BASIC SCIENCE
Cell Biology
Simvastatin Modulates Angiotensin II Signaling Pathway by Preventing Rac1-Mediated Upregulation of p27
Statins: Here’s Another Thing They Do Independent of Lipid-Lowering Effects.
By way of background, Angiotensin II has pleiotropic effects in renal disease, including hemodynamic effects, pro-fibrotic effects, and effects on cell hypertrophy mediated through p27, a negative regulator of the cell cycle. Statins reduce cholesterol levels and benefit cardiovascular disease and perhaps renal disease as well. However, it is not uncommon that drugs are found to exert beneficial effects for reasons different from their known biological actions. In this study, Zeng et al. follow up on the observation that Angiotensin II upregulates local p27 expression in mesangial cells, thus favoring hypertrophy, and show that simvastatin blocks a signaling pathway that leads to p27 upregulation by Angiotensin II, thus favoring proliferation rather than hypertrophy. This same pathway leads to oxidant production by mesangial cells. While these effects to inhibit hypertrophy and oxidant production might be postulated to be beneficial in a disease like diabetes, this study was performed only in cell culture. Whether or not it translates into clinical benefits, it does expand our knowledge of how statins work, and it suggests other situations in which inhibition of p27 via the Rac-1 pathway might be beneficial. Page 1711
Genetics and Development
Defective Trafficking of Nephrin Missense Mutants Rescued by a Chemical Chaperone
Chemical Chaperone to Treat Congenital Nephrotic Syndrome.
Congenital nephrotic syndrome of the Finnish type is caused by mutations of the slit diaphragm protein, nephrin. Missense mutations of nephrin cause misfolding of the protein, which leads to retention in the endoplasmic reticulum and degradation by the proteasome. Recent studies suggest that human diseases that are characterized by protein misfolding and endoplasmic reticulum retention, including cystic fibrosis and (1-antitrypsin deficiency, may be treated with chemical chaperones that promote trafficking to the plasma membrane and secretion. Liu et al. treated cells stably expressing nephrin missense mutations with a chemical chaperone, 4-phenylbutyrate, which promoted the trafficking of some mutant proteins to the cell surface. Importantly, the mutant proteins could interact with Neph1 and were phosphorylated, suggesting that they retained function. Since 4-phenylbutyrate has been safely used in humans for the treatment of urea cycle disorders, these studies identify a potential new treatment of congenital nephrotic syndrome that could be targeted to patients with specific nephrin mutations. Page 1731
Hemodynamics and Vascular Regulation
Alterations in Renal Endothelial Nitric Oxide Synthase Expression by Salt Diet in Angiotensin Type 1α Receptor Gene-Knockout Mice
Roles of Angiotensin II and Nitric Oxide in Regulating Renal Vascular Tone.
The article by Sato et al. explores the links between Angiotensin II and endothelial nitric oxide synthase (eNOS) in regulating vasculature tone. The angiotensin AT1 receptor knockout mouse appears to have lost autoregulation with striking variations in BP and body weight in response to changes in dietary salt intake. Hydralazine reduced the BP responses to dietary salt, consistent with the role of eNOS in regulating vascular tone. These responses are magnified in the knockout model, illustrating the push-pull relation between the effects of NO and Angiotensin II on the renal vasculature. Superimposed on the regulation of vascular tone, the macula densa mediates feedback responses on glomerular blood flow. Of note, the relevant NO synthase in the macula densa is the neuronal isoform. Studies of the effects of changes in dietary salt intake and nNOS activity in the macula densa in this model would be of great interest. Page 1756
Basic Immunology and Pathology
Nephritis-Associated Plasmin Receptor and Acute Poststreptococcal Glomerulonephritis: Characterization of the Antigen and Associated Immune Response
The Nephritogenic Antigen in Post-Strep GN: Are We There Yet?
