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This Month's Highlights

	Basic Science Articles

Top Basic Science Articles Clinical Science Articles

The Expanding Role of COX-2, Another Piece in the Puzzle.

Prostaglandins derived from inducible cyclooxygenase-2 (COX-2) mediate a wide variety of physiologic and pathophysiologic cellular responses. Numerous studies have shown that COX-2 expression in inflammation and in malignancies confers resistance to apoptosis, and potential consequences include persistence of proinflammatory cells in lesions and resistance of cancer cells to chemotherapy. Sorokin’s group has previously shown that transfected mesangial cells overexpressing COX-2 express high levels of multidrug resistance protein 1 (MDR1), which mediates cellular efflux of many chemotherapeutic drugs. In the article by Miller et al., the authors show that increased 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 which COX-2–derived prostanoids may prevent apoptosis and provide a rationale for why pretreatment with selective COX-2 inhibitors may be useful in the prevention of multidrug resistance in response to cancer chemotherapy. See Miller et al., pages 977–985.

Targeting Diabetic Nephropathy through the Mitochondria.

In diabetes, increased reactive oxygen species (ROS) production by mitochondria has 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 rest are imported from the cytosol by transport systems found in mitochondrial membranes. A component of one of these, Tim44 is upregulated in diabetes and could mediate increased import of antioxidant proteins and reduce ROS production. Zhang et al. examined whether further Tim44 overexpression would be protective and found that gene delivery of Tim44 to diabetic mice reduced renal hypertrophy, proliferation, and apoptosis, as well as decreasing proteinuria and ROS production, and suppressed ROS production and increased ATP production in vitro. Although these studies are preliminary, they indicate that targeting specific mitochondrial proteins and/or functions may provide new directions for development of therapeutic options for diabetic complications. See Zhang et al., pages 1090–1101.

A Complementary Approach to Reducing Ischemia Reperfusion Injury Posttransplant.

Ischemia reperfusion injury contributes to posttransplant delayed renal allograft function, particularly after transplantation of cadaveric organs with prolonged cold ischemic times. Local activation of the complement cascade in the allograft has been implicated as one important mechanism underlying postischemic injury. In this issue of JASN, Patel et al. perfused rat kidneys with a membrane-localizing form of a complement regulatory protein (CR1) prior to exposing the kidneys to prolonged cold ischemia and transplantation into syngeneic hosts. The CR1-perfused organs exhibited significantly improved posttransplant survival and function, with reduced acute tubular injury, compared with control treated organs. The findings underscore the importance of the complement cascade in the pathophysiology of this disease process and provide the foundation for new strategies that could improve human allograft function after prolonged cold ischemia. See Patel et al., pages 1102–1111.

	Clinical Science Articles

Top Basic Science Articles Clinical Science Articles

 
Why Are Risk Factors for Progression and Cardiovascular Disease the Same?

The striking overlap between risk factors for progression of kidney injury and those associated with progressive atherogenesis and plaque rupture suggests that a "common ground" may exist. Bode-Böger and her colleagues report in this issue of JASN that symmetrical dimethylarginine (SDMA), a competitive antagonist of arginine transport in the kidney, increased as GFR declined in patients undergoing elective coronary angiography. Furthermore, SDMA concentrations were independently associated with the severity of coronary artery disease. These observations suggested that the association between SDMA and coronary atherosclerosis might reflect perturbations of nitric oxide (NO) synthesis, a possibility supported by cell culture studies that demonstrated a competitive inhibition of the NOS system by SDMA reversed by L-arginine. NO is a scavenger of reactive oxygen species and Bode-Böger et al. further demonstrated that inhibition of NOS by SDMA was associated with increased oxidative stress, a key component in the pathogenesis of atherosclerosis. SDMA now joins the NOS inhibitor asymmetric dimethylarginine as another possible biomarker linking coronary artery and kidney disease through perturbations in nitric oxide synthesis. See Bode-Böger et al., pages 1128–1134.

A Genetic Locus for Vesicoureteral Reflux.

Vesicoureteral reflux (VUR) occurs in about 1% of infants and is associated with the development of reflux nephropathy. The observation of parent–child transmission and increased incidence in siblings suggests that VUR has a genetic basis. Familial VUR occurs in renal malformation syndromes, such as the renal-coloboma syndrome, but no disease genes that cause primary, nonsyndromic VUR have been identified. Sally Feather et al. first identified linkage of VUR to a locus on chromosome 1. They also found evidence for genetic heterogeneity, a finding that was confirmed last year by Ali Gharavi’s group. In this issue of JASN, Vats and colleagues identified three children with chromosomal deletions associated with VUR and/or reflux nephropathy. The critical region was mapped to a 7-Mb region on chromosome 13q33-34. This region contains 24 genes encoding collagen subunits, ankyrin, transcription factors, and other proteins expressed in the kidney and urinary tract. Further studies will be required to determine whether 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 association between hemoglobin and mortality in hemodialysis patients remains a controversial subject with little evidence to guide the selection of appropriate therapeutic targets. Regidor and coworkers used a large database with serial information about hemoglobin and treatment with erythropoiesis-stimulating agents (ESA) to examine the association between attained hemoglobin and risk of death. They report that, among prevalent patients who were already treated with an ESA and who continued treatment, maintenance of hemoglobin between between 12 and 13 g/dl was associated with the greatest survival and that both lower and higher levels of attained hemoglobin confer increased risk of mortality. Furthermore, they report that resistance to an ESA confers increased risk of death. Although the study is limited by the absence of a randomized design, these and other observational data provide ample evidence to guide contemporary practice. More important questions raised by Regidor et al. deal with the causes and optimal management of resistant patients. Further exploration of these issues will help clarify the optimal management of anemia in dialysis patients. See Regidor et al., pages 1181–1191.

Why Is There a Defect in IgA Glycosylation in IgA Nephropathy?

The pathogenesis of IgA nephropathy is now believed to involve passive trapping of immunoglobulin aggregates composed predominantly of IgA₁ that are underglycosylated in the hinge region of the molecules, thus rendering them less susceptible to clearance by asialoglycoprotein receptors in the liver and spleen. The mechanism responsible for this glycosylation defect in patients with IgA nephropathy, and often their family members, remains obscure. This paper by Smith and colleagues illuminates that question by looking at glycosylation patterns in IgA₁ from patients with IgA nephropathy and controls and comparing them to patterns seen in IgD, the only other glycosylated immunoglobulin. They report that, in contrast to IgA₁, which is characteristically underglycosylated in the patients, IgD is overglycosylated. These findings establish that the biochemical machinery for glycosylating immunoglobulins is intact in these patients. Thus the defective molecules that result in the renal disease must be produced later in B cell development, perhaps as a consequence of aberrant immune regulation in response to an antigenic challenge. See Smith et al., pages 1192–01199.

Related Articles

A Locus for Renal Malformations Including Vesico-Ureteric Reflux on Chromosome 13q33–34

Kalyani R. Vats, Chandra Ishwad, Ish Singla, Ashutosh Vats, Robert Ferrell, Demetrius Ellis, Michael Moritz, Urvashi Surti, Parul Jayakar, Donald R. Frederick, and Abhay N. Vats
J. Am. Soc. Nephrol. 2006 17: 1158-1167. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Search for Related Content Related Collections Related Articles