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This Month’s Highlights

Cell and Transport Physiology
Differential Regulation of Basolateral C1/HCO3- exchangers SLC26A7 and AE1 in Kidney Outer Medullary Collecting Duct
Bicarbonate Two-Step across the Basolateral Membrane?

The proton-secreting cells of the outer medullary collecting duct participate in acid secretion, and in water reabsorption during volume deprivation. When protons are secreted across the apical membrane, base equivalents are generated that must be moved across the basolateral membrane to complete the circuit and accomplish net acid secretion. Two potential bicarbonate transport systems have been identified in the basolateral membranes of these cells, a classical Cl^–/HCO₃^– exchanger (AE-1) akin to the red blood cell band-3 protein, and a recently identified Cl^–/HCO₃^– exchanger that is called SLC26A7. The results presented by Barone et al. now show that these two transporters are specifically and differently regulated in response to volume deprivation. SLC26A7 is markedly up-regulated in response to volume depletion, suggesting that its physiological role is involved in volume regulation and perhaps in the metabolic alkalosis associated with volume depletion, while AE-1 would be more directly involved in the transepithelial proton secretory pathway. Page 2002

Cell Biology
High Ambient Glucose Enhances Sensitivity to TGF-ß1 Via ERK and PKC Activities in Human Mesangial Cells
High Blood Sugar is a Profibrotic Factor Independent of TGF Beta.

Diabetic nephropathy, the leading cause of chronic and endstage renal failure, is characterized by mesangial expansion due to increased extracellular matrix accumulation. Studies have focused on the pro-fibrogenic cytokine transforming growth factor-ß (TGF-ß). The TGF-ß effect is mediated downstream by specific signaling molecules called SMADs. In the current study, Hayashida and Schnapper show that in mesangial cells, high glucose can also increase SMADs, and that this is independent of TGF-ß. The authors describe the mechanisms underlying this novel observation. Finally, they show that high glucose-induced SMADs augment the effects of TGF-ß, leading to increased extracellular matrix accumulation. These intriguing results shed new light on potential targets for therapy in reducing mesangial expansion in diabetic nephropathy. Page 2032

Genetics and Development
Siah-1 Interacts with the Intracellular Region of Polycystin-1 and Affects its Stability Via the Ubiquitin-proteasome Pathway
Regulation of Polycystin-1 Stability.

Mutations of PKD1 cause autosomal dominant polycystic kidney disease (ADPKD). PKD1 encodes a large integral membrane protein, called polycystin-1, which is involved in the regulation of cell growth and differentiation. The C-terminal domain of polycystin-1 has been shown to activate a number of intracellular signaling pathways, including Wnt/ß-catenin, AP-1, JAK/STAT, and G-protein signaling. Kim et al. performed a two-hybrid screen and discovered that the C-terminal domain of polycystin-1 interacts with Siah-1. Siah-1 is a RING-finger protein that regulates protein degradation via the ubiquitin-proteasome pathway. Over-expression of Siah-1 stimulates the ubiquitination of the polycystin-1 C-terminal domain and reduces its half-life in the cell. These results suggest that polycystin-1 signaling may be regulated by Siah-1-dependent protein degradation. Page 2042

Specific Cre/lox Recombination in the Mouse Proximal Tubule
Proximal Tubule-Specific Cre/lox Recombination.

The Cre/lox system is a method for creating deletions and other genetic alterations in DNA. The system utilizes an enzyme, called Cre, which recombines DNA at specific sequences, called loxP sites. Cre/lox recombination can be used to create tissue-specific gene knockouts in mice. The first step involves the generation of transgenic mice that express the Cre enzyme in specific tissues. Rubera et al. linked the promoter of the sodium-glucose cotransporter gene (Sglt2) to the Cre gene and produced transgenic mice. Like Sglt2, Cre was expressed only in the kidney and not in the other tissues examined. Crosses with a lacZ reporter mouse showed that Cre/lox recombination occurred only in renal proximal tubules. Sglt2-Cre mice are a new reagent that should be very useful for producing kidney-specific gene knockouts, as described in the accompanying editorial. Page 2050

Basic Mineral Metabolism
An Acidic Peptide Sequence of Nucleolin-related Protein can Mediate the Attachment of Calcium Oxalate to Renal Tubule Cells
New Insight into Nephrolithiasis?

