Chronic infection with hepatitis C virus (HCV) is a major public health problem, with nearly 170 million infected individuals worldwide. Current treatment for chronic infection is a combination of pegylated IFN-α 2 and ribavirin (RBV); however, this treatment is effective in fewer than 50% of patients infected with HCV genotype 1 or 4. Recent studies identified the chemokine CXCL10 (also known as IP-10) as an important negative prognostic biomarker. Given that CXCL10 mediates chemoattraction of activated lymphocytes, it is counterintuitive that this chemokine correlates with therapeutic nonresponsiveness. Herein, we offer new insight into this paradox and provide evidence that CXCL10 in the plasma of patients chronically infected with HCV exists in an antagonist form, due to in situ amino-terminal truncation of the protein. We further demonstrated that dipeptidyl peptidase IV (DPP4; also known as CD26), possibly in combination with other proteases, mediates the generation of the antagonist form(s) of CXCL10. These data offer what we believe to be the first evidence for CXCL10 antagonism in human disease and identify a possible factor contributing to the inability of patients to clear HCV.

Plasmacytoid dendritic cells (pDCs) are the professional type I interferon (IFN)-producing cells, and upon activation they traffic to lymph organs, where they bridge innate and adaptive immunity. Using multianalyte profiling (MAP), we have mapped the key chemokines and cytokines produced in response to pDC activation, taking into consideration the role of autocrine IFN, as well as paracrine effects on other innate cells (e.g., monocytes and conventional DCs). Interestingly, we identify four distinct cytokine/chemokine loops initiated by Toll-like receptor engagement. Finally, we applied this analytic approach to the study of pDC activity in chronic hepatitis C patients. Based on the activation state of pDCs in fresh blood, the lack of agonistic activity of infectious virions, the production of a broad array of cytokines/chemokines once stimulated, and the direct effects of pDCs on other PBMCs, we conclude that the pDCs from hepatitis C virus (HCV)-infected individuals are fully functional and are, indeed, a viable drug target. In sum, this study provides insight into the use of MAP technology for characterizing cytokine networks, and highlights how a rare cell type integrates the activation of other inflammatory cells. Furthermore, this work will help evaluate the therapeutic application of pDC agonists in diseases such as chronic HCV infection.

Diabetic nephropathy represents a major complication of diabetes mellitus (DM), and the origin of this complication is poorly understood. Vasopressin (VP), which is elevated in type I and type II DM, has been shown to increase glomerular filtration rate in normal rats and to contribute to progression of chronic renal failure in 5͞6 nephrectomized rats. The present study was thus designed to evaluate whether VP contributes to the renal disorders of DM. Renal function was compared in Brattleboro rats with diabetes insipidus (DI) lacking VP and in normal Long-Evans (LE) rats, with or without streptozotocin-induced DM. Blood and urine were collected after 2 and 4 weeks of DM, and creatinine clearance, urinary glucose and albumin excretion, and kidney weight were measured. Plasma glucose increased 3-fold in DM rats of both strains, but glucose excretion was Ϸ40% lower in DI-DM than in LE-DM, suggesting less intense metabolic disorders. Creatinine clearance increased significantly in LE-DM (P < 0.01) but failed to increase in DI-DM. Urinary albumin excretion more than doubled in LE-DM but rose by only 34% in DI-DM rats (P < 0.05). Kidney hypertrophy was also less intense in DI-DM than in LE-DM (P < 0.001). These results suggest that VP plays a critical role in diabetic hyperfiltration and albuminuria induced by DM. This hormone thus seems to be an additional risk factor for diabetic nephropathy and, thus, a potential target for prevention and͞or therapeutic intervention.One of the major complications of diabetes mellitus (DM) is a progressive nephropathy that develops in about one-third of patients within 10-20 years after the onset of the disease and leads in most cases to end stage renal failure (1). This represents a major problem of public health because a large fraction of dialysis requirements is attributable to DM nephropathy. Although a number of studies have already been devoted to this problem, the factors contributing to diabetic nephropathy are not yet fully identified.A characteristic feature observed in diabetic patients is an elevation of plasma vasopressin (VP), well documented in both type I and type II DM (2-5). This elevation also occurs in animal models of DM, whether experimental or genetically determined (6, 7). Several studies have investigated the possible factors responsible for this increase in VP secretion (3,6,8,9). But they did not succeed in identifying the responsible stimulus for this increase. They revealed a resetting of the osmostat in diabetics but concluded that hyperglycemia was not responsible for this resetting because increasing plasma glucose and osmolality by intravenous infusion of hypertonic dextrose produced no increase in plasma vasopressin in diabetics or in healthy controls (8).Little attention has been given to the possible functional consequences of the rise in plasma VP. To our knowledge, the possible contribution of VP to the renal complications of DM has never been investigated in spite of several previous findings suggesting that this hormone represents a ...

