Humans create vast quantities of wastewater through inefficiencies and poor management of water systems. The wasting of water poses sustainability challenges, depletes energy reserves, and undermines human water security and ecosystem health. Here we review emerging approaches for reusing wastewater and minimizing its generation. These complementary options make the most of scarce freshwater resources, serve the varying water needs of both developed and developing countries, and confer a variety of environmental benefits. Their widespread adoption will require changing how freshwater is sourced, used, managed, and priced.

Abstract-The aim of this study was to explore the effects of the renin inhibitor aliskiren in streptozotocin-diabetic TG(mRen-2)27 rats. Furthermore, we investigated in vitro the effect of aliskiren on the interactions between renin and the (pro)renin receptor and between aliskiren and prorenin. Aliskiren distributed extensively to the kidneys of normotensive (non)diabetic rats, localizing in the glomeruli and vessel walls after 2 hours exposure. In diabetic TG(mRen-2)27 rats, aliskiren (10 or 30 mg/kg per day, 10 weeks) lowered blood pressure, prevented albuminuria, and suppressed renal transforming growth factor-␤ and collagen I expression versus vehicle. Aliskiren reduced (pro)renin receptor expression in glomeruli, tubules, and cortical vessels compared to vehicle (in situ hybridization). In human mesangial cells, aliskiren (0.1 mol/L to 10 mol/L) did not inhibit binding of 125 I-renin to the (pro)renin receptor, nor did it alter the activation of extracellular signal-regulated kinase 1/2 by renin (20 nmol/L) preincubated with aliskiren (100 nmol/L) or affect gene expression of the (pro)renin receptor. Evidence was obtained that aliskiren binds to the active site of prorenin. The above results demonstrate the antihypertensive and renoprotective effects of aliskiren in experimental diabetic nephropathy. The evidence that aliskiren can reduce in vivo gene expression for the (pro)renin receptor and that it may block prorenin-induced angiotensin generation supports the need for additional work to reveal the mechanism of the observed renoprotection by this renin inhibitor. Key Words: aliskiren Ⅲ renin inhibitor Ⅲ TG(mRen-2)rat Ⅲ diabetic nephropathy Ⅲ (pro)renin receptor A central role for the renin-angiotensin-aldosterone system (RAAS) in the pathogenesis of diabetic nephropathy (DN) is widely accepted, based largely on the attenuation of DN by angiotensin (Ang) converting enzyme inhibitors (ACEi) 1 and Ang II receptor blockers (ARB). 2 However, these agents do not halt renal decline, possibly because of insufficient suppression of the intrarenal RAAS. Theoretically, agents that more effectively suppress the RAAS should confer improved tissue protection over current treatments for DN. Renin inhibitors, by acting at the point of activation of the RAAS cascade, may represent such agents. Aliskiren is a potent inhibitor of human renin; it lowers blood pressure (BP) in patients with mild-moderate hypertension 3,4 and shows cardiorenal protection in hypertensive double transgenic rats expressing human genes for renin and angiotensinogen. 5

Urate is a cause of gout, kidney stones, and acute kidney injury from tumor lysis syndrome, but its relationship to kidney disease, cardiovascular disease, and diabetes remains controversial. A scientific workshop organized by the National Kidney Foundation was held in September 2016 to review current evidence. Cell culture studies and animal models suggest that elevated serum urate concentrations can contribute to kidney disease, hypertension, and metabolic syndrome. Epidemiologic evidence also supports elevated serum urate concentrations as a risk factor for the development of kidney disease, hypertension, and diabetes, but differences in methodologies and inpacts on serum urate concentrations by even subtle changes in kidney function render conclusions uncertain. Mendelian randomization studies generally do not support a causal role of serum urate in kidney disease, hypertension, or diabetes, although interpretation is complicated by nonhomogeneous populations, a failure to consider environmental interactions, and a lack of understanding of how the genetic polymorphisms affect biological mechanisms related to urate. Although several small clinical trials suggest benefits of urate-lowering therapies on kidney function, blood pressure, and insulin resistance, others have been negative, with many trials having design limitations and insufficient power. Thus, whether uric acid has a causal role in kidney and cardiovascular diseases requires further study.

The role of the renin angiotensin system (RAS) in atherosclerosis is complex because of the involvement of multiple peptides and receptors. Renin is the rate-limiting enzyme in the production of all angiotensin peptides. To determine the effects of renin inhibition on atherosclerosis, we administered the novel renin inhibitor aliskiren over a broad dose range to fat-fed LDL receptor-deficient (Ldlr -/-) mice. Renin inhibition resulted in striking reductions of atherosclerotic lesion size in both the aortic arch and the root. Subsequent studies demonstrated that cultured macrophages expressed all components of the RAS. To determine the role of macrophage-derived angiotensin in the development of atherosclerosis, we transplanted renin-deficient bone marrow to irradiated Ldlr -/-mice and observed a profound decrease in the size of atherosclerotic lesions. In similar experiments, transplantation of bone marrow deficient for angiotensin II type 1a receptors failed to influence lesion development. We conclude that renin-dependent angiotensin production in macrophages does not act in an autocrine/paracrine manner. Furthermore, in vitro studies demonstrated that coculture with renin-expressing macrophages augmented monocyte adhesion to endothelial cells. Therefore, although previous work suggests that angiotensin peptides have conflicting effects on atherogenesis, we found that renin inhibition profoundly decreased lesion development in mice.

