The solutecarriers (SLC) are families of anion exchangers. Several membersof SLC4 family mediate Cl–/HCO3– exchange. SLC26is a new family of Cl–/HCO3– exchangers with veryspecific tissue distribution, with expression in the apicalmembranes of B-intercalated cells and proximal tubule cells.The current report by Xu et al. examines the functional characteristicsof SLC26A7, which is expressed on the basolateral membrane andintracellularly in the A-intercalated cells in the outer medullarycollecting duct and in gastric parietal cells. In response tohypertonicity, the distribution of SLC26A7 changes from theendosomal compartment to the basolateral membrane. A similarresponse was seen with low potassium in the external bath. Theseresults suggest that enhanced bicarbonate absorption in hypokalemiaand in conditions associated with increased medullary tonicitymay have an explanation at the level of regulation of traffickingof anion exchangers between the endosomes and basolateral membrane.See Xu et al., pages 956–967.
The Expanding Role of COX-2, Another Piece in the Puzzle.
Prostaglandinsderived from inducible cyclooxygenase-2 (COX-2) mediate a widevariety of physiologic and pathophysiologic cellular responses.Numerous studies have shown that COX-2 expression in inflammationand in malignancies confers resistance to apoptosis, and potentialconsequences include persistence of proinflammatory cells inlesions and resistance of cancer cells to chemotherapy. Sorokin’sgroup has previously shown that transfected mesangial cellsoverexpressing COX-2 express high levels of multidrug resistanceprotein 1 (MDR1), which mediates cellular efflux of many chemotherapeuticdrugs. In the article by Miller et al., the authors show thatincreased endogenous expression of COX-2 also induces MDR1 expression,which confers resistance to apoptotic cell death by adriamycin.Therefore, these studies elucidate another mechanism by whichCOX-2–derived prostanoids may prevent apoptosis and providea rationale for why pretreatment with selective COX-2 inhibitorsmay be useful in the prevention of multidrug resistance in responseto cancer chemotherapy. See Miller et al., pages 977–985.
Targeting Diabetic Nephropathy through the Mitochondria.
In diabetes,increased reactive oxygen species (ROS) production by mitochondriahas emerged as a potential common mediator of vascular injury.Although more than 1000 different proteins are found in mitochondria,the mitochondrial genome encodes only 37 genes, and the restare imported from the cytosol by transport systems found inmitochondrial membranes. A component of one of these, Tim44is upregulated in diabetes and could mediate increased importof antioxidant proteins and reduce ROS production. Zhang etal. examined whether further Tim44 overexpression would be protectiveand found that gene delivery of Tim44 to diabetic mice reducedrenal hypertrophy, proliferation, and apoptosis, as well asdecreasing proteinuria and ROS production, and suppressed ROSproduction and increased ATP production in vitro. Although thesestudies are preliminary, they indicate that targeting specificmitochondrial proteins and/or functions may provide new directionsfor development of therapeutic options for diabetic complications.See Zhang et al., pages 1090–1101.
A Complementary Approach to Reducing Ischemia Reperfusion Injury Posttransplant.
Ischemiareperfusion injury contributes to posttransplant delayed renalallograft function, particularly after transplantation of cadavericorgans with prolonged cold ischemic times. Local activationof the complement cascade in the allograft has been implicatedas one important mechanism underlying postischemic injury. Inthis issue of JASN, Patel et al. perfused rat kidneys with amembrane-localizing form of a complement regulatory protein(CR1) prior to exposing the kidneys to prolonged cold ischemiaand transplantation into syngeneic hosts. The CR1-perfused organsexhibited significantly improved posttransplant survival andfunction, with reduced acute tubular injury, compared with controltreated organs. The findings underscore the importance of thecomplement cascade in the pathophysiology of this disease processand provide the foundation for new strategies that could improvehuman allograft function after prolonged cold ischemia. SeePatel et al., pages 1102–1111.
Why Are Risk Factors for Progression and Cardiovascular Disease the Same?