A.Parent. Extracellular cAMP inhibits proximal reabsorption: are plasma membrane cAMP receptors involved? Am J Physiol Renal Physiol 282: F376-F392, 2002; 10.1152/ajprenal.00202.2001.-Glucagon binding to hepatocytes has been known for a long time to not only stimulate intracellular cAMP accumulation but also, intriguingly, induce a significant release of liver-borne cAMP in the blood. Recent experiments have shown that the well-documented but ill-understood natriuretic and phosphaturic actions of glucagon are actually mediated by this extracellular cAMP, which inhibits the reabsorption of sodium and phosphate in the renal proximal tubule. The existence of this "pancreato-hepatorenal cascade" indicates that proximal tubular reabsorption is permanently influenced by extracellular cAMP, the concentration of which is most probably largely dependent on the insulinto-glucagon ratio. The possibility that renal cAMP receptors may be involved in this process is supported by the fact that cAMP has been shown to bind to brush-border membrane vesicles. In other cell types (i.e., adipocytes, erythrocytes, glial cells, cardiomyocytes), cAMP eggress and/or cAMP binding have also been shown to occur, suggesting additional paracrine effects of this nucleotide.Although not yet identified in mammals, cAMP receptors (cARs) are already well characterized in lower eukaryotes. The amoeba Dictyostelium discoideum expresses four different cARs during its development into a multicellular organism. cARs belong to the superfamily of seven transmembrane domain G protein-coupled receptors and exhibit a modest homology with the secretin receptor family (which includes PTH receptors). However, the existence of specific cAMP receptors in mammals remains to be demonstrated. Disturbances in the pancreato-hepatorenal cascade provide an adequate pathophysiological understanding of several unexplained observations, including the association of hyperinsulinemia and hypertension, the hepatorenal syndrome, and the hyperfiltration of diabetes mellitus. The observations reviewed in this paper show that cAMP should no longer be regarded only as an intracellular second messenger but also as a first messenger responsible for coordinated hepatorenal functions, and possibly for paracrine regulations in several other tissues. Dictyostelium discoideum; liver; adipose tissue; glucagon; epinephrine; parathyroid hormone; insulin; hypertension; hepatorenal syndrome; diabetes mellitus; sodium; phosphate GLUCAGON, A PANCREATIC HORMONE secreted after ingestion of proteins, has been known for a long time to be natriuretic and phosphaturic (56,66,105,142) and to increase renal blood flow and glomerular filtration rate

Clearance experiments were performed in anesthetized male Wistar rats to determine the level of peripheral glucagon concentration required to elicit changes in glomerular filtration rate (GFR) and in solute excretion. Glucagon was intravenously infused at a rate of 1.25 (group G-1, n = 8), 3.75 (group G-3, n = 7), or 12.5 (group G-10, n = 7) ng.min-1.100 g body wt-1 for 100 min. Measurements were performed before, during, and after this infusion. Group G-10 resulted in a plasma concentration of glucagon severalfold higher than usually observed in peripheral blood after a protein meal but normal for the hepatic circulation. Group G-10 simultaneously increased GFR, plasma adenosine 3',5'-cyclic monophosphate (cAMP) concentration, and the excretion of water (i.e., urinary flow rate), Na, Cl, PO4, K, and urea. Some of the effects of glucagon on electrolyte excretion were also observed with group G-1 and/or G-3 and were fully reversible, suggesting a direct renal action of glucagon. The significant and reversible increase in K excretion in group G-3 suggests that glucagon exerts a direct stimulatory influence on K secretion in the distal nephron. Increases in urinary flow rate, PO4, Na, and urea fractional excretions were seen with group G-10 only and were not reversible, suggesting an indirect action of glucagon on the proximal tubule. Because glucagon stimulates cAMP formation in hepatocytes and because this cAMP is released in the blood and secreted by proximal tubule cells, cAMP of hepatic origin could induce a parathyroid hormone-like effect in this nephron segment. In summary, these experiments suggest that glucagon influences different aspects of renal function by a combination of direct and indirect (probably liver-dependent) effects.

