elastin and Renal-Insufficiency--Chronic

Patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) have significant cardiovascular morbidity and mortality that is in part due to the development of vascular calcification. Vascular calcification is an active, highly regulated process that shares many similarities with normal bone formation. New discoveries related to extracellular vesicles, microRNAs, and calciprotein particles continue to reveal the mechanisms that are involved in the initiation and progression of vascular calcification in CKD. Further innovations in these fields are critical for the development of biomarkers and therapeutic options for patients with CKD and ESRD.

Topics: Calcium; Disease Progression; Elastin; Humans; Kidney Failure, Chronic; Muscle, Smooth, Vascular; Phosphorus; Renal Insufficiency, Chronic; Risk Factors; Vascular Calcification

Cardiovascular complications are accompanied by life-threatening complications and represent the major cause of death in patients with chronic kidney disease (CKD). Magnesium is important for the physiology of cardiac function, and its deficiency is common in CKD. In the present study, we investigated the impact of oral magnesium carbonate supplementation on cardiac function in an experimental model of CKD induced in Wistar rats by an adenine diet. Echocardiographic analyses revealed restoration of impaired left ventricular cardiac function in animals with CKD. Cardiac histology and real-time PCR confirmed a high amount of elastin protein and increased collagen III expression in CKD rats supplemented with dietary magnesium as compared with CKD controls. Both structural proteins are crucial in maintaining cardiac health and physiology. Aortic calcium content increased in CKD as compared with tissue from control animals. Magnesium supplementation numerically lowered the increases in aortic calcium content as it remained statistically unchanged, compared with controls. In summary, the present study provides evidence for an improvement in cardiovascular function and aortic wall integrity in a rat model of CKD by magnesium, as evidenced by echocardiography and histology.

Topics: Animals; Calcium; Elastin; Magnesium; Rats; Rats, Wistar; Renal Insufficiency, Chronic; Uremia

Topics: Animals; Biological Products; Blood Pressure; Body Weight; Breast Neoplasms; Capillary Permeability; Disease Models, Animal; Elastin; Female; Gene Expression; Glomerular Filtration Rate; Heterografts; Humans; Hypotension; Mice; Molecular Mimicry; Neovascularization, Pathologic; Neovascularization, Physiologic; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins; Renal Insufficiency, Chronic; Swine; Toxicity Tests, Chronic; Vascular Endothelial Growth Factor A; X-Ray Microtomography

Chronic kidney disease (CKD) universally associates with renal microvascular rarefaction and inflammation, but whether a link exists between these 2 processes is unclear. We designed a therapeutic construct of VEGF (vascular endothelial growth factor) fused to an ELP (elastin-like polypeptide) carrier and show that it improves renal function in experimental renovascular disease. We test the hypothesis that ELP-VEGF therapy will improve CKD, and that recovery will be driven by decreasing microvascular rarefaction partly via modulation of macrophage phenotype and inflammation. CKD was induced in 14 pigs, which were observed for 14 weeks. At 6 weeks, renal blood flow and filtration were quantified using multidetector computed tomography, and then pigs received single intrarenal ELP-VEGF or placebo (n=7 each). Renal function was quantified again 4 and 8 weeks later. Pigs were euthanized and renal microvascular density, angiogenic and inflammatory markers, fibrosis, macrophage infiltration, and phenotype were quantified. Loss of renal hemodynamics in CKD was progressively recovered by ELP-VEGF therapy, accompanied by improved renal microvascular density, fibrosis, and expression of inflammatory mediators. Although renal macrophage infiltration was similar in both CKD groups, ELP-VEGF therapy distinctly shifted their phenotype from proinflammatory M1 to VEGF-expressing M2. Our study unravels potential mechanisms and feasibility of a new strategy to offset progression of CKD using drug-delivery technologies. The results indicate that renal recovery after ELP-VEGF therapy was largely driven by modulation of renal macrophages toward VEGF-expressing M2 phenotype, restoring VEGF signaling and sustaining improvement of renal function and microvascular integrity in CKD.

