Prophylactic mineralocorticoid receptor (MR) antagonism with spironolactone (Sp) in rats completely prevents renal damage induced by ischemia. Because acute renal ischemia cannot typically be predicted, this study was designed to investigate whether Sp could prevent renal injury after an ischemic/reperfusion insult. Six groups of male Wistar rats were studied: rats that received a sham abdominal operation (S); rats that underwent 20 min of ischemia and reperfusion for 24 h (I/R) and four groups of rats treated with Sp (20 mg/kg) 0, 3, 6 or 9 h after ischemia. As expected, I/R resulted in renal dysfunction characterized by a fall in renal blood flow and glomerular filtration rate and severe tubular injury which was confirmed by a significant increase in tubular damage biomarkers including kidney injury molecule-1, heat shock protein 72 and urinary protein excretion. The renal injury induced by I/R was in part due to Rho-kinase, endothelin and angiotensin II type 1 receptor upregulation. Interestingly, Sp administration at 0 and 3 h after ischemia completely reversed and prevented the damage induced by I/R. The protection induced by Sp given 6 h after ischemia was partial, but no protection was observed by administering Sp 9 h after ischemia. Our results show that MR antagonism administered, either immediately or 3 h after I/R, effectively prevented ischemic acute renal injury, indicating that spironolactone is a promising agent for preventing acute kidney injury once an ischemic insult has occurred.

Obesity during childhood can lead to increased risk of adverse cardiometabolic diseases such as type 2 diabetes and coronary artery disease during adult life. Evidence for strong genetic correlations between child and adult body mass index (BMI) suggest the possibility of shared genetic effects. We performed a test for pleiotropy (shared genetics) and functional enrichment of single nucleotide polymorphisms (SNPs) associated with childhood BMI and 15 adult cardiometabolic traits using a unified statistical approach that integrates pleiotropy and functional annotation data. Pleiotropic genetic effects were significantly abundant in 13 out of 15 childhood BMI-adult cardiometabolic trait tests (P < 3.3 × 10−3). SNPs associated with both childhood BMI and adult traits were more likely to be functionally deleterious than SNPs associated with neither trait. Genetic variants associated with increased childhood obesity tend to increase risk of cardiometabolic diseases in adulthood. We replicated 39 genetic loci that are known to be associated with childhood BMI and adult traits (coronary artery disease, HDL cholesterol, myocardial infarction, triglycerides, total cholesterol, type 2 diabetes, BMI, waist circumference, and waist-to-hip ratio) in previous genome-wide association studies. We also found a novel association of rs12446632 near GPRC5B, which is highly expressed in adipose tissue and the central nervous system, with adult HDL cholesterol. This study found significant pleiotropic genetic effects and enrichment of functional annotations in genetic variants that were jointly associated with childhood obesity and adult cardiometabolic diseases. The findings provide new avenues to disentangle the genetic basis of life course associations between childhood obesity and adult cardiometabolic diseases.

Background: In Mexico, approximately 25% of patients with type 2 diabetes (T2D) have adequate glycemic control. Polymorphisms in pharmacogenetic genes have been shown to have clinical consequences resulting in drug toxicity or therapeutic inefficacy.Objective: The study aimed to evaluate the impact of variants in genes known to be involved in response to oral hypoglycemic drugs, such as CYP2C9, OCT, MATE, ABCA1 and C11orf65, in the Mexican Mestizo population of T2D patients.Methods: In this study, 265 patients with T2D were enrolled from the Hospital Juárez de México, Mexico City. Genotyping was performed by TaqMan® assays. SNP-SNP interactions were analyzed using the multifactor dimensionality reduction (MDR) method.Results: Carriers of the del allele of rs72552763 could achieve better glycemic control than noncarriers. There was a significant difference in plasma glucose and HbA1c levels among rs622342 genotypes. The results suggested an SNP-SNP interaction between rs72552763 and rs622342 OCT1 and rs12943590 MATE2.Conclusion: The interaction between rs72552763 and rs622342 in OCT1, and rs12943590 in MATE2 suggested an important role of these polymorphisms in metformin response in T2D Mexican Mestizo population.