Urea, the major end product of protein metabolism in mammals, is the most abundant solute in the urine. Urea excretion is thought to result from filtration curtailed by some passive reabsorbtion along the nephron. This reabsorption is markedly enhanced by vasopressin and slow urinary flow rate (V), the fraction of filtered urea excreted in the urine (FEurea) falling from approximately 60% at high V to only approximately 20% at low V. In concentrated urine, normal urea excretion can be maintained only if urea filtration is elevated. This can be achieved by increasing plasma urea concentration (Purea) and/or GFR. We have shown that both parameters do increase when normal rats are submitted to chronic alterations in the water intake/vasopressin axis within the normal range of physiologic regulation. This situation is very similar to that observed after alterations in protein intake. In both cases more urea needs to be filtered, either because more of it has to be excreted, or because the efficiency of its excretion is reduced. A common mechanism is proposed to explain the rise in GFR observed in the two situations. In summary, our studies demonstrate that the antidiuretic effects of vasopressin are responsible for a significant elevation of GFR. This GFR adaptation limits the rise in Purea, a favorable effect because urea is not as harmless as usually thought. However, this hyperfiltration might have deleterious consequences in diseased kidneys.

In diabetes mellitus (DM), the urine flow rate is increased, and the fluid turnover in the body is accelerated because of the glucose-induced osmotic diuresis. On the other hand, plasma vasopressin (VP) is elevated in both type 1 and type 2 DM. This elevation seems to be due to a resetting of the osmostat. A high VP level is beneficial in the short term because it limits to some extent the amount of water required for the excretion of a markedly enhanced load of osmoles (mainly glucose). However, in the long run, it may have adverse effects by favoring the developement of diabetic nephropathy. VP has been shown in normal rats to induce kidney hypertrophy, glomerular hyperfiltration, and an increase in urinary albumin excretion (features also occurring in association in the period preceding diabetic nephropathy). Moreover, VP has been shown to participate in the progression of renal failure in rats with five-sixths reduction in renal mass. In recent studies, we have shown (1) that creatinine clearance, albuminuria and renal mass increased much less during experimental DM in Brattleboro rats unable to secrete VP than in their VP-replete Long-Evans controls, and (2) that albuminuria was prevented during experimental DM in Wistar rats when a VP nonpeptidic, highly selective V2 receptor antagonist was administered chronically for 9 weeks. Taken together, these results strongly suggest that VP plays a crucial role in the onset and aggravation of the renal complications of DM. The mechanisms by which VP exerts these adverse V2-dependent effects are not yet elucidated. They are most likely indirect and may involve several intermediate steps comprising VP-induced changes in the composition of the tubular fluid in the loop of Henle (due to solute recycling in the renal medulla associated with improved concentrating activity of the kidney), inhibition of the tubuloglomerular feedback control of glomerular function, and alterations in glomerular hemodynamics by the intrarenal renin-angiotensin system.

Clearance experiments were performed in anesthetized male Wistar rats to reevaluate the renal effects of glucagon (Gluc) on glomerular filtration rate (GFR) and solute and water excretion. After an 80-min control period, these effects were evaluated in the last 80 min of a 2-h intravenous Gluc infusion. Gluc induced significant increases in GFR (+20%), urine flow rate (+150%), free water reabsorption (+50%), urea synthesis and urea excretion (+66%), and nonurea solute excretion (+67%). In addition, fractional urea excretion (FEurea) increased by 43% (P less than 0.01). Additional experiments showed that increases in either urea excretion or urine flow rate (induced by appropriate infusion of urea or half-dilute saline), similar to those seen after Gluc, could not account for the increased FEurea. All significant effects of Gluc were also observed during infusion of antidiuretic hormone or during water diuresis. The tubular effects of Gluc could be explained by a reduction in proximal reabsorption. The dose of Gluc required to induce all the effects described above was 12 ng.min-1.100 g body wt-1, a dose producing an approximately 10-fold supraphysiological peripheral plasma concentration but a "physiological" level for the liver. Infusion of 1.2 ng induced almost no change in renal function, and infusion of 120 ng induced no greater effects than 12 ng. These results suggest 1) that Gluc, a hormone liberated after protein ingestion, exerts coordinated effects on liver and kidney to increase simultaneously urea synthesis and excretion and to promote water conservation and 2) that these effects could, at least in part, be indirect and depend on the Gluc-induced stimulation of hepatocyte metabolism.