The protease renin is the key enzyme of the renin-angiotensin-aldosterone cascade, which is relevant under both physiological and pathophysiological settings. The kidney is the only organ capable of releasing enzymatically active renin. Although the characteristic juxtaglomerular position is the best known site of renin generation, renin-producing cells in the kidney can vary in number and localization. (Pro)renin gene transcription in these cells is controlled by a number of transcription factors, among which CREB is the best characterized. Pro-renin is stored in vesicles, activated to renin, and then released upon demand. The release of renin is under the control of the cAMP (stimulatory) and Ca2+(inhibitory) signaling pathways. Meanwhile, a great number of intrarenally generated or systemically acting factors have been identified that control the renin secretion directly at the level of renin-producing cells, by activating either of the signaling pathways mentioned above. The broad spectrum of biological actions of (pro)renin is mediated by receptors for (pro)renin, angiotensin II and angiotensin-( 1 – 7 ).

Sepsis-associated acute renal failure is characterized by decreased GFR and tubular dysfunction. The pathogenesis of endotoxemic tubular dysfunction with failure in urine concentration and increased fractional sodium excretion is poorly understood. This study investigated the regulation of renal sodium transporters during severe inflammation in vivo and in vitro. Injection of high-dosage LPS reduced BP and GFR, increased fractional sodium excretion, and strongly decreased the expression of Na . ARF is present in 20% of patients with severe sepsis and 50% of patients with septic shock (2) and is clinically defined as a deterioration of GFR and tubular function. Little is known about the pathophysiology of endotoxemic tubular dysfunction with failure in urine concentration and increased fractional sodium excretion.Urine concentration requires establishment and maintenance of a hypertonic medullary interstitium, which depends on the NaCl reabsorption (3). The Na ϩ /H ϩ -exchanger (NHE3) and the functional unit of ROMK and Na ϩ -K ϩ -2Cl Ϫ co-transporter (NKCC2) are key components that are responsible for sodium reabsorption by the thick ascending limb (3,4). ROMK, also located in the cortical collecting duct (CCD), is responsible for recycling K ϩ across the apical membrane, which is critical for continuous sodium uptake by NKCC2 (5-8). In the collecting duct, the vasopressin-regulated epithelial sodium channel (ENaC), composed of three homologous subunits (9,10), accounts for the fine adjustment of the sodium reabsorption. The Na ϩ /K ϩ -ATPase in the basolateral membrane is essential for the efficient sodium reabsorption along the whole nephron.Findings that endotoxemia diminishes expression of renal V 2 receptors and aquaporin-2 (11) directed our interest toward the regulation of tubular sodium transporters during experimental sepsis. We hypothesized that endotoxemia downregulates tubular sodium transporters. On the basis of our previous findings that proinflammatory cytokines downregulate several vasoconstrictive receptors in renal tissue (12-15), we assumed that cytokines affect the expression of renal sodium transporters.To test our hypotheses, we performed in vivo experiments with (1) mice that were administered an injection of LPS as a model for severe experimental Gram-negative sepsis; (2) mice that were administered injections the cytokines TNF-␣, IL-1␤, or IFN-␥; (3) knockout mice that had a deficiency for TNF-␣, IL-1 receptor-1 (IL-1R1), or IFN-␥ and were administered an injection of LPS; (4) mice that did or did not have glucocorticoid pretreatment, which attenuates LPS-induced cytokine production (16 -18) and were administered an injection of LPS; (5) mice that were administered an injection of low-dosage LPS using as a model of inflammation without systemic hypotension and renal ischemia; (6) mice with renal artery clipping to reduce renocortical flux to 40% of controls to imitate LPS-induced renal hypoperfusion (19); and (7) mice with renal ischemia-reperfusion injury by complete renal artery occlus...

These findings indicate that signalling of cGKIbeta via IRAG is an essential functional part for regulation of smooth muscle tone and of intracellular calcium by NO (exogenously applicated or endogenously synthesized) and by ANP. IRAG signalling does not modulate basal tone but might be important for blood pressure regulation under pathophysiological conditions.

Abstract. On the basis of recent evidence that the cyclooxygenase-2 (COX-2) gene promoter contains functional binding sites for the nuclear factor of activated T cells (NFAT) and that COX-2 is expressed in a regulated fashion in the kidney, this study aimed to assess the effect of immunosuppressants on COX-2 expression in the kidney. Therefore, Wistar-Kyoto rats were treated with cyclosporine A (CsA; 15 mg/kg per day) or tacrolimus (5 mg/kg per day) for 7 d each. Both drugs markedly lowered COX-2 expression while COX-1 expression remained unaltered. Furthermore, CsA blunted the increase of renocortical COX-2 expression in response to low salt intake or a combination of low-salt diet with the ACE inhibitor ramipril (10 mg/kg per day), which strongly stimulates renocortical COX-2 expression. At the same time, calcineurin inhibitors moderately enhanced basal as well as stimulated renin secretion and renin gene expression. These findings suggest that inhibition of calcineurin could be a crucial determinant for the regulated expression of COX-2 in the kidney. Inhibition of COX-2 expression may therefore at least in part account for the well-known adverse effects of immunosuppressants in the kidney. Moreover, our data suggest that the stimulation of the renin system by low salt and by ACE inhibitors is not essentially mediated by COX-2 activity.The family of cyclooxygenases (COX)

Chronic heart failure is one of the most frequent causes of death in humans. Knockout of type 5 adenylyl cyclase (AC) in mice causes longevity and protection from cardiomyopathy, and an AC5 inhibitor reduces ␤-adrenoceptor-stimulated Ca 2ϩ inward currents in isolated mouse cardiomyocytes. These data indicate that selective AC5 inhibitors may be beneficial in chronic heart failure. Therefore, we characterized AC in mouse heart membranes. Real-time polymerase chain reaction and immunoblot analysis suggested that AC5 is an important heart AC isoform. Enzyme kinetics of heart AC and recombinant AC5 in the presence of Mg 2ϩ were similar. Moreover, the inhibitory profile of eight 2Ј(3Ј)-O-(N-methylanthraniloyl) (MANT)-nucleoside 5Ј-([␥-thio])triphosphates on mouse heart in the presence of Mg 2ϩ was almost identical to that of AC5. MANT-ITP was the most potent inhibitor of heart AC and recombinant AC5, with K i values in the 15 to 25 nM range in the presence of Mg 2ϩ and in the 1 to 5 nM range in the presence of Mn 2ϩ . However, in the presence of Mn 2ϩ , we also noted differences between mouse heart AC and AC5 with respect to enzyme kinetics and forskolin analog effects. In conclusion, with regard to expression and kinetics and inhibition by MANT-nucleotides in the presence of Mg 2ϩ , AC5 is an important AC isoform in heart, with MANT-ITP being an excellent starting point for the design of AC5-selective inhibitors. Unfortunately, a limitation of our study is the fact that immunologically and biochemically, AC5 and AC6 are quite similar, although they have different roles in heart. Moreover, lack of antibody specificity and Mn 2ϩ masking AC5 effects were problems.