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  • Benetos, Athanase; Bulpitt, Christopher J.; Petrovic, Mirko; Ungar, Andrea; Rosei, Enrico Agabiti; Cherubini, Antonio; Redon, Josep; Grodzicki, Tomasz; Dominiczak, Anna; Strandberg, Timo; Mancia, Giuseppe (2016)
  • Siltari, Aino; Korpela, R.; Vapaatalo, H. (2016)
    Bradykinin exerts its vascular actions via two types of receptors, the non-constitutively expressed bradykinin receptor type 1 (BR1) and the constitutive type 2 receptor (BR2). Bradykinin-induced vasorelaxation is age-dependent, a phenomenon related to the varying amounts of BR1 and BR2 in the vasculature. Isoleucine-proline-proline (Ile-Pro-Pro), a bioactive tripeptide, lowers elevated blood pressure and improves impaired endothelium-dependent vasorelaxation in hypertensive rats. It inhibits angiotensin converting enzyme 1 (ACE1). Other mechanisms of action have also been postulated. The aims of the study were to clarify the underlying mechanisms of the age-dependency of bradykinin-induced vasodilatation such as the roles of the two bradykinin receptors, themas-receptor and synergism with Ile-Pro-Pro. The vascular response studies were conducted using mesenteric artery and aorta rings from normotensive 6 wk. (young) and 22 wk. (old) Wistar rats. Cumulative dosing of acetylcholine, bradykinin and angiotensin(1-7) (Ang(1-7))were tested in phenylephrine-induced vasoconstriction with or without 10 min pre-incubation with antagonists against BR1-, BR2- or mas-receptors,Ang(1-7) or ACE1-inhibitors captopril and Ile-Pro-Pro. The bradykinin-induced vasorelaxation in vitro was age-dependent and it was improved by pre incubation with Ile-Pro-Pro, especially in old rats with endothelial dysfunction. The mas-receptor antagonist, D-Pro7-Ang(1-7) abolished bradykinin-induced relaxation totally. Interestingly, BR1 and BR2 antagonists only slightly reduced bradykinin-induced vasorelaxation, as an evidence for the involvement of other mechanisms in addition to receptor activation. In conclusion, bradykinin-induced vasorelaxation was age -dependent and He-Pro-Pro improved it. Mas receptor antagonist abolished relaxation while bradykinin receptor antagonist only slightly reduced it, suggesting that bradykinin-induced vasorelaxation is regulated also by other mechanisms than the classical BR1/BR2 pathway. (C) 2016 Elsevier Inc: All rights reserved.
  • Törmänen, Suvi; Pörsti, Ilkka; Lakkisto, Päivi; Tikkanen, Ilkka; Niemelä, Onni; Paavonen, Timo; Mustonen, Jukka; Eräranta, Arttu (2017)
    Background: We studied whether endothelin receptor antagonist and calcimimetic treatments influence renal damage and kidney renin-angiotensin (RA) components in adenine-induced chronic renal insufficiency (CRI). Methods: Male Wistar rats (n = 80) were divided into 5 groups for 12 weeks: control (n = 12), 0.3% adenine (Ade; n = 20), Ade + 50 mg/kg/day sitaxentan (n = 16), Ade + 20 mg/kg/day cinacalcet (n = 16), and Ade + sitaxentan + cinacalcet (n = 16). Blood pressure (BP) was measured using tail-cuff, kidney histology was examined, and RA components measured using RT-qPCR. Results: Adenine caused tubulointerstitial damage with severe CRI, anemia, hyperphosphatemia, 1.8-fold increase in urinary calcium excretion, and 3.5-fold and 18-fold increases in plasma creatinine and PTH, respectively. Sitaxentan alleviated tubular atrophy, while sitaxentan + cinacalcet combination reduced interstitial inflammation, tubular dilatation and atrophy in adenine-rats. Adenine diet did not influence kidney angiotensin converting enzyme (ACE) and AT(4) receptor mRNA, but reduced mRNA of renin, AT(1a), AT(2), (pro) renin receptor and Mas to 40-60%, and suppressed ACE2 to 6% of that in controls. Sitaxentan reduced BP by 8 mmHg, creatinine, urea, and phosphate concentrations by 16-24%, and PTH by 42%. Cinacalcet did not influence BP or creatinine, but reduced PTH by 84%, and increased hemoglobin by 28% in adenine-rats. The treatments further reduced renin mRNA by 40%, while combined treatment normalized plasma PTH, urinary calcium, and increased ACE2 mRNA 2.5-fold versus the Ade group (p <0.001). Conclusions: In adenine-induced interstitial nephritis, sitaxentan improved renal function and tubular atrophy. Sitaxentan and cinacalcet reduced kidney renin mRNA by 40%, while their combination alleviated tubulointerstitial damage and urinary calcium loss, and increased kidney tissue ACE2 mRNA.
