Studies of nitric oxide over the past two decades have highlighted the fundamental importance of gaseous signaling molecules in biology and medicine. The physiological role of other gases such as carbon monoxide and hydrogen sulfide (H 2 S) is now receiving increasing attention. Here we show that H 2 S is physiologically generated by cystathionine γ-lyase (CSE) and that genetic deletion of this enzyme in mice markedly reduces H 2 S levels in the serum, heart, aorta, and other tissues. Mutant mice lacking CSE display pronounced hypertension and diminished endothelium-dependent vasorelaxation. CSE is physiologically activated by calcium-calmodulin, which is a mechanism for H 2 S formation in response to vascular activation. These findings provide direct evidence that H 2 S is a physiologic vasodilator and regulator of blood pressure.Nitric oxide (NO) and carbon monoxide (CO) are established physiologic messenger molecules, and NO has an important role as an endothelial cell-derived relaxing factor (EDRF) and regulator of blood pressure (1,2). Indirect evidence has implicated another endogenous gasotransmitter, hydrogen sulfide (H 2 S), in similar functions (3-7). H 2 S can be produced by cystathionine γ-lyase (CSE) or cystathionine β-synthase (CBS) (3,4), but definitive evidence for either of these enzymes in the physiologic formation of H 2 S is lacking.To investigate the role of H 2 S as a physiologic vasorelaxant and determinant of blood pressure, we generated mice with a targeted deletion of the gene encoding CSE (8) (fig. S1, A to C). The homozygous (CSE −/− ) and heterozygous (CSE −/+ ) mutant mice were viable, fertile, and indistinguishable from their control wild-type littermates (CSE +/+ ) in terms of growth pattern.

Hydrogen sulfide (H 2 S), a messenger molecule generated by cystathionine γ-lyase, acts as a physiologic vasorelaxant. Mechanisms whereby H 2 S signals have been elusive. We now show that H 2 S physiologically modifies cysteines in a large number of proteins by S-sulfhydration. About 10 to 25% of many liver proteins, including actin, tubulin, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), are sulfhydrated under physiological conditions. Sulfhydration augments GAPDH activity and enhances actin polymerization. Sulfhydration thus appears to be a physiologic posttranslational modification for proteins.

Hyperuricemic rats have a decrease in serum nitric oxide which is reversed by lowering uric acid levels. Soluble uric acid also impairs nitric oxide generation in cultured endothelial cells. Thus, hyperuricemia induces endothelial dysfunction; this may provide insight into a pathogenic mechanism by which uric acid may induce hypertension and vascular disease.

TGF-beta1 is a key mediator that regulates, in a dose-dependent fashion, transdifferentiation of tubular epithelial cells into alpha-SMA+ myofibroblasts. This transdifferentiation is markedly enhanced by growth on collagen type I. These findings have identified a novel pathway that may contribute to renal fibrosis associated with overexpression of TGF-beta1 within the diseased kidney.

ABSTRACT. TGF-β is a key mediator in renal fibrosis. Kidney-targeted gene therapy with anti–TGF-β strategies is expected to have therapeutic potential, but this has been hampered by concerns over the safety and practicability of viral vectors and the inefficiency of nonviral transfection techniques. The present study explored the potential role of TGF-β/Smad signaling in renal fibrosis in vivo and developed a safe and effective gene therapy to specifically block TGF-β signaling and renal fibrosis in a rat unilateral ureteral obstruction (UUO) model by transferring a doxycycline-regulated Smad7 gene or control empty vectors using an ultrasound-microbubble (Optison)-mediated system. The Smad7 transgene expression was tightly controlled by addition of doxycycline in the daily drinking water. Groups of six rats were sacrificed at day 7, and the transfection rate, Smad7 transgene expression, and tubulointerstitial fibrosis including α-smooth muscle actin and collagen matrix mRNA and protein expression were determined. Compared with the non-ultrasound treatment, the combination of ultrasound with Optison largely increased the transfection rate of FITC-ODN and Smad7 transgene expression up to a 1000-fold, and this was found in all kidney tissues. Compared with normal rats, Smad7 expression within the UUO kidney was significantly reduced, and this was associated with up to a sixfold increase in Smad2 and Smad3 activation and severe tubulointerstitial fibrosis. In contrast, treatment with inducible Smad7 resulted in a fivefold increase in Smad7 expression with complete inhibition of Smad2 and Smad3 activation and tubulointerstitial fibrosis in terms of tubulointerstitial myofibroblast accumulation (85%↓) and collagen I and III mRNA and protein expression (60 to 70%↓). In conclusion, the ultrasound-mediated inducible Smad7 gene transfer is a safe, effective, and controllable gene therapy. TGF-β–mediated renal fibrosis is regulated positively by Smad2/3, but negatively by Smad7. Target blockade of TGF-β/Smad signaling by expression of Smad7 may provide a new therapeutic potential for renal fibrosis. E-mail: hlan@bcm.tmc.edu

This study provides phenotypic and morphological evidence to support the hypothesis that TEC are pro-fibrogenitor cells capable of tubular epithelial-myofibroblast transdifferentiation in progressive renal fibrosis. In addition, we postulate that disruption of the TBM, which facilitates epithelial cell contact with the interstitial matrix, promotes this process of transdifferentiation.

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RJ, Scarpace PJ. Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding. Am J Physiol Regul Integr Comp Physiol 295: R1370 -R1375, 2008. First published August 13, 2008 doi:10.1152/ajpregu.00195.2008.-It has been suggested that increased fructose intake is associated with obesity. We hypothesized that chronic fructose consumption causes leptin resistance, which subsequently may promote the development of obesity in response to a high-fat diet. Sprague-Dawley rats were fed a fructose-free control or 60% fructose diet for 6 mo and then tested for leptin resistance. Half of the rats in each group were then switched to high-fat diet for 2 wk, while the other half continued on their respective diets. Chronic fructose consumption caused leptin resistance, while serum leptin levels, weight, and adiposity were the same as in control rats that were leptin responsive. Intraperitoneal leptin injections reduced 24-h food intake in the fructose-free group (73.7 Ϯ 6.3 vs. 58.1 Ϯ 8 kcal, P ϭ 0.02) but had no effect in fructose-fed rats (71.2 Ϯ 6.6 vs. 72.4 Ϯ 6.4 kcal, P ϭ 0.9). Absence of anorexic response to intraperitoneal leptin injection was associated with 25.7% decrease in hypothalamic signal transducer and activator of transcription 3 phosphorylation in the high-fructose-fed rats compared with controls (P ϭ 0.015). Subsequent exposure of the fructose-mediated, leptin-resistant rats to a high-fat diet led to exacerbated weight gain (50.2 Ϯ 2 g) compared with correspondingly fed leptin-responsive animals that were pretreated with the fructose-free diet (30.4 Ϯ 5.8 g, P ϭ 0.012). Our data indicate that chronic fructose consumption induces leptin resistance prior to body weight, adiposity, serum leptin, insulin, or glucose increases, and this fructose-induced leptin resistance accelerates highfat induced obesity.