Although it is conventionally regarded as the human equivalent of the acute serum sickness model in rabbits, there are several aspects of the pathogenesis of poststreptococcal nephritis that remain poorly understood. One is the nature of the nephritogenic antigen. Several candidate streptococcal proteins have been proposed, but the one of most recent interest is nephritis-associated plasmin receptor (NAPir). This component of the bacterial cell wall has been extensively studied by Yoshizawa et al., who have previously shown that patients with poststreptococcal nephritis have antibody to it, that it localizes in glomeruli of these patients, and that it has the capacity to activate complement in glomeruli independently of antibody. This study extends these observations using nucleotide sequencing to show that NAPir is identical to GAPDH, that poststreptococcal nephritis patients have higher titers of long-lasting antibody than other exposed patients without nephritis, and that it is present in glomeruli in 100% of patients with poststreptococcal nephritis early in the disease. The study represents a another small step forward in this evolving story, but it leaves several important questions unanswered, such as whether NAPir can cause nephritis alone without antibody present, how this antigen (which localizes only in mesangial and subendothelial sites) relates to the subepithelial humps that characterize poststreptococcal nephritis, and whether circulating immune complexes participate in this process or not. The current status of this important topic is discussed in more detail in an editorial by Rodriguez-Iturbe elsewhere in this issue. Page 1785
Pathophysiology of Renal Disease and Progression
Mesenchymal Stem Cells Are Renotropic, Help Repairing the Kidney, and Improve Function in Acute Renal Failure
Stem Cells for ATN: Another Step Closer.
Several papers in JASN and elsewhere in the past year have explored the possibility of using stem cells to repopulate injured renal tubules and accelerate recovery from acute renal failure. To date, it is known that such cells can localize and proliferate in injured tubules, but substantial effects on renal function have been harder to demonstrate. In this study, Morigi et al. from the Mario Negri Institute in Bergamo utilize mesenchymal stem cells from male donors to treat female recipients with acute renal failure induced by the anti-neoplastic drug cisplatin. The results demonstrate that donor-derived stem cells of mesenchymal origin can localize in injured tubules, transform into tubular epithelial cells, and substantially (75% reduction in blood urea nitrogen) protect from loss of renal function when given a day after administration of the nephrotoxin but before the blood urea nitrogen is elevated. Like most, this study is not flawless, and questions about some of the technical details can be raised. However, it provides strong evidence for the potential of stem cells, when the necessary details are worked out, to benefit patients with ATN, an entity sorely lacking in introduction of any recent therapeutic advances. Page 1794
Basic Transplantation
Differential Expression of Chemokines and Chemokine Receptors in Murine Islet Allografts: The Role of CCR2 and CCR5 Signaling Pathways
Attracting Immune Cells to the Allograft: Chemokines and their Redundancy.
Chemokines and chemokine receptors play critical functions in attracting immune cells to the allograft site during the course of rejection. Indeed, targeting of chemokines and/or their receptors has been reported to affect allograft rejection in experimental animals. In humans, associations have been reported between organ transplant outcomes and genetic polymorphisms of specific chemokine receptors. The article by Schroppel et al. describes the expression pattern of key chemokines and chemokine receptors on islet cells in vitro and in vivo during the course of rejection. Interestingly, and in contradistinction to other recent reports in vascularized grafts and even in islet cells, gene targeting of specific receptors did not have a major impact on islet allograft survival highlighting the complexity and redundancies of the these pathways. The results emphasize that chemokine/chemokine receptor targeting will need to involve multiple ones in order to prevent islet cell allograft rejection. Page 1853
CLINICAL SCIENCE
Clinical Nephrology
Acute Renal Failure after Non-Myeloablative Hematopoietic Cell Transplantation
Bone Marrow Transplantation: New Procedures, New Forms of Acute Renal Failure.
Bone marrow transplantation without complete myeloablation is considerably less aggressive than conventional bone marrow transplantation and offers the advantage that the graft versus host reaction helps to eliminate tumor cells. One would anticipate that this less aggressive procedure carries less risk of acute renal failure. Nevertheless the experience of the Denver group shows that renal dysfunction is quite frequent. Even dialysis-dependent acute renal failure, although infrequent, may occur particularly after artificial ventilation and contributes significantly to mortality. Several clinical characteristics differ from acute renal failure after conventional bone marrow transplantation—a new challenge to the nephrologist. Page 1868
Epidemiology and Outcomes
Kidney Dysfunction, Inflammation, and Coronary Events: A Prospective Study
Patients with Chronic Kidney Disease Are More Susceptible to Cardiovascular Consequences of Chronic Inflammation.
