Water Channels, Hypertonicity, and Gene Expression.
Waterflow across the collecting tubule involves a series of stepsdependent on vasopressin and the insertion of aquaporin-2 (AQP2)into the apical membrane. The tonicity-responsive enhancer bindingprotein (TonEBP) protects renal cells from hypertonic challengeand has a long-term stimulatory effect on AQP2 expression. Usinga cultured mouse collecting cell system, Hasler et al. showthat decreasing TonEBP activity reduces AQP2 expression underiso-osmotic conditions and blunts the increase of AQP2 abundanceinduced after 24 h of hypertonic challenge. Mutation of a TonEBPenhancer element located 489 bp upstream from the AQP2 transcriptionalstart site abolishes the stimulatory response to hypertonicityof luciferase activity in cells expressing AQP2 promoter–luciferaseplasmid constructs, indicating that TonEBP influences AQP2 transcriptionalactivity with a direct effect on the AQP2 promoter. These findingsdemonstrate that, in collecting duct principal cells, TonEBPplays a central role in regulating AQP2 expression at the transcriptionallevel. See Hasler et al., pages 1521–1531.
Is Diabetic Nephropathy a Disorder of Gap Junctions?
Gap junctionsserve as intercellular channels for the passage of small moleculessuch as metabolites, ions, and second messengers. This gap junctionintercellular communication has been implicated in cell growth,differentiation, and homeostasis. Connexins are integral membraneproteins that make up gap junctions. In this issue of JASN,Zhang et al. examine the role of connexin 43 (Cx43) in the mediationof phenotypic alterations to glomerular mesangial cells inducedby elevated glucose. They find that decreased Cx43 expressionin response to high glucose leads to mesangial cell senescence,which is prevented by Cx43 overexpression. These studies arethe first to suggest that abnormal expression of a connexin,and by inference, gap junction intercellular communication,may be involved in the development of diabetic nephropathy.See Zhang et al., pages 1532–1542.
Yet Another (Nonhemodynamic) Role for the Renin-Angiotensin System in Renal Disease.
The oldnotion that angiotensin II serves only as a hormone regulatingvascular tone and salt and water balance has been supplantedby current understanding of its pleotrophic effects, which includeproinflammatory properties. In this issue of JASN, Wolf et al.examine whether angiotensin II can modulate expression of Toll-likereceptor 4 (TLR4) in mouse mesangial cells. TLR4 is an importantcomponent of the innate immune system that senses lipopolysaccharide(LPS). Wolf et al. use a combined in vitro and in vivo approachto demonstrate angiotensin II–mediated TLR4 upregulationand augmentation of NFB and chemokine expression in responseto LPS. These studies elucidate another potential, nonhemodynamicmechanism for the renin-angiotensin system to contribute todisease, which may be relevant in both infectious and noninfectiousrenal disorders. See Wolf et al., pages 1585–1593.
A Novel Approach to Prevent Chronic Allograft Injury.
Immunomediatedchronic allograft injury, a common cause of late allograft failure,could theoretically be diminished via induced overproductionof exogenous therapeutic proteins within the graft. To testthis hypothesis, Benigni et al. overexpressed the costimulation-blockingagent CTLA4Ig in donor rat kidney allografts through ex vivotransduction using an adenovirus-associated vector. The authorsshow that the approach effectively leads to long-term expressionof CTLA4Ig by the graft. In a fully allogeneic transplant model,CTLA4Ig-transduced kidney transplants produce lower amountsof proteinuria and exhibit improved histology compared to controlallografts. The underlying mechanism of the induced toleranceis attributed to T cell anergy and regulation. In addition todemonstrating the feasibility of targeting a donor organ withan immunomodulatory agent to prevent chronic injury, this strategycould potentially limit systemic side effects related to chronicimmunosuppression. See Benigni et al., pages 1665–1672.
Validity of Claims-Based Case Ascertainment of Acute Renal Failure.
