Association of the rs5186 polymorphism of the AGTR1 gene with decreased eGFR in patients with type 2 diabetes from Mexico City.

BACKGROUND: Early biomarkers search for Diabetic Kidney Disease (DKD) in patients with Type 2 Diabetes Mellitus (T2DM), as genetic markers to identify vulnerable carriers of the disease even before Glomerular Filtration Rate (GFR) decline or microalbuminuria development, has been relevant during the last few years. The rs5186 (A116C) polymorphism of the Angiotensin II Receptor Type I gene (AGTR1), has been associated to multiple effects of renal injury risk, commonly detected in patients with Diabetes Mellitus (DM). It has been described that rs5186 could have an effect in stability proteins that assemble Angiotensin II Receptor Type I (AT1), modifying its action, which is why it should be considered as a risk factor for Chronic Kidney Disease (CKD), characterized by a GFR progressive reduction. Even though, the association between rs5186 AGTR1 gene polymorphism and DKD in patients with T2DM has been controversial, inconclusive, and even absent. This disputable issue might be as a result of association studies in which many and varied clinical phenotypes included are contemplated as CKD inductors and enhancers. Although, the sample sizes studied in patients with T2DM are undersized and did not have a strict inclusion criteria, lacking of biochemical markers or KDOQI classification, which have hindered its examination. OBJECTIVE: The aim of our study was to establish an association between rs5186 AGTR1 gene polymorphism and GFR depletion, assessed as a risk factor to DKD development in patients with T2DM. METHODS: We analyzed 297 not related patients with T2DM, divided into 221 controls (KDOQI 1) and 76 cases (KDOQI 2). Arterial pressure, anthropometric and biochemical parameters were measured. rs5186 of AGTR1 genotyping was performed by TaqMan assay real-time PCR method. Allele and genotype frequencies, and Hardy-Weinberg equilibrium were measured. Normality test for data distribution was analyzed by Shapiro-Wilk test, variable comparison by Student's t-test for continuous variables, and Chi-squared test for categorical variables; ANOVA test was used for mean comparison of more than two groups. Effect of rs5186 to DKD was estimated by multiple heritability adjustment models for risk variables of DKD. Statistical significance was indicated by p<0.05. Data was analyzed using Statistical Package STATA v11 software. RESULTS: Dominant and Over-dominant models showed a likelihood ratio to GFR depletion of 1.89 (1.05-3.39, p=0.031) and 2.01 (1.08-3.73, p=0.023) in patients with T2DM. Risk factor increased to 2.54 (1.10-5.89) in women in Over-dominant model. CONCLUSION: In clinical practice, most of nephropathies progress at a slow pace into a total breakdown of renal function, even asymptomatic. This is the first study, reporting that rs5186 polymorphism of AGTR1 gene contribution to GFR depletion, and this could be evaluated as a predisposing factor for DKD in patients with T2DM.

Circadian aspects of hyperthermia in mice induced by Aconitum napellus.

BACKGROUND: Aconitum napellus (Acn) is used topically to relieve pain, itching and inflammation, and internally to reduce febrile states, among others. Any circadian time-related consequences of Acn administration are unknown. The objective of this study was to explore the effects of two doses of Acn on body temperature (BT) of mice treated at six different times over 24 hours. MATERIALS AND METHODS: BALB/c female mice were housed in six chambers (six mice each) with air temperature 24 ± 3°C, humidity 60 ± 4%, and a 12-hours light (L)/12-hours dark cycle, but with L-onset staggered by 4 hours between chambers so that study at one external test time resulted in six test times (02, 06, 10, 14, 18 and 22 hours [h] after light onset). Rectal temperature (RT; in °C) was measured at baseline (B) and 1 hour after oral treatment with placebo (P) or two doses of Acn (6C and 30C, two studies each) in six studies over an 8 day span. The difference in RT for each mouse from the respective B + P timepoint mean RT was computed following each Acn treatment, and data from each of the six studies (original RT and difference from B + P) were analyzed for time-effect by analysis of variance (ANOVA) and for circadian rhythm by 24-hour cosine fitting. RESULTS: A CIRCADIAN RHYTHM IN RT WAS FOUND AT B AND AFTER P (MEAN: 35.58°C vs. 35.69°C; peak: 15:31 h vs. 15:40 h) and after each Acn dose (30C or 6C). Acn induced hyperthermia and the overall change in BT was rhythmically significant for each dose (mean = +1.95°C vs. +1.70°C), with greatest hyperthermia observed during the L-span for each dose (peak = 08:56 h vs. 05:17 h). CONCLUSION: Acn administered around the clock induced hyperthermia overall and in a time-dependent manner, with greatest effects during the resting (L) span. Thus, time of day may significantly impact the outcome of Acn and other homeopathic treatments and should be considered in determining optimal dosing and treatment time(s) in order to increase the desired outcome and decrease undesired effects.