Knight et al. examine the association between inflammatory biomarkers and the risk of cardiovascular events among participants in the Nurses Health Study. They observe that low renal function and markers of inflammatory stress, including high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor receptors I and II, interact to increase the risk of cardiovascular events, noted primarily among individuals with creatinine clearance below 75 ml/min. It is not clear why the same level of inflammatory stress conferred increased risk of cardiovascular events among individuals with impaired but not normal creatinine clearance. As discussed by the authors, chronic kidney disease may be a proatherogenic state that promotes atherosclerotic plaque progression and rupture. A second possibility is that inflammatory biomarkers are a consequence of subclinical atherosclerotic disease and that the chronic kidney disease was a consequence of shared risk factors for progressive renal injury and atherosclerotic cardiovascular disease. Common risk factors that might account for endothelial and renal injury include hypertension, diabetes mellitus, dyslipidemia, smoking, activation of the sympathetic and renin angiotensin systems, and inflammatory stress. This report suggests that understanding the reciprocal roles of early atherosclerotic cardiovascular disease and progressive renal injury might provide important insight into the pathogenesis of both diseases. Page 1897
Moderate Renal Impairment and Risk of Dementia Among Older Adults: The Cardiovascular Health Cognition Study
It’s Not Just Cardiovascular Disease That’s Increased in Patients with Chronic Kidney Disease.
End-stage renal disease patients have a higher prevalence of dementia than observed in the general population. The Cardiovascular Heart Study (CHS) is a study of a representative selection of Medicare patients living in four communities in the United States. Seliger et al. used neurocognitive testing performed on CHS participants to examine the association between decreased renal function and subsequent risk of dementia in otherwise healthy adults. Healthy CHS participants with moderately impaired renal function had a 37% increased risk of developing dementia compared with individuals with normal renal function. Dementia was categorized using clinical and neuroimaging criteria as either Alzheimer or vascular dementia, and impaired renal function was an independent risk factor for vascular but not Alzheimer dementia. As discussed by the authors, this raises the possibility that the increased risk of dementia noted across the spectrum of impaired renal function is related to the generally increased risk of atherosclerotic cardiovascular disease. This observation needs to be replicated by other observational studies like the Chronic Renal Insufficiency Cohort Study. Page 1904
Clinical Transplantation
Alloreactivity in Renal Transplant Recipients with and without Chronic Allograft Nephropathy
Immunologic Monitoring Revisited in Renal Transplantation.
Chronic allograft nephropathy remains a major problem, limiting successful long-term outcome in renal transplantation and resulting in end-stage renal disease that requires dialysis or retransplantation in a significant number of kidney transplant recipients. Abnormal renal function and development of the pathological changes of chronic allograft nephropathy are both late changes; therefore, development of novel surrogate markers to predict early disease is very important for development of early therapies to halt progression. The paper by Poggio et al. described the results of a cross-sectional study comparing T cell and humoral alloreactivity in kidney transplant recipients with chronic allograft nephropathy. The study is the first to report in the same population on direct, indirect, and humoral alloreactivity. The study confirms that patients who have established chronic allograft nephropathy have heightened alloimmune response, as evidenced by T cell alloreactivity and de novo alloantibody production. Interestingly, others have previously reported that direct T cell anti-donor alloreactivity is suppressed in recipients with chronic allograft nephropathy, a different observation from what is being reported here. Nonetheless, the results from this study highlight that prospective controlled studies are required to monitor the immune response in kidney transplant recipients before and during development of chronic allograft nephropathy, and they show that such monitoring assays should be accompanied by clinical trials to evaluate new immunosuppressive therapies. Page 1952
- © 2004 American Society of Nephrology
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