Topics: Animals; Biopsy, Needle; Cells, Cultured; Disease Models, Animal; Drug Carriers; Elastin; Immunohistochemistry; Injections, Intralesional; Kidney Function Tests; Macrophages; Microcirculation; Multidetector Computed Tomography; Random Allocation; Recovery of Function; Renal Circulation; Renal Insufficiency, Chronic; Sensitivity and Specificity; Sus scrofa; Tissue and Organ Harvesting; Treatment Outcome; Vascular Endothelial Growth Factor A

Elastin deficiency causes vascular stiffening, a leading risk for hypertension and chronic kidney disease (CKD). The mechanisms mediating hypertension and/or CKD pathogenesis due to elastin deficiency are poorly understood. Using the elastin heterozygous (Eln+/-) mouse model, we tested whether renal dysfunction due to elastin deficiency occurs independently of and precedes the development of hypertension. We assessed blood pressure and renal hemodynamics in 30-day and 12-week-old male and female mice. At P30, blood pressure of Eln+/- mice was similar to wild-type controls; however, renal blood flow was lower, whereas renal vascular resistance was augmented at baseline in Eln+/- mice. At 12 weeks, renal vascular resistance remained elevated while filtration fraction was higher in male Eln+/- relative to wild-type mice. Heterozygous mice showed isolated systolic hypertension that was evident only at nighttime. Acute salt loading with 6% dietary sodium increased daytime systolic blood pressure only in male Eln+/- mice, causing a rightward shift and blunted slope of the pressure-natriuresis curve. Renal interlobar artery basal tone and myogenic response to increasing intraluminal pressure at day 10 were similar, whereas they were augmented at day 30 and at 12 weeks old in Eln+/- mice, and normalized by the AT1R blocker, candesartan. Heterozygous mice also exhibited podocyte foot process damage that persisted even when blood pressure was normalized to wild-type levels with hydralazine. Thus, elastin insufficiency triggers structural defects and abnormal remodeling of renal vascular signaling involving AT1R-mediated vascular mechanotransduction and renal hyperfiltration with increased blood pressure sensitivity to dietary sodium contributing to systolic hypertension.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Disease Models, Animal; Elastin; Female; Humans; Hypertension; Kidney; Male; Mechanotransduction, Cellular; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptor, Angiotensin, Type 1; Renal Elimination; Renal Insufficiency, Chronic; Signal Transduction; Sodium Chloride, Dietary; Tetrazoles; Vascular Resistance

Accelerated elastin degradation is an important pathogenic mechanism in chronic obstructive pulmonary disease (COPD) leading to irreversible lung function loss and cardiovascular comorbidities. The rate of elastin breakdown is a predictor of mortality in patients with COPD. Decelerating elastinolysis might be an attractive therapeutic target in this debilitating condition. Vascular calcification starts in the elastin network of the arterial wall and is enhanced in patients with COPD. Elastin calcification is accompanied by an upregulation of matrix metalloproteinase gene expression and consequently a shift in the elastase/anti-elastase balance towards degradation. Magnesium can be regarded as a natural calcium antagonist and has the proven ability to ameliorate vascular calcification. Furthermore, an animal study has suggested that magnesium deficiency promotes elastin degradation. I hypothesize that inhibiting elastin calcification by means of magnesium supplementation might counteract both vascular calcification and elastin degradation in COPD. This could potentially have a favorable impact on cardiovascular and respiratory related morbidity/mortality in patients with COPD.

Topics: Animals; Elastin; Humans; Magnesium; Magnesium Deficiency; Models, Biological; Proteolysis; Pulmonary Disease, Chronic Obstructive; Renal Insufficiency, Chronic; Vascular Calcification

Elastin deficiency in aging and disease is linked to increased vascular stiffness and hypertension, which are both associated with chronic kidney disease. Owens et al. show that alterations in renal arteries and kidney structure precede or are independent of hypertension in elastin haploinsufficient mice. This commentary addresses the authors' findings in light of the relationships between elastin amounts, vascular stiffness, and pressure wave reflection and transmission in the kidney vasculature.