Health services and outcomes research frequently employ existingadministrative databases that increasingly contain not onlydemographic and diagnostic information, but also laboratoryand pharmacy information, which potentially increases the capacityof these data to address critical issues relevant to patientcare and outcomes. A key step in developing a research questionbased on administrative data is determining which patients willbe cases, and misassignment can result in biased estimates ofassociations between care and outcomes. The report by Waikaret al. in this issue of JASN addresses this issue for the studyof acute renal failure. The investigators compared case definitionsin 97,705 patients based on ICD-9-CM codes to changes in serumcreatinine based on review of medical records, and they foundsubstantial congruence between the laboratory and ICD-9-CM–baseddefinitions of acute renal failure, although nondialysis acuterenal failure was underreported by the claims data. These findingsshould remind clinicians of the importance of accurate and inclusivedischarge diagnoses that capture the full complexity of theirpatient care, because these diagnoses become important researchdata for outcomes studies. See Waikar et al., pages 1688–1694.
Obesity and the Risk of Chronic Kidney Disease—Bad News.
It is common knowledge that there is a worldwide epidemic ofobesity, with almost 50% of the population in some developedcountries qualifying as obese and an increasingly large proportionof children following the same path. Clearly, obesity is associatedwith a number of risk factors for chronic kidney disease (CKD)such as diabetes and hypertension. What is less well establishedis whether obesity per se is a CKD risk factor. In this studyof a large Swedish database, Ejerblad et al. report a two- tothree-fold increase in risk of severe CKD (stage 4 to 5) inindividuals with a body mass index exceeding 25 at age 20 yr,independent of known histories of diabetes. The study has limitations,as discussed by Chertow and colleagues in an accompanying editorialin this issue of JASN, but the message is a frightening onefor the nephrology community. It should provide a major impetusfor advocates of prevention programs involving modificationof lifestyle factors as the most cost-effective approach tothe worldwide epidemic of CKD. See Ejerblad et al., pages 1695–1702.
Why Do Blacks Have More ESRD?
Thereis a disproportionate burden of ESRD among black Americans relativeto white Americans. Cross-sectional studies from representativepopulation samples have suggested a roughly equivalent prevalenceof nondialysis-requiring chronic kidney disease (CKD). However,these studies were limited by concerns of misclassificationof CKD stage. The study by McClellan et al. in this issue ofJASN clarifies this issue. The Reasons for Geographic and RacialDifferences in Stroke (REGARDS) cohort is a nationally representativesample that includes approximately 50% blacks. About 10% ofREGARDS participants had an eGFR <45 ml/min per 1.73 m2.The adjusted odds of mild to moderate CKD (20 to 59 ml/min per1.73 m2) were lower in blacks, while the adjusted odds of severeCKD (<20 ml/min per 1.73 m2 not on dialysis) were significantlyhigher. While the mechanism(s) underlying differences in CKDstage prevalence among blacks and whites in the US remain elusive,these data confirm earlier reports and are consistent with the"differential progression" and "competing mortality" hypotheses.See McClellan et al., pages 1710–1715.
If IgA Doesn’t Do It, How Is Complement Activated in IgA Nephropathy?
IgA nephropathy(IgAN) is characterized by deposits of IgA and complement. Mechanismsof activation of complement have previously been suggested toinvolve the alternative complement pathway. In this issue ofJASN, Roos et al. show convincing data from human renal biopsiesof IgAN with complementary in vitro studies, indicating thatlectin can activate complement in IgAN. Mannose-binding lectin(MBL) was colocalized in glomeruli with MBL-associated serineprotease (MASP-2) and C4d, supporting activation of complementvia the lectin pathway. In vitro data indicate that polymeric,but not monomeric, IgA plays a role in this activation. Patientswith positive staining for MBL had worse histological and clinicalparameters than those without. These studies thus point to animportant pathway of activation of complement in IgAN, whichcould pave the way for new prognostic markers and therapeuticapproaches. See Roos et al., pages 1724–1734.
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B and chemokine expression in response to LPS. These studies elucidate another potential, nonhemodynamic mechanism for the renin-angiotensin system to contribute to disease, which may be relevant in both infectious and noninfectious renal disorders. See Wolf et al., pages 1585–1593. 
