MicroRNA-181a binds to the 3' untranslated region of messenger RNA (mRNA) for renin, a rate-limiting enzyme of the renin-angiotensin system. Our objective was to determine whether this molecular interaction translates into a clinically meaningful effect on blood pressure and whether circulating miR-181a is a measurable proxy of blood pressure. In 200 human kidneys from the TRANScriptome of renaL humAn TissuE (TRANSLATE) study, renal miR-181a was the sole negative predictor of renin mRNA and a strong correlate of circulating miR-181a. Elevated miR-181a levels correlated positively with systolic and diastolic blood pressure in TRANSLATE, and this association was independent of circulating renin. The association between serum miR-181a and systolic blood pressure was replicated in 199 subjects from the Genetic Regulation of Arterial Pressure of Humans In the Community (GRAPHIC) study. Renal immunohistochemistry and in situ hybridization showed that colocalization of miR-181a and renin was most prominent in collecting ducts where renin is not released into the systemic circulation. Analysis of 69 human kidneys characterized by RNA sequencing revealed that miR-181a was associated with downregulation of four mitochondrial pathways and upregulation of 41 signaling cascades of adaptive immunity and inflammation. We conclude that renal miR-181a has pleiotropic effects on pathways relevant to blood pressure regulation and that circulating levels of miR-181a are both a measurable proxy of renal miR-181a expression and a novel biochemical correlate of blood pressure. Online address: http://www.molmed.org doi: 10.2119/molmed.2015.00096 Address correspondence to Maciej Tomaszewski, Institute of CardiovascularSciences, AV Hill Building, Dover Street, Manchester, M13 9PT, United Kingdom. Phone: +44-(0)116-275-0232; E-mail: maciej.tomaszewski@manchester.ac.uk. Submitted April 29, 2015; Accepted for publication August 17, 2015; Published Online (www.molmed.org ) August 24, 2015 m i R -1 8 1 a , T H E K I D N E Y A N D B L O O D P R E S S U R E7 4 0 | M a r q u E s E T a L . | M O L M E D 2 1 : 7 3 9 -7 4 8 , 2 0 1 5

The fibroblast growth factor 1 (FGF1) gene is expressed primarily in the kidney and may contribute to hypertension. However, the biologic mechanisms underlying the association between FGF1 and BP regulation remain unknown. We report that the major allele of FGF1 single nucleotide polymorphism rs152524 was associated in a dose-dependent manner with systolic BP (P=9.65310 25) and diastolic BP (P=7.61310 23) in a meta-analysis of 14,364 individuals and with renal expression of FGF1 mRNA in 126 human kidneys (P=9.0310 23). Next-generation RNA sequencing revealed that upregulated renal expression of FGF1 or of each of the three FGF1 mRNA isoforms individually was associated with higher BP. FGF1-stratified coexpression analysis in two separate collections of human kidneys identified 126 FGF1 partner mRNAs, of which 71 and 63 showed at least nominal association with systolic and diastolic BP, respectively. Of those mRNAs, seven mRNAs in five genes (MME, PTPRO, REN, SLC12A3, and WNK1) had strong prior annotation to BP or hypertension. MME, which encodes an enzyme that degrades circulating natriuretic peptides, showed the strongest differential coexpression with FGF1 between hypertensive and normotensive kidneys. Furthermore, higher level of renal FGF1 expression was associated with lower circulating levels of atrial and brain natriuretic peptides. These findings indicate that FGF1 expression in the kidney is at least under partial genetic control and that renal expression of several FGF1 partner genes involved in the natriuretic peptide catabolism pathway, reninangiotensin cascade, and sodium handling network may explain the association between FGF1 and BP. Essential hypertension is a net product of genetic factors and environmental exposure acting together on regulatory systems in key organs for BP homeostasis. The kidney is central to BP regulation and drives the development of hypertension through numerous mechanisms including glomerular hemodynamics, tubular reabsorption of sodium, actions of the renin-angiotensin system, and natriuretic peptides. 1 Rare genetic variants that affect expression of molecules and pathways operating within the kidney lead to elevated BP in monogenic forms of hypertension. 2 Several common variants in genes associated with BP and/or susceptibility to hypertension are also believed to act through the

IntroductionOur aim was to evaluate the effects of metformin and orlistat on body composition and glucose–insulin homeostasis in obese premenopausal women.Material and methodsSeventy-three obese premenopausal Caucasian women aged 32.4 ±8.3 years were treated with either metformin (1000 mg/day; n = 37) or orlistat (360 mg/day; n = 36). Anthropometric parameters were measured using dual-energy X-ray absorptiometry. Glucose tolerance, using the oral glucose tolerance test; insulin resistance, using the homeostasis model assessment (HOMA-IR); and insulin sensitivity, using the Matsuda insulin sensitivity index (ISI Matsuda), were assessed at the commencement of the study and after 3 months.ResultsThose treated with orlistat showed greater weight loss (−9.4 ±2.3 vs. –4.9 ±1.3 kg, p < 0.05) and decrease of fat mass (−5.4 ±3.0 vs. –3.5 ±0.7 kg, p < 0.05) than those treated with metformin. The percentage of android and gynoid fat deposits was reduced in both groups; however, a greater decrease in android fat was observed in those treated with metformin. Improvement in ISI Matsuda and post-load insulin were similar in both groups. High initial post-load insulin and low ISI Matsuda corresponded with reductions in total fat, trunk fat, and waist circumference in both groups, and a decrease in android fat in those treated with metformin.ConclusionsOrlistat treatment resulted in greater weight loss and improvement in body composition; metformin treatment resulted in a reduction of android fat. Both drugs produced a comparable improvement in insulin/glucose homeostasis. Overall, insulin-resistant women showed improvement with treatment, irrespective of which drug was used.

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Urotensin-II controls ion/water homeostasis in fish and vascular tone in rodents. We hypothesised that common genetic variants in urotensin-II pathway genes are associated with human blood pressure or renal function. We performed family-based analysis of association between blood pressure, glomerular filtration and genes of the urotensin-II pathway (urotensin-II, urotensin-II related peptide, urotensin-II receptor) saturated with 28 tagging single nucleotide polymorphisms in 2024 individuals from 520 families; followed by an independent replication in 420 families and 7545 unrelated subjects. The expression studies of the urotensin-II pathway were carried out in 97 human kidneys. Phylogenetic evolutionary analysis was conducted in 17 vertebrate species. One single nucleotide polymorphism (rs531485 in urotensin-II gene) was associated with adjusted estimated glomerular filtration rate in the discovery cohort (p = 0.0005). It showed no association with estimated glomerular filtration rate in the combined replication resource of 8724 subjects from 6 populations. Expression of urotensin-II and its receptor showed strong linear correlation (r = 0.86, p<0.0001). There was no difference in renal expression of urotensin-II system between hypertensive and normotensive subjects. Evolutionary analysis revealed accumulation of mutations in urotensin-II since the divergence of primates and weaker conservation of urotensin-II receptor in primates than in lower vertebrates. Our data suggest that urotensin-II system genes are unlikely to play a major role in genetic control of human blood pressure or renal function. The signatures of evolutionary forces acting on urotensin-II system indicate that it may have evolved towards loss of function since the divergence of primates.