It is well recognized that the initial precipitating event in kidney stone formation is focused at a nidus for crystallization. Multiple inhibitors and accelerators of kidney stone formation have been identified, and Sorokina et al. have now identified a cellular protein that appears to participate in the aggregation of calcium oxalate crystals on renal tubule cells. This protein (nucleolin-related protein, NRP) is expressed on the surface of inner medullary collecting duct cells early in their differentiation cycle. If local crystal aggregation injures the tubular epithelium, then the resultant proliferative response could augment crystal formation and thus accelerate further stone formation. It would be worth understanding if the sequence or expression of NRP could be involved in cases of familial nephrolithiasis, and if pharmacologic agents that could modify the binding to the acidic peptide sequence could be used to reduce the crystal aggregation rate. Page 2057

Basic Immunology and Pathology
Coupled Induction of iNOS and p53 Up-regulation in Renal Resident Cells May be Linked with Apoptotic Activity in the Pathogenesis of Progressive IgA Nephropathy
Apoptosis, p53, iNOS: Links to Outcome in IgA?

This study provides evidence of a relationship between iNOS induction, p53 expression, and apoptosis that has not been previously described in human IgA nephropathy. The findings are correlative, and the link underlying expression of iNOS and p53 in glomeruli and severely damaged tubules and their correlation with functional indices of poor outcome (diminished creatinine clearance and increased proteinuria) remains obscure. The authors suggest increased NO activity resulting from increased iNOS activity may be pro-apoptotic in IgAN, but there remain many vagaries in the data available from studies to date in support of this hypothesis. This study increases our interest in this hypothesis and indicates its potential clinical relevance in a major human renal disease. Page 2066

Mitogenic Signaling of uPAR-deficient Kidney Fibroblasts: Actions of an Alternative Urokinase Receptor and LDL Receptor-related Protein
Multiple Faces for Urokinase in Chronic Kidney Disease.

In addition to renal tubules, urokinase (uPA) is also produced by inflammatory cells and (myo)fibroblasts in the interstitium where it is likely to modulate fibrogenic events. It may do so either as an extracellular protease or via cell-dependent signaling and scavenging activities that are initiated when uPA binds to its receptor (uPAR). The importance of the cell-dependent actions is illustrated by worse renal fibrosis in uPAR null mice in response to ureteral obstruction. As reported in the present study, absence of uPAR has unmasked another uPA-dependent cellular effect: proliferation of uPAR null kidney fibroblasts is enhanced by a pathway that appears to involve an alternative uPA receptor and ERK signaling. Not only might this "hyper-proliferative" phenotype of uPAR-deficient fibroblasts contribute to a higher density of interstitial myofibroblasts, as was observed after ureteral obstruction, but these fibroblasts may manifest other phenotypic and functional differences that enhance its fibrosis-promoting activities. As an example, the uPAR null fibroblasts were shown to express lower levels of the low density lipoprotein receptor-related protein (LRP), a multifunctional scavenging and signaling receptor. Whether the alternative (non-uPAR) uPA receptor is up-regulated and/or unmasked by uPAR deficiency remains to be determined. Currently the identity of this receptor remains unknown although several good candidates have been proposed. Page 2090

