The Serum and Glucocorticoid-Inducible Kinase SGK1 and the Na+/H+ Exchange Regulating Factor NHERF2 Synergize to Stimulate the Renal Outer Medullary K+ Channel ROMK1
Molecular Insights into PotassiumSecretion. Although it has long been appreciated that aldosteronestimulates both collecting duct Na+ resorption and K+ secretion,the molecular mechanisms have only recently come to light. Amajor advance was the demonstration by several groups that theserum and glucocorticoid-dependent kinase 1 (SGK1), which istranscriptionally induced by aldosterone, stimulates the collectingduct Na+ channel ENaC. Since Na+ absorption and K+ secretionare tightly coupled, it was puzzling when SGK failed to alteractivity of the apical K+ secretory channel ROMK in vitro. Inthis issue, Yun et al. show that such reconstitution experimentsmust include the sodium-hydrogen exchanger regulatory factor-2(NHERF2), which was first discovered by Ed Weinman’s group.SKG plus NHERF2 results in strong stimulation of ROMK1 activityin Xenopus oocytes. NHERF2 had been known to stabilize othermembrane proteins, such as NHE-3 and the PTH receptor. ROMKhas now been added to the list. Once again, nature creates atool to solve one problem and then uses it as needed elsewhere.
Immunology and Pathology
Prominent Renal Expression of a Murine Leukemia Retrovirus in Experimental Systemic Lupus Erythematosus
Viruses in Lupus Nephritis? –New Data on an Old Idea. In this study, Alexander et al. usegene microarray chip technology to make the novel observationof a highly expressed gene that corresponds to a murine retrovirusin kidneys from mice demonstrating lupus nephritis–typepathology. This study followed up on this observation with confirmatoryRTPCR studies and, importantly, in situ hybridization to localizethe gene transcript in renal tissues of diseased mice. The transgenewas found principally in tubular epithelium, as illustrated.Interestingly, greater expression of the retroviral gene correspondedto the periods when the nephritic injury was at its most active.While the pathogenetic significance of the gene expressed inthis setting remains unclear, this finding renews interest ina decades-old but still tantalizing hypothesis that a uniqueviral infection underlies the pathogenesis of the autoimmunedisease manifestations of lupus, although substantial evidenceto substantiate this premise is lacking. These studies illustratesome of the novel findings that may emerge from the "discovery"approach to scientific investigation that is the current promiseof gene chip studies. This study also demonstrates some of thenecessary types of confirmatory studies needed to validate thefindings from a gene microarray experiment.
Pathophysiology of Renal Disease
A Role for Uric Acid in the Progression of Renal Disease
Uric Acid – Another Playerin Progression. Although hyperuricemia and gout are common featuresof progressive kidney diseases of any etiology, elevated uricacids levels were regarded as secondary events until recently,rather than as etiologic factors in the pathogenesis of kidneydisease. In this article, Kang et al. induce hyperuricemia inthe standard rat remnant kidney model of progressive renal diseaseand document a significant increase in severity of both structuraland functional features of progression that was independentof blood pressure and crystallization. The changes were blockedby allopurinol. The authors also provide data suggesting thaturic acid may act via the renin angiotensin system and upregulationof Cox 2. Together with other recent studies from this samegroup, the results call for a reevaluation of the importanceof uric acid in progressive renal injury and the potential efficacyof more aggressive therapy to reduce uric acid levels.
How to Fully Protect the Kidney in a Severe Model of Progressive Nephropathy: A Multidrug Approach
Can We Really Halt Progression withMedications? As our understanding of the factors that mediateprogressive renal disease expands, the list of potential therapeuticinterventions to slow or halt progression increases. ACE inhibitorsare now standard therapy for progressive proteinuric disorders.However, there are few data to tell us whether maximal clinicalbenefit requires treating only one, several, or all of the featuresthat modulate progression. In this article, Zoja et al. employa model of progressive membranous nephropathy in rats to explorethe relative efficacy of utilizing a combination of ACE inhibitor,angiotensin receptor blocker, and lipid-lowering statin therapyon disease progression. The findings are both interesting anddramatic. They include a clear additive effect of receptor blockerson ACE inhibitors independent of blood pressure as well as aremarkable additional effect of adding a statin in further reducingACE activity and TGF- expression. The combination of all threedrugs virtually halted any sign of progressive disease. It isobviously a long way from rat to human, but translation of findingsin rodent models of progression to humans has been remarkablygood. This observation needs confirmation in humans, but theresults provide great encouragement that halting progressionof proteinuric renal disease with non–disease-specifictherapy may be an achievable goal. This concept is discussedfurther by Hostetter in an editorial in this issue.