  • Kristensen, Peter L.; Pedersen-Bjergaard, Ulrik; Due-Andersen, Rikke; Hoi-Hansen, Thomas; Grimmeshave, Lise; Lyssenko, Valeriya; Groop, Leif; Holst, Jens J.; Vaag, Allan A.; Thorsteinsson, Birger (2016)
    Introduction: In healthy carriers of the T allele of the transcription factor 7-like 2 (TCF7L2), fasting plasma glucagon concentrations are lower compared with those with the C allele. We hypothesised that presence of the T allele is associated with a diminished glucagon response during hypoglycaemia and a higher frequency of severe hypoglycaemia (SH) in type 1 diabetes (T1DM). Material and methods: This is a post hoc study of an earlier prospective observational study of SH and four mechanistic studies of physiological responses to hypoglycaemia. 269 patients with T1DM were followed in a one-year observational study. A log-linear negative binomial model was applied with events of SH as dependent variable and TCF7L2 alleles as explanatory variable. In four experimental studies including 65 people, TCF7L2 genotyping was done and plasma glucagon concentration during experimental hypoglycaemia was determined. Results: Incidences of SH were TT 0.54, TC 0.98 and CC 1.01 episodes per patient-year with no significant difference between groups. During experimental hypoglycaemia, the TCF7L2 polymorphism did not influence glucagon secretion. Discussion: Patients with T1DM carrying the T allele of the TCF7L2 polymorphism do not exhibit diminished glucagon response during hypoglycaemia and are not at increased risk of severe hypoglycaemia compared with carriers of the C allele.
  • Dammacco, Rosanna; Biswas, Jyotirmay; Kivelä, Tero T.; Zito, Francesco Alfredo; Leone, Patrizia; Mavilio, Alberto; Sisto, Dario; Alessio, Giovanni; Dammacco, Franco (2020)
    Purpose To describe the ocular manifestations in a cohort of patients with systemic sarcoidosis (SS). Recent advances in the pathophysiology, diagnosis, and therapy of SS are also discussed. Methods Data from 115 Italian patients diagnosed between 2005 and 2016 were retrospectively reviewed. All but the first 17 patients underwent a comprehensive ophthalmologic examination. The diagnosis was based on clinical features, the demonstration of non-caseating granulomas in biopsies from involved organs, and multiple imaging techniques. Data on broncho-alveolar lavage fluid analysis, calcemia, calciuria, serum angiotensin-converting enzyme levels and soluble interleukin-2 receptor levels were retrieved when available. Results Ocular involvement, detected in 33 patients (28.7%), was bilateral in 29 (87.9%) and the presenting feature in 13 (39.4%). Anterior uveitis was diagnosed in 12 patients (36.4%), Lofgren syndrome and uveoparotid fever in one patient each (3%), intermediate uveitis in 3 patients (9.1%), posterior uveitis in 7 (21.2%), and panuveitis in 9 (27.3%). First-line therapy consisted of corticosteroids, administered as eyedrops (10 patients), sub-Tenon's injections (1 patient), intravitreal implants (9 patients), or systemically (23 patients). Second-line therapy consisted of steroid-sparing immunosuppressants, including methotrexate (10 patients) and azathioprine (10 patients). Based on pathogenetic indications that tumor necrosis factor (TNF)-alpha is a central mediator of granuloma formation, adalimumab, targeting TNF-alpha, was employed in 6 patients as a third-line agent for severe/refractory chronic sarcoidosis. Conclusion Uveitis of protean type, onset, duration, and course remains the most frequent ocular manifestation of SS. Diagnostic and therapeutic advancements have remarkably improved the overall visual prognosis. An ophthalmologist should be a constant component in the multidisciplinary approach to the treatment of this often challenging but intriguing disease.
  • Dahlstrom, Emma; Sandholm, Niina (2017)
    Purpose of Review Diabetic complications affecting the kidneys, retina, nerves, and the cardiovasculature are the major causes of morbidity and mortality in diabetes. This paper aims to review the current understanding of the genetic basis of these complications, based on recent findings especially from genome-wide association studies. Recent Findings Variants in or near AFF3, RGMA-MCTP2, SP3-CDCA7, GLRA3, CNKSR3, and UMOD have reached genome-wide significance (p value <5 x 10(-8)) for association with diabetic kidney disease, and recently, GRB2 was reported to be associated at genome-wide significance with diabetic retinopathy. While some loci affecting cardiovascular disease in the general population have been replicated in diabetes, GLUL affects the risk of cardiovascular disease specifically in diabetic subjects. Summary Genetic findings are emerging for diabetic complications, although the studies remain relatively small compared to those for type 1 and type 2 diabetes. In addition to pinpointing specific loci, the studies also reveal biological information on correlated traits and pathways.
  • Törmänen, Suvi; Lakkisto, Päivi; Eräranta, Arttu; Kööbi, Peeter; Tikkanen, Ilkka; Niemelä, Onni; Mustonen, Jukka; Pörsti, Ilkka (2020)
    Chronic renal insufficiency (CRI) is characterized by increased endothelin 1 (ET-1) synthesis. We studied rat kidney endothelin receptor A (ETA) and receptor B (ETB) expressions after 12 and 27 weeks of 5/6 nephrectomy, and after 12 weeks of 0.3% adenine diet, representing proteinuric and interstitial inflammation models of CRI, respectively. Uric acid and calcium-phosphate metabolism were modulated after 5/6 nephrectomy, while ETA blocker and calcimimetic were given with adenine. Endothelin receptor mRNA levels were measured using RT-qPCR and protein levels using autoradiography (5/6 nephrectomy) or ELISA (adenine model). Both 12 and 27 weeks after 5/6 nephrectomy, kidney cortex ETA protein was increased by similar to 60% without changes in ETB protein, and the ETB:ETA ratio was reduced. However, the ETB:ETA mRNA ratio did not change. In the adenine model, kidney ETA protein was reduced by similar to 70%, while ETB protein was suppressed by similar to 95%, and the ETB:ETA ratio was reduced by similar to 85%, both at the protein and mRNA levels. The additional interventions did not influence the observed reductions in the ETB:ETAratio. To conclude, unfavorable reduction in the ETB:ETA protein ratio was observed in two different models of CRI. Therefore, ETA blockade may be beneficial in a range of diseases that cause impaired kidney function.