Abstract-We tested the hypothesis that the renin inhibitor aliskiren ameliorates organ damage in rats transgenic for human renin and angiotensinogen genes (double transgenic rat [dTGR]). Six-week-old dTGR were matched by albuminuria (2 mg per day) and divided into 5 groups. Untreated dTGR were compared with aliskiren (3 and 0.3 mg/kg per day)-treated and valsartan (Val; 10 and 1 mg/kg per day)-treated rats. Treatment was from week 6 through week 9. At week 6, all groups had elevated systolic blood pressure (BP). Untreated dTGR showed increased BP (202Ϯ4 mm Hg), serum creatinine, and albuminuria (34Ϯ5.7 mg per day) at week 7. At week 9, both doses of aliskiren lowered BP (115Ϯ6 and 139Ϯ5 mm Hg) and albuminuria (0.4Ϯ0.1 and 1.6Ϯ0.6 mg per day) and normalized serum creatinine. Although high-dose Val lowered BP (148Ϯ4 mm Hg) and albuminuria (2.1Ϯ0.7 mg per day), low-dose Val reduced BP (182Ϯ3 mm Hg) and albuminuria (24Ϯ3.8 mg per day) to a lesser extent. Mortality was 100% in untreated dTGR and 26% in Val (1 mg/kg per day) treated rats, whereas in all other groups, survival was 100%. dTGR treated with low-dose Val had cardiac hypertrophy (4.4Ϯ0.1 mg/g), increased left ventricular (LV) wall thickness, and diastolic dysfunction. LV atrial natriuretic peptide and ␤-myosin heavy chain mRNA, albuminuria, fibrosis, and cell infiltration were also increased. In contrast, both aliskiren doses and the high-dose Val lowered BP to a similar extent and more effectively than low-dose Val. We conclude that in dTGR, equieffective antihypertensive doses of Val or aliskiren attenuated end-organ damage. Thus, renin inhibition compares favorably to angiotensin receptor blockade in reversing organ damage in dTGR. Key Words: renin Ⅲ rats, transgenic Ⅲ hypertrophy R enin is the rate-limiting step in the generation of angiotensin II (Ang II). 1 Thus, inhibiting this step reduces Ang II levels. Historically, renin inhibitors have not been clinically successful because of lack of potency or bioavailability. The new nonpeptidic renin inhibitor aliskiren is a potent human renin inhibitor (IC 50 ϭ0.6 nmol/L). 2 Because renin displays species specificity for its substrate, human renin inhibitors cannot be tested efficiently in conventional hypertensive rat models. To circumvent this problem, transgenic rats and mice were developed harboring the human renin and the human angiotensinogen genes. 3,4 Human renin does not effectively cleave rat angiotensinogen, and similarly, rat renin cleaves human angiotensinogen poorly. 5 Consequently, the single transgenic rats and mice (ie, transgenic for either human angiotensinogen or renin) are normotensive. However, when cross-bred, the double transgenic rat (dTGR) offspring develop hypertension with severe organ damage and do not live beyond the seventh or eighth week of age. We extensively studied these animals; the injury features nuclear factor B (NF-B) and activator protein-1 transcription factor activation, upregulation of surface adhesion molecules, cytokines, and the influx of inflammatory cells. 6 ...

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Mean sea level has risen tenfold in recent decades compared to the most recent millennia, posing a serious threat for population and assets in flood‐prone coastal zones over the next century. An increase in the frequency of nuisance (minor) flooding has also been reported due to the reduced gap between high tidal datums and flood stage, and the rate of sea level rise (SLR) is expected to increase based on current trajectories of anthropogenic activities and greenhouse gases emissions. Nuisance flooding (NF), however nondestructive, causes public inconvenience, business interruption, and substantial economic losses due to impacts such as road closures and degradation of infrastructure. It also portends an increased risk in severe floods. Here we report substantial increases in NF along the coasts of United States due to SLR over the past decades. We then take projected near‐term (2030) and midterm (2050) SLR under two representative concentration pathways (RCPs), 2.6 and 8.5, to estimate the increase in NF. The results suggest that on average, ‐ 80 ± 10% local SLR causes the median of the NF distribution to increase by 55 ± 35% in 2050 under RCP8.5. The projected increase in NF will have significant socio‐economic impacts and pose public health risks in coastal regions.

Objective This study determined whether angiotensinogen (AGT) has angiotensin (Ang)II-independent effects using multiple genetic and pharmacological manipulations. Approach and Results All study mice were in LDL receptor -/- background and fed a saturated fat-enriched diet. In mice with floxed alleles and a neomycin cassette in intron 2 of the AGT gene (hypoAGT mice), plasma AGT concentrations were > 90% lower compared to their wild type littermates. HypoAGT mice had lower SBP, less atherosclerosis, and diminished body weight gain and liver steatosis. Low plasma AGT concentrations and all phenotypes were recapitulated in mice with hepatocyte-specific deficiency of AGT or pharmacological inhibition of AGT by antisense oligonucleotide (ASO) administration. In contrast, inhibition of AGT cleavage by a renin inhibitor, aliskiren, failed to alter body weight gain and liver steatosis in LDL receptor -/- mice. In mice with established adiposity, administration of AGT ASO versus aliskiren led to equivalent reductions of SBP and atherosclerosis. AGT ASO administration ceased body weight gain and further reduced body weight, whereas aliskiren did not affect body weight gain during continuous saturated fat-enriched diet feeding. Structural comparisons of AGT proteins in zebrafish, mouse, rat and human revealed 4 highly conserved sequences within the des(AngI)AGT domain. des(AngI)AGT, through adeno-associated viral infection in hepatocyte-specific AGT deficient mice, increased body weight gain and liver steatosis, but did not affect atherosclerosis. Conclusions AGT contributes to body weight gain and liver steatosis through functions of the des(AngI)AGT domain, which are independent of AngII production.