxidative stress, as noted by renal nitrotyrosine level and urine 8-hydroxy-2′-deoxyguanosine, were elevated in this model and was significantly reduced by nicorandil treatment. Treatment was associated with maintenance of the mitochondrial antioxidant, manganese SOD, in podocytes and with suppression of xanthine oxidase expression in infiltrating macrophages. Interestingly, these two cell types express sulfonylurea receptor 2 (SUR2), a binding site of nicorandil in the ATP-dependent K channel. Consistently, we found that stimulating SUR2 with nicorandil prevented angiotensin II-mediated upregulation of xanthine oxidase in the cultured macrophage, while xanthine oxidase expression was rather induced by blocking SUR2 with glibenclamide. In conclusion, nicorandil reduces albuminuria and ameliorates renal injury by blocking oxidative stress in chronic kidney disease.

Questioning the renoprotective role of L-type calcium channel blockers in chronic kidney disease using physiological modeling

2021 ◽  
Vol 321 (4) ◽  
pp. F548-F557
Author(s):  
Kyle H. Moore ◽  
John S. Clemmer
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Calcium Channel ◽  
Disease Progression ◽  
Physiological Model ◽  
Tubuloglomerular Feedback ◽  
Channel Blockers ◽  
Glomerular Injury ◽  
Kidney Disease Progression ◽  
Clinical Trial Results

Our physiological model replicates clinical trial results and provides unique insights into possible mechanisms that play a role in glomerular injury and hypertensive kidney disease progression during chronic calcium channel blocker (CCB) therapy. Specifically, these simulations predict the temporal changes in renal function with CCB treatment and demonstrate important roles for tubuloglomerular feedback and efferent arteriolar conductance in the control of chronic kidney disease progression.

Paricalcitol, Microvascular and Endothelial Function in Non-Diabetic Chronic Kidney Disease: A Randomized Trial

2015 ◽  
Vol 42 (4) ◽  
pp. 265-273 ◽  
Author(s):  
Kristina Lundwall ◽  
Gun Jörneskog ◽  
Stefan H. Jacobson ◽  
Jonas Spaak
Keyword(s):  
Chronic Kidney Disease ◽  
Vitamin D ◽  
Kidney Disease ◽  
Endothelial Function ◽  
Muscle Sympathetic Nerve Activity ◽  
Microvascular Dysfunction ◽  
Diabetic Patients ◽  
Sympathetic Activation ◽  
Double Blind

Background: Vitamin D deficiency, sympathetic activation and endothelial dysfunction are associated with increased cardiovascular risk in patients with chronic kidney disease (CKD). Studies have so far failed to establish the role of vitamin D and vitamin D receptor activator (VDRA) treatment in moderate CKD. This trial was designed to assess whether VDRA treatment can ameliorate sympathetic activation and macro- and microvascular dysfunction in non-diabetic patients with moderate CKD. Methods: We conducted a randomized controlled double-blind trial using placebo, 1 or 2 μg of paricalcitol, a VDRA, for 3 months. We assessed muscle sympathetic nerve activity (MSNA) by microneurography, pulse wave velocity (PWV) by tonometry, flow mediated vasodilatation (FMD) by brachial ultrasound, skin microcirculation assessed by iontophoresis and capillary blood velocity (CBV) by videophotometric capillaroscopy. Results: Thirty-six patients with a mean age of 65 years and mean estimated glomerular filtration rate of 40 ml/min/1.73 m2 were included. We found a significant decline in endothelial function after 3 months, except in the group receiving 2 μg of paricalcitol. The higher dose (2 μg) seemed to attenuate the decline in microvascular endothelial function, assessed by iontophoresis of acetylcholine (p = 0.06 for all groups, p = 0.65 for the 2 μg group) and for FMD (p = 0.006 for all groups, p = 0.54 for the 2 μg group). We found a borderline significance (p = 0.05) for improved CBV in the treated groups. We found no significant changes between treatments in MSNA, PWV or albuminuria. Conclusions: Endothelial function declined significantly over 3 months in patients with moderate CKD, and this decline could be ameliorated by VDRA treatment (NCT01204528).

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