CLINICAL SCIENCE

Epidemiology and Outcomes
Association between Smoking and Chronic Renal Failure in a Nationwide Population-based Case-control Study
Smoking and Risk of CKD.
The use of tobacco has been found to be associated with the presence and rate of progression among high-risk populations and patients with established kidney disease. The report by Ejerblad and her colleagues extends these observations to the general population. In this population case-control study they observed a graded increase between increasing cigarette use and risk of prevalent kidney disease among individuals with glomerulonephritis and hypertensive renal disease. This raises an interesting possibility that the increased risk of kidney disease associated with smoking may be related to disease, specific mechanisms. If this observation is confirmed by future investigation, then we must consider how the behavioral characteristics of cigarette use and the components of cigarette smoke might be related to the pathogenesis of progressive renal injury in these conditions. The report also underscores for the clinician the importance of smoking cessation counseling in the management of individuals at high risk for CKD. Page 2178

Renal Function, Digoxin Therapy, and Heart Failure Outcomes—Evidence from the Digoxin Intervention Group Trial
Heart Failure Patients with CKD—An Undertreated Population?

The report by Shlipak and his associates from the DIG trial reminds us once again of the high prevalence of CKD among hospitalized heart failure patients, with a GFR of <60 ml/min/1.73 m2 observed for 46% of the participants of this clinical trial despite exclusion of individuals with a serum creatinine > 3 mg/dl. The presence of CKD was associated with increased mortality with the excess risk appearing below an estimated GFR of <50 ml/min/1.73 m2, near the K/DOQI threshold for CKD based on renal function alone. Despite the existing evidence-based guidelines that recommend that heart failure patients with CKD be treated with ACE-inhibitors, use of these drugs decreased as renal function declined, a problem noted in other heart failure populations. Based on other studies of care of heart failure patients with CKD, it is likely that other aspects of CKD care, including detection and management of anemia and nutritional counseling, could also be improved. Clinicians caring for heart failure patients should be encouraged to use GFR estimation equations to detect CKD and to aggressively pursue both cardio- and renoprotective therapy in these patients. Page 2195

Human Mineral Metabolism and Bone Disease
Mineral Metabolism, Mortality, and Morbidity in Maintenance Hemodialysis
Does Phosphate Kill ESRD Patients?

Renal bone disease is a preventable cause of morbidity among end-stage renal disease patients, and guidelines are available to guide the management of the complication of kidney failure. The report by Chertow and his associates in this issue of JASN adds further support for an association between disorders of calcium and phosphorous metabolism in ESRD and increased risk of death. They observed a strong, graded, and independent increase in the risk of death for serum phosphorous levels in excess of 5 mg/dL and for calcium levels in excess of 8.5 mg/dL. These observations raise the possibility that interventions to improve control of phosphorous and calcium management in ESRD may contribute to reductions in the risk of mortality in these patients. This possibility can be answered only by appropriately designed clinical trials. Page 2208

Clinical Transplantation
Angiotensin Converting Enzyme Genotype and Chronic Allograft Nephropathy in Protocol Biopsies
ACE Gene Polymorphisms and Chronic Allograft Nephropathy (CAN), Revisited!

In this study, Hueso et al. studied the association between the ACE-DD genotype and prevalence of CAN as well as graft outcome. They also measured intragraft mRNA levels of ACE. The data show that ACE-DD genotype is not associated with an increased prevalence or incidence of CAN, but it is actually associated with higher ACE mRNA levels in the transplant and poorer graft survival in patients already displaying CAN. It is interesting that these data do mimic the results of studies in native kidneys showing that the ACE-DD is not associated with an increased incidence of native renal diseases. It could modulate progression to renal failure in patients already displaying chronic lesions, providing evidence for an important role of ACE-DD in progression of renal dysfunction in the setting of native as well as transplanted kidneys. The data also support the notion that blocking angiotensin II may be a desirable therapeutic strategy to prevent progression of renal allograft dysfunction in patients with early CAN. Page 2229

Related Articles

Differential Regulation of Basolateral Cl^–/HCO₃^– Exchangers SLC26A7 and AE1 in Kidney Outer Medullary Collecting Duct

Sharon Barone, Hassane Amlal, Jie Xu, Minna Kujala, Juha Kere, Snezana Petrovic, and Manoocher Soleimani
J. Am. Soc. Nephrol. 2004 15: 2002-2011. [Abstract] [Full Text] [PDF]

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