The strikingoverlap between risk factors for progression of kidney injuryand those associated with progressive atherogenesis and plaquerupture suggests that a "common ground" may exist. Bode-Bögerand her colleagues report in this issue of JASN that symmetricaldimethylarginine (SDMA), a competitive antagonist of argininetransport in the kidney, increased as GFR declined in patientsundergoing elective coronary angiography. Furthermore, SDMAconcentrations were independently associated with the severityof coronary artery disease. These observations suggested thatthe association between SDMA and coronary atherosclerosis mightreflect perturbations of nitric oxide (NO) synthesis, a possibilitysupported by cell culture studies that demonstrated a competitiveinhibition of the NOS system by SDMA reversed by L-arginine.NO is a scavenger of reactive oxygen species and Bode-Bögeret al. further demonstrated that inhibition of NOS by SDMA wasassociated with increased oxidative stress, a key componentin the pathogenesis of atherosclerosis. SDMA now joins the NOSinhibitor asymmetric dimethylarginine as another possible biomarkerlinking coronary artery and kidney disease through perturbationsin nitric oxide synthesis. See Bode-Böger et al., pages1128–1134.
A Genetic Locus for Vesicoureteral Reflux.
Vesicoureteralreflux (VUR) occurs in about 1% of infants and is associatedwith the development of reflux nephropathy. The observationof parent–child transmission and increased incidence insiblings suggests that VUR has a genetic basis. Familial VURoccurs in renal malformation syndromes, such as the renal-colobomasyndrome, but no disease genes that cause primary, nonsyndromicVUR have been identified. Sally Feather et al. first identifiedlinkage of VUR to a locus on chromosome 1. They also found evidencefor genetic heterogeneity, a finding that was confirmed lastyear by Ali Gharavi’s group. In this issue of JASN, Vatsand colleagues identified three children with chromosomal deletionsassociated with VUR and/or reflux nephropathy. The criticalregion was mapped to a 7-Mb region on chromosome 13q33-34. Thisregion contains 24 genes encoding collagen subunits, ankyrin,transcription factors, and other proteins expressed in the kidneyand urinary tract. Further studies will be required to determinewhether mutations in these genes produce VUR. See Vats et al.,pages 1158–1167.
Anemia and Mortality in Dialysis Patients—Another Piece of the Puzzle.
The associationbetween hemoglobin and mortality in hemodialysis patients remainsa controversial subject with little evidence to guide the selectionof appropriate therapeutic targets. Regidor and coworkers useda large database with serial information about hemoglobin andtreatment with erythropoiesis-stimulating agents (ESA) to examinethe association between attained hemoglobin and risk of death.They report that, among prevalent patients who were alreadytreated with an ESA and who continued treatment, maintenanceof hemoglobin between between 12 and 13 g/dl was associatedwith the greatest survival and that both lower and higher levelsof attained hemoglobin confer increased risk of mortality. Furthermore,they report that resistance to an ESA confers increased riskof death. Although the study is limited by the absence of arandomized design, these and other observational data provideample evidence to guide contemporary practice. More importantquestions raised by Regidor et al. deal with the causes andoptimal management of resistant patients. Further explorationof these issues will help clarify the optimal management ofanemia in dialysis patients. See Regidor et al., pages 1181–1191.
Why Is There a Defect in IgA Glycosylation in IgA Nephropathy?
The pathogenesisof IgA nephropathy is now believed to involve passive trappingof immunoglobulin aggregates composed predominantly of IgA1that are underglycosylated in the hinge region of the molecules,thus rendering them less susceptible to clearance by asialoglycoproteinreceptors in the liver and spleen. The mechanism responsiblefor this glycosylation defect in patients with IgA nephropathy,and often their family members, remains obscure. This paperby Smith and colleagues illuminates that question by lookingat glycosylation patterns in IgA1 from patients with IgA nephropathyand controls and comparing them to patterns seen in IgD, theonly other glycosylated immunoglobulin. They report that, incontrast to IgA1, which is characteristically underglycosylatedin the patients, IgD is overglycosylated. These findings establishthat the biochemical machinery for glycosylating immunoglobulinsis intact in these patients. Thus the defective molecules thatresult in the renal disease must be produced later in B celldevelopment, perhaps as a consequence of aberrant immune regulationin response to an antigenic challenge. See Smith et al., pages1192–01199.
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