Topics: Animals; Elastin; Humans; Hypertension; Kidney; Mice; Renal Insufficiency, Chronic; Vascular Stiffness

This study investigated the effects of hypertension on regional aortic biomechanical and structural properties in three rat models of vascular calcification: the hypertensive Lewis polycystic kidney (LPK; n = 13) model of chronic kidney disease, spontaneously hypertensive rats (SHRs; n = 12), and calcification in normotensive Lewis rats induced by vitamin D3 and nicotine (VDN; n = 8). Lewis and Wistar-Kyoto rats were controls. Thoracic and abdominal aortic stiffness parameters were assessed by tensile testing. In models where aortic stiffness differences compared with controls existed in both thoracic and abdominal segments, an additional cohort was quantified by histology for thoracic and abdominal aortic elastin, collagen, and calcification. LPK and VDN animals had higher thoracic breaking strain than control animals (P < 0.01 and P < 0.05, respectively) and lower energy absorption within the tensile curve of the abdominal aorta (P < 0.05). SHRs had a lower abdominal breaking stress than Wistar-Kyoto rats. LPK and VDN rats had more elastic lamellae fractures than control rats (P < 0.001), which were associated with calcium deposition (thoracic R = 0.37, P = 0.048; abdominal: R = 0.40, P = 0.046). LPK rats had higher nuclear density than control rats (P < 0.01), which was also evident in the thoracic but not abdominal aorta of VDN rats (P < 0.01). In LPK and VDN rats, but not in control rats, media thickness and cross-sectional area were at least 1.5-fold greater in thoracic than abdominal regions. The calcification models chronic kidney disease and induced calcification in normotension caused differences in regional aortic stiffness not seen in a genetic form of hypertension. Detrimental abdominal aortic remodeling but lower stiffness in the thoracic aorta with disease indicates possible compensatory mechanisms in the proximal aorta.

Topics: Animals; Aorta, Abdominal; Aorta, Thoracic; Biomechanical Phenomena; Cholecalciferol; Collagen; Disease Models, Animal; Elastin; Female; Hemodynamics; Hypertension; Male; Oxazines; Rats; Rats, Inbred Lew; Rats, Inbred SHR; Rats, Inbred WKY; Renal Insufficiency, Chronic; Tensile Strength; Vascular Calcification; Vascular Stiffness

Vascular calcification is common in chronic kidney disease, where cardiovascular mortality remains the leading cause of death. Patients with kidney disease are often prescribed vitamin D receptor agonists (VDRAs) that confer a survival benefit, but the underlying mechanisms remain unclear. Here we tested two VDRAs in a mouse chronic kidney disease model where dietary phosphate loading induced aortic medial calcification. Mice were given intraperitoneal calcitriol or paricalcitol three times per week for 3 weeks. These treatments were associated with half of the aortic calcification compared to no therapy, and there was no difference between the two agents. In the setting of a high-phosphate diet, serum parathyroid hormone and calcium levels were not significantly altered by treatment. VDRA therapy was associated with increased serum and urine klotho levels, increased phosphaturia, correction of hyperphosphatemia, and lowering of serum fibroblast growth factor-23. There was no effect on elastin remodeling or inflammation; however, the expression of the anticalcification factor, osteopontin, in aortic medial cells was increased. Paricalcitol upregulated osteopontin secretion from mouse vascular smooth muscle cells in culture. Thus, klotho and osteopontin were upregulated by VDRA therapy in chronic kidney disease, independent of changes in serum parathyroid hormone and calcium.

Topics: Animals; Aorta; Aortic Diseases; Calcitriol; Calcium; Cells, Cultured; Diet; Disease Models, Animal; Elastin; Ergocalciferols; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucuronidase; Injections, Intraperitoneal; Klotho Proteins; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Osteopontin; Parathyroid Hormone; Phosphates; Receptors, Calcitriol; Renal Insufficiency, Chronic; Time Factors; Up-Regulation; Vascular Calcification

Vascular calcification is a major contributor to cardiovascular disease, a leading cause of death in patients with chronic kidney disease. Mechanistic studies highlight the importance of dysregulated mineral metabolism, vascular osteochondrogenic processes, apoptosis, and deficiencies in calcification inhibitors as potential mediators of calcification in renal disease. However, the contribution of the extracellular matrix in vascular calcification associated with chronic kidney disease is less understood. Here we examine evidence that suggests important roles for elastin and elastin-degrading enzymes as potential key regulators of calcification. Additional studies aimed at further understanding their role are critical for the design of therapeutic interventions.

Topics: Animals; Calcinosis; Elastin; Humans; Matrix Metalloproteinases; Renal Insufficiency, Chronic; Vascular Diseases