AQP2 is a substrate for endogenous PP2B activity within an inner medullary AKAP-signaling complex.

We have demonstrated that inner medullary collecting duct (IMCD) heavy endosomes purified from rat kidney IMCD contain the type II protein kinase A (PKA) regulatory subunit (RII), protein phosphatase (PP)2B, PKCzeta, and an RII-binding protein (relative molecular mass ~90 kDa) representing a putative A kinase anchoring protein (AKAP). Affinity chromatography of detergent-solubilized endosomes on cAMP-agarose permits recovery of a protein complex consisting of the 90-kDa AKAP, RII, PP2B, and PKCzeta. With the use of small-particle flow cytometry, RII and PKCzeta were localized to an identical population of endosomes, suggesting that these proteins are components of an endosomal multiprotein complex. (32)P-labeled aquaporin-2 (AQP2) present in these PKA-phosphorylated endosomes was dephosphorylated in vitro by either addition of exogenous PP2B or by an endogenous endosomal phosphatase that was inhibited by the PP2B inhibitors EDTA and the cyclophilin-cyclosporin A complex. We conclude that IMCD heavy endosomes possess an AKAP multiprotein-signaling complex similar to that described previously in hippocampal neurons. This signaling complex potentially mediates the phosphorylation of AQP2 to regulate its trafficking into the IMCD apical membrane. In addition, the PP2B component of the AKAP-signaling complex could also dephosphorylate AQP2 in vivo.

Economic class and popular support for franklin roosevelt in war and peace.

History has judged FDR as one of America's greatest leaders in part because he maintained the public's confidence in seeing the nation through the travails of the Depression and World War II. During this era, the two most widely employed explanatory variables in contemporary presidential popularity scholarship-the economy and war-assumed their most extreme values of the twentieth century. Hence, not only is understanding Roosevelt's public support historically important, but it represents a valuable case for filling in our understanding of the opinion dynamics of presidential support more generally. Yet, surprisingly, Roosevelt's approval ratings have attracted little systematic scrutiny. Compiling time-series data from 1937 to 1943, partially disaggregated by economic class, we investigate FDR's popular support among different classes during both national crises. We find that Roosevelt's peacetime support divided along class lines, while during the war class divisions blurred. Roosevelt's support was indeed conditioned by external events, refracted through the interests of different societal groups. We conclude that public support for modern presidents should be similarly studied as the sum of opinions among heterogeneous constituencies.

Loss of living donor renal allograft survival advantage in children with focal segmental glomerulosclerosis.

BACKGROUND: Because of concerns of increased risk of graft loss with recurrent disease, living donor (LD) transplantation in children with focal segmental glomerulosclerosis (FSGS) has been controversial. METHODS: The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database from January 1987 to January 2000 was examined to determine differences in demographics, treatment, and outcomes in children with FSGS compared with other renal diseases. RESULTS: Data on 6484 children, 752 (11.6%) with FSGS, demonstrated that FSGS patients were more likely to be older and black, and were less likely to receive either pre-emptive or LD transplant (P < 0.001). No differences existed in human lymphocyte antigen (HLA) matching or immunosuppression regimens. Acute tubular necrosis occurred in more FSGS patients following LD (11.8 vs. 4.6%) or cadaveric (CD; 27.9 vs. 16.3%) transplants (P < 0.001). Graft survival was worse for LD FSGS patients (5 years 69%) compared with no FSGS (82%, P < 0.001) and was not significantly different than CD graft survival in the FSGS (60%) and No FSGS groups (67%). The LD to CD ratios of relative risk of graft failure were higher in FSGS patients (test for interaction, P = 0.01). Recurrence of original disease was the only cause of graft failure that differed between groups (P < 0.001). A greater percentage of LD FSGS graft failures was attributed to recurrence (P = 0.06). CONCLUSIONS: The impact of FSGS on graft survival in children is greatest in LD transplants, resulting in loss of expected LD graft survival advantage. The rationale for LD grafts in children with FSGS should be based on factors other than better outcomes typically associated with LD transplantation.

The role of the graft endothelium in transplant rejection: evidence that endothelial activation may serve as a clinical marker for the development of chronic rejection.

In this review, we discuss the role of the allograft endothelium in the recruitment and activation of leukocytes during acute and chronic rejection. We discuss associations among endothelial activation responses, the expression of adhesion molecules, chemokines and chemokine receptors, and rejection; and we propose that endothelial vascular cellular adhesion molecule-1 (VCAM-1) may be used as a surrogate marker of acute rejection and allograft vasculopathy. In addition, we describe potential mechanistic interpretations of persistent endothelial cell (EC) expression of major histocompatibility complex (MHC) class II molecules in allorecognition. The graft endothelium may provide an antigen-specific signal to transmigrating, previously activated, T cells and may induce B7 expression on locally transmigrating leukocytes to promote costimulation. Taken together, these functions of the EC provide it with a potent regulatory role in rejection and in the maintenance of T-cell activation via the direct and/or the indirect pathways of allorecognition.

Recent insights into the coordinate regulation of body water and divalent mineral ion metabolism.