Pentoxifylline Attenuated the Renal Disease Progression in Rats with Remnant Kidney
Phosphodiesterase Inhibition —The Next Step in Renal Disease Prevention? Angiotensin II inhibitionslows the progression to end-stage renal disease, but this agentalone does not appear to prevent ESRD. Multi-drug therapy willalmost certainly be necessary to achieve this goal. The presentstudy in 5/6 nephrectomized rats reports that the phosphodiesteraseinhibitor pentoxifylline (PTX) affords additional renal protectionwhen combined with an ACE inhibitor (CLZ). Oral therapy witheither drug alone decreased interstitial fibrosis to ~50%, whilecombined drug therapy decreased fibrosis to ~20% of vehicle-treatmentlevels. PTZ had no effect on blood pressure. Although its primaryantifibrotic mechanism remains unknown, PTX reduced interstitialinflammation, interstitial myofibroblast numbers, and renalexpression of several fibrosis-promoting genes and matrix proteins.In vitro studies found that PTX inhibited monocyte chemoattractantprotein-1 and suppressed connective tissue growth factor viaa TGF-–independent action. This is one of the first reportsof important chronic renoprotective effects of PTX therapy,an orally active drug. This impressive finding deserves furtherevaluation in ways discussed by Hostetter in an editorial ontreating progressive renal disease in this issue.
Glomerular Oxidative and Antioxidative Systems in Experimental Mesangioproliferative Glomerulonephritis
Oxidants Again – This Timein the Mesangium. Recent studies in the antithymocyte serum(ATS) model of mesangioproliferative glomerulonephritis in ratshave taught us a great deal about the mesangial response toinjury and the consequences of that response for glomerularstructure and function. In diseases like IgA nephropathy, itis the mesangial response to immune reactants, including IgAaggregates and C5b-9, that likely govern disease expression.One aspect of this response is the production of oxidants byproliferating mesangial cells. In this article, Gaertner etal. examine the oxidant levels and expression of oxidant andantioxidant enzymes in the ATS model and find increases in oxidants,particularly H2O2, but also decreases in antioxidant enzymeactivity, thus documenting a substantial dysregulation of theoxidant–antioxidant system in the mesangium after injury.The article does not provide any data on effects of antioxidanttherapy to establish that the increased oxidant activity ispathogenic, but it likely is. Antioxidant therapy has not yetfound a place in the treatment of renal inflammation, but studieslike this one suggest that it may well in the future.
Clinical Nephrology
Long-Term Renal Effects of Low-Dose Cyclosporine in Uveitis-Treated Patients: Follow-up Study
Calcineurin Inhibitor Nephrotoxicityin Native Kidneys: Is There a Safe Dose? There is somethinginherently discomforting about giving nephrotoxic drugs to peoplewith kidney disease, yet indications for using calcineurin inhibitorsexist in diseases like membranous nephropathy and focal glomerularsclerosis. How can we most safely do this? In this study Bagniset al. confirm the long-term nephrotoxicity of low-dose calcineurininhibitors (cyclosporine) in native kidneys in patients withautoimmune uveitis but normal kidneys. Patients were prospectivelystudied, and data on renal function, hypertension, and a smallnumber of renal biopsies were collected. The study establishedthe negative impact of cyclosporine on renal function, increasedincidence of hypertension, and occurrence of intrarenal fibrosis,even with doses of approximately 4 mg/kg. The study did notanswer the question of reversibility, but it concludes thata does of <3 mg/kg may be advisable to prevent nephrotoxicity.
Epidemiology and Outcomes
Donor Hepatitis C Seropositivity: Clinical Correlates and Effect on Early Graft and Patient Survival in Adult Cadaveric Kidney Transplantation
A Relook at the Impact of TransplantingHepatitis C–Positive Kidneys. Bucci et al. used the USRDSto analyze the impact of transplanting hepatitis C–positivekidneys into either hepatitis C–negative or –positiverecipients. This study is important and timely. The analysisof a large number of patients established the negative impacton recipient mortality when using hepatitis C–positivedonors. The conclusions are intriguing and question some ofthe current organ allocation policies regarding using hepatiticC–positive organs.
Transplantation
Reversibility with Interleukin-2 Suggests that T cell Anergy Contributes to Donor-Specific Hyporesponsiveness in Renal Transplant Patients
A Mechanistic Look at Donor-SpecificHyporesponsiveness in Renal Transplant Recipients. It has longbeen recognized that some renal transplant recipients exhibitimmune hyporesponsiveness to donor alloantigen, but the mechanismsof this hyporesponsiveness are unclear. Ng et al. examined thesemechanisms in human renal transplant recipients and showed thatsuch hyporesponsiveness can be recovered by the addition ofIL-2 to the culture, indicating, at least in two thirds of patientsexamined, a mechanism of anergy. Four questions arise from thestudy and warrant further investigations. What are the mechanismsin the remaining one third of recipients? Can these types ofassays be used to consider minimizing or withdrawing immunosuppression?If anergy is reversible in vitro, is it also potentially reversiblein vivo, such as after an infectious or inflammatory processassociated with a cytokine surge? Finally, what are the mechanismsof donor-specific hyporesponsiveness to the indirect pathwayreported by the authors and others?
expression. The combination of all three drugs virtually halted any sign of progressive disease. It is obviously a long way from rat to human, but translation of findings in rodent models of progression to humans has been remarkably good. This observation needs confirmation in humans, but the results provide great encouragement that halting progression of proteinuric renal disease with non–disease-specific therapy may be an achievable goal. This concept is discussed further by Hostetter in an editorial in this issue. 
