Noble Experiments withWater Channels and Steroids. When glucocorticoid-deficient ratsare water-deprived, they cannot maximally concentrate theirurine. In this issue of JASN, Chen et al. have precisely describeddecreased expression of the Na-K-2Cl cotransporter in the thickascending limb, of urea transporters and water channels in theinner medulla, and of the Gs protein in the outer medulla, whichwould transduce the stimulatory effects of antidiuretic hormoneon urinary concentration. A consequence of these deficienciesis a decrease in medullary hypertonicity, which is the drivingforce for water absorption in the collecting tubule during waterdeprivation. It is not clear how glucocorticoids regulate theexpression of the entire ensemble of processes and transportersrequired for maximal urinary concentration, nor is the proximatesignal clearly defined. It is clear that glucocorticoid-deficientrats have reduced cardiac output and mean arterial BP, whichcan be attributed to their failure to optimally concentratethe urine in this model of nephrogenic diabetes insipidus. SeeChen et al., pages 2864–2871.
Interactions of Hypoxiaand Inflammation Promote sPLA2 Expression. Phospholipase A2(PLA2) constitutes a superfamily of enzymes that release fattyacids, including arachidonic acid, from membrane phospholipids,for synthesis of key inflammatory mediators such as prostaglandinsand leukotrienes. PLA2 is increased in inflammatory conditions.In the glomerulus, the mesangial cells cross-communicate withinfiltrating inflammatory cells and in turn synthesize proinflammatorymediators, proliferate, and increase ECM synthesis. In thisissue of JASN, Petry et al. show that whereas hypoxia aloneis insufficient to activate the sPLA2-IIA promoter in mesangialcells, in the presence of an inflammatory stimulus, hypoxiapotentiates sPLA2 expression. This enhancing effect was dueto direct binding of HIF-2-alpha to HRE sites in the sPLA2-IIApromoter. This study thus demonstrates that inflammation andhypoxia may interact to enhance the formation of inflammatorylipid mediators relevant to a diverse range of kidney diseases.See Petry et al., pages 2897–2905.
Podocyte Loss and Glomerulosclerosis.Podocytes may be the initial target for various human renaldiseases, and regardless of initial injury, podocyte loss hasbeen postulated to contribute to progressive nephron injury.In this issue of JASN, Wharram et al. provide direct evidencein support of this hypothesis. Transgenic rats expressing thehuman diphtheria toxin receptor specifically on podocytes weregiven various doses of diphtheria toxin, resulting in a dose-dependentvarying amount of podocyte depletion. Minor depletion resultedonly in transient abnormalities and mesangial expansion, whereasintermediate depletion (21 to 40% loss) resulted in synechiaeand focal segmental glomerulosclerosis, and severe podocyteloss (>40%) resulted in sustained renal dysfunction and moreextensive glomerulosclerosis. These studies thus provide elegantevidence supporting the hypothesis that podocyte loss, whensufficiently extensive, may be a contributing mechanism to progressiveglomerulosclerosis. See Wharram et al., pages 2941–2952.
Glomerulosclerosis—CanProteomics Help Us Understand It Better? We currently identifysclerotic glomeruli only by light and electron microscopy, butclearly there must be more subtle changes that precede these.Others have searched with limited success for such changes withmolecular techniques such as DNA arrays. Xu et al. have employeda newer proteomic methodology to compare sclerotic to nonscleroticand normal glomeruli in the remnant kidney model of secondaryfocal sclerosis. Not surprisingly, the sclerotic glomeruli differedsubstantially from normal ones. But of more interest, the nonscleroticglomeruli in remnant kidneys were more like sclerotic than normalones, thus identifying early changes that likely predict, andmay even cause, the development of sclerosis. A clue is providedby further studies of thymosin 4, one of the unregulated proteins,that itself exerts a profibrotic effect by inhibiting PAI 1,which impairs breakdown of fibrin and extracellar matrix. Thesestudies are important because they not only show the feasibilityof applying proteomics to the detection and study of glomerularscarring, but also yield a new insight into what the mechanismsinvolved may be. See Xu et al., pages 2967–2975.