Traditionally, arginine vasopressin modulation of renal water, sodium, and urea excretion has been considered somewhat in isolation from factors that control divalent mineral ion homeostasis. Similarly, previous considerations of divalent mineral ion metabolism have focused mainly on the role of hormones, eg, parathyroid hormone and various forms of vitamin D, as principal modifiers of renal calcium handling. Recent data, however, have now suggested the existence of novel linkages that coordinate control of water and divalent mineral ion homeostasis. This article summarizes these data and highlights the fundamental roles of the extracellular calcium polyvalent cation-sensing receptor (CaR) as an integrator of water and divalent mineral ion homeostasis on a cellular, organ-specific, and whole-body basis. Organs where CaRs may integrate water and divalent mineral ion metabolism include endocrine tissues that express CaRs, the brain, various nephron segments of the kidney, bone, and the gastrointestinal tract. These new data suggest that considerable regulatory overlap exists between water and divalent mineral ion homeostasis.

The perinatal expression of aquaporin-2 and aquaporin-3 in developing kidney.

The kidney provides an important contribution to permit the fetus to successfully transition to an independent existence by production of urine with significantly different osmolality compared with plasma. Although recent work has uncovered many aspects of the maturation and regulation of the renal concentrating and diluting mechanism, understanding of how alterations in the expression of aquaporin (AQP) water channels contribute to the formation of urine in the perinatal period is incomplete. Here, we report that both AQP-2 and -3 are expressed during fetal life as early as embryonic d 18 in ureteric buds of rat kidneys, where each is localized to the apical and basolateral membranes of epithelial cells, respectively. Northern analyses demonstrate that the 1.9-kb AQP-2 transcript is present in fetal and postnatal rat kidneys similar to that observed in adults. AQP-2 mRNA expression increases after d 3 of postnatal life. Immunoblotting reveals an increase in total kidney AQP-2 protein particularly with respect to its glycosylated form after postnatal d 3. AQP-3 protein also exhibits a similar alteration likely due to a similar increase in its glycosylation state. Both AQP-2 and AQP-3 display a distribution in the collecting ducts of human postnatal infants and adults identical to that exhibited in rat kidneys. These data show that both AQP-2 and -3 are present in collecting duct epithelia of fetal and postnatal kidneys. Thus, the reduced AVP-responsiveness and decreased urinary concentrating ability of the kidney during the fetal and immediate postnatal period does not appear to be caused by lack of AQP-2 or AQP-3 proteins.

Vasopressin-elicited water and urea permeabilities are altered in IMCD in hypercalcemic rats.

To investigate how hypercalcemia blunts renal concentrating ability, alterations in basal and arginine vasopressin (AVP)-elicited osmotic water (Pf) and urea (Purea) permeabilities were measured in isolated perfused terminal inner medullary collecting ducts (IMCD) from control and chronically hypercalcemic rats after dihydrotachysterol (DHT) (M. Levi, L. Peterson, and T. Berl. Kidney Int. 23: 489-497, 1983) treatment. The IMCD Pf of DHT-treated rats did not increase significantly after AVP and was accompanied by a significant 87 +/- 4% reduction in aquaporin-2 (AQP-2) protein but not mRNA. In contrast, both basal and AVP-elicited IMCD Purea from DHT rats were significantly increased and accompanied by a significant 41 +/- 11% increase in AVP-regulated urea transporter protein content. Immunoblotting with anti-calcium/polyvalent cation-sensing receptor protein (CaR) antiserum revealed specific alterations in CaR bands in endosomes purified from the apical membranes of inner medulla of DHT rats. These data are the first detailed analyses of hypercalcemia-induced alterations in AVP-regulated permeabilities and membrane transporters in IMCD. We conclude that selective alterations in IMCD transport occur in hypercalcemia, permitting the body to dispose of excess calcium without forming calcium-containing renal stones.

Renovascular hypertension in Marfan syndrome.

A defect in fibrillin integrity predisposes patients with Marfan syndrome to vascular wall abnormalities, most notably aortic rupture and dissection. Renal vascular anomalies have not been described previously in children with Marfan syndrome. In this report, we detail data from a hypertensive 14-year-old girl with clinical stigmata of Marfan syndrome and a diagnostic evaluation significant for characteristic aortic root dilatation and aneurysm, as well as a disparity in renal size and function exacerbated by captopril administration. Renal arteriography confirmed a left main renal artery stenosis that was not amendable to balloon angioplasty. Surgical resection resulted in significant improvement in hypertension. Pathological examination of the resected renal artery segment revealed intimal proliferation, fragmentation of the elastic media, and inner medial dissection. This patient demonstrates that, in addition to the aorta, renal arteries can be affected with the characteristic vascular wall pathology of Marfan syndrome, resulting in systemic hypertension. These data suggest that children with Marfan syndrome and hypertension need to be evaluated carefully for the presence of renal anomalies.

Planning health care delivery systems.

The increasing concern and interest in the health delivery system in the United States has placed the health system planners in a difficult position. They are inadequately prepared, in many cases, to deal with the management techniques that have been designed for use with system problems. This situation has been compounded by the failure, until recently, of educational programs to train new health professionals in these techniques. Computer simulation is a technique that allows the planners dynamic feedback on his proposed plans. This same technique provides the planning student with a better understanding of the systems planning process.