Blood Pressure—HowLow Is Low Enough? While specific antihypertensive agents havebeen shown to slow progression in diabetic and other types ofnondiabetic kidney disease, the independent effect of BP controlon progression is unclear. In a secondary analysis of the IrbesartanDiabetic Nephropathy Trial (IDNT) data, Pohl et al. demonstratedassociations among follow-up systolic BP and the risks of progressionand all-cause mortality, with reduced progression rates observedto a systolic BP of 120 mmHg, but not below. While confoundingby the severity of kidney disease and other factors could notbe eliminated, among patients treated with inhibitors of therenin-angiotensin-aldosterone system, the authors’ conclusionto target systolic BP in the 120 to 130 mmHg range appears reasonable.See Pohl et al., pages 3027–3037.
Hypomagnesemia Caused byTRP Channel Mutations. Primary hypomagnesemia and secondaryhypocalcemia (HSH) is a rare, autosomal recessive disorder causedby mutations in TRPM6, a member of the transient receptor potentialfamily of ion channels. Schlingmann et al. describe 16 new TRPM6mutations in addition to the seven mutations previously reported.When the mutant proteins were coexpressed in Xenopus oocyteswith the homologous protein TRPM7, the normal increase in channelactivity was completely inhibited. Interestingly, mutationswithin the kinase domain as well as the pore region decreasedchannel activity. Clinically, the affected individuals presentedwith seizures in infancy. Laboratory examination revealed severehypomagnesemia as well as secondary hypoparathyroidism and hypocalcemia.Urine studies showed that the fractional excretion of magnesiumwas inappropriately elevated. Both the hypomagnesemia and hypocalcemiaimproved with magenesium supplementation. Taken together, thesestudies further demonstrate that mutations of TRPM6 are responsiblefor HSH and support the existence of a renal leak due to impairedmagnesium reabsorption in the distal convoluted tubule. SeeSchlingmann et al., pages 3061–3069.
Assessing Disease Activityin Vasculitis by Analyzing Circulating Endothelial Cells. Studiesover the past several decades have provided a wealth of insightinto mechanisms that underlie vasculitis and have identifiedendothelial cells as the principal targets of injury. Despitethe identification of roles for antineutrophil cytoplasm antibodies(ANCA), neutrophils, anti-DNA antibodies, etc., and detailedunderstanding of the endothelial response to inflammatory injury,however, these studies have generally not provided reliableways to measure ongoing vasculitic disease activity. Holmenet al. isolated, counted, and studied circulating endothelialcells in patients with Wegener’s granulomatosis and foundthat these cells are present in increased numbers, exhibit changesthat indicate their recent participation in active inflammatoryevents, correlate well with organ involvement, and even seemto impair the function of circulating endothelial progenitorcells that are presumably attempting to replace them, thus augmentingvascular injury. The prospect of being able to simply biopsythe blood to get a detailed look at what is happening in inflamedvascular beds is a truly tantalizing one that could have a majorimpact on our ability to successfully manage this frustratinggroup of patients. See Holmén et al., pages 3110–3120.
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protein in the outer medulla, which would transduce the stimulatory effects of antidiuretic hormone on urinary concentration. A consequence of these deficiencies is a decrease in medullary hypertonicity, which is the driving force for water absorption in the collecting tubule during water deprivation. It is not clear how glucocorticoids regulate the expression of the entire ensemble of processes and transporters required for maximal urinary concentration, nor is the proximate signal clearly defined. It is clear that glucocorticoid-deficient rats have reduced cardiac output and mean arterial BP, which can be attributed to their failure to optimally concentrate the urine in this model of nephrogenic diabetes insipidus. See Chen et al., pages 2864–2871. 
4, one of the unregulated proteins, that itself exerts a profibrotic effect by inhibiting PAI 1, which impairs breakdown of fibrin and extracellar matrix. These studies are important because they not only show the feasibility of applying proteomics to the detection and study of glomerular scarring, but also yield a new insight into what the mechanisms involved may be. See Xu et al., pages 2967–2975. 
