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, AngiotensinII has pleiotropic effects in renal disease, including hemodynamiceffects, pro-fibrotic effects, and effects on cell hypertrophymediated through p27, a negative regulator of the cell cycle.Statins reduce cholesterol levels and benefit cardiovasculardisease and perhaps renal disease as well. However, it is notuncommon that drugs are found to exert beneficial effects forreasons different from their known biological actions. In thisstudy, Zeng et al. follow up on the observation that AngiotensinII upregulates local p27 expression in mesangial cells, thusfavoring hypertrophy, and show that simvastatin blocks a signalingpathway that leads to p27 upregulation by Angiotensin II, thusfavoring proliferation rather than hypertrophy. This same pathwayleads to oxidant production by mesangial cells. While theseeffects to inhibit hypertrophy and oxidant production mightbe postulated to be beneficial in a disease like diabetes, thisstudy was performed only in cell culture. Whether or not ittranslates into clinical benefits, it does expand our knowledgeof how statins work, and it suggests other situations in whichinhibition 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 ofthe Finnish type is caused by mutations of the slit diaphragmprotein, nephrin. Missense mutations of nephrin cause misfoldingof the protein, which leads to retention in the endoplasmicreticulum and degradation by the proteasome. Recent studiessuggest that human diseases that are characterized by proteinmisfolding and endoplasmic reticulum retention, including cysticfibrosis and (1-antitrypsin deficiency, may be treated withchemical chaperones that promote trafficking to the plasma membraneand secretion. Liu et al. treated cells stably expressing nephrinmissense mutations with a chemical chaperone, 4-phenylbutyrate,which promoted the trafficking of some mutant proteins to thecell surface. Importantly, the mutant proteins could interactwith Neph1 and were phosphorylated, suggesting that they retainedfunction. Since 4-phenylbutyrate has been safely used in humansfor the treatment of urea cycle disorders, these studies identifya potential new treatment of congenital nephrotic syndrome thatcould 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 1 Receptor Gene-Knockout Mice Roles of Angiotensin II and Nitric Oxide in Regulating Renal Vascular Tone.
The article by Sato et al. exploresthe links between Angiotensin II and endothelial nitric oxidesynthase (eNOS) in regulating vasculature tone. The angiotensinAT1 receptor knockout mouse appears to have lost autoregulationwith striking variations in BP and body weight in response tochanges in dietary salt intake. Hydralazine reduced the BP responsesto dietary salt, consistent with the role of eNOS in regulatingvascular tone. These responses are magnified in the knockoutmodel, illustrating the push-pull relation between the effectsof NO and Angiotensin II on the renal vasculature. Superimposedon the regulation of vascular tone, the macula densa mediatesfeedback responses on glomerular blood flow. Of note, the relevantNO synthase in the macula densa is the neuronal isoform. Studiesof the effects of changes in dietary salt intake and nNOS activityin 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 regardedas the human equivalent of the acute serum sickness model inrabbits, there are several aspects of the pathogenesis of poststreptococcalnephritis that remain poorly understood. One is the nature ofthe nephritogenic antigen. Several candidate streptococcal proteinshave been proposed, but the one of most recent interest is nephritis-associatedplasmin receptor (NAPir). This component of the bacterial cellwall has been extensively studied by Yoshizawa et al., who havepreviously shown that patients with poststreptococcal nephritishave antibody to it, that it localizes in glomeruli of thesepatients, and that it has the capacity to activate complementin glomeruli independently of antibody. This study extends theseobservations using nucleotide sequencing to show that NAPiris identical to GAPDH, that poststreptococcal nephritis patientshave higher titers of long-lasting antibody than other exposedpatients without nephritis, and that it is present in glomeruliin 100% of patients with poststreptococcal nephritis early inthe disease. The study represents a another small step forwardin this evolving story, but it leaves several important questionsunanswered, such as whether NAPir can cause nephritis alonewithout antibody present, how this antigen (which localizesonly in mesangial and subendothelial sites) relates to the subepithelialhumps that characterize poststreptococcal nephritis, and whethercirculating immune complexes participate in this process ornot. The current status of this important topic is discussedin more detail in an editorial by Rodriguez-Iturbe elsewherein 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 elsewherein the past year have explored the possibility of using stemcells to repopulate injured renal tubules and accelerate recoveryfrom acute renal failure. To date, it is known that such cellscan localize and proliferate in injured tubules, but substantialeffects on renal function have been harder to demonstrate. Inthis study, Morigi et al. from the Mario Negri Institute inBergamo utilize mesenchymal stem cells from male donors to treatfemale recipients with acute renal failure induced by the anti-neoplasticdrug cisplatin. The results demonstrate that donor-derived stemcells 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 renalfunction when given a day after administration of the nephrotoxinbut before the blood urea nitrogen is elevated. Like most, thisstudy is not flawless, and questions about some of the technicaldetails can be raised. However, it provides strong evidencefor the potential of stem cells, when the necessary detailsare worked out, to benefit patients with ATN, an entity sorelylacking 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 receptorsplay critical functions in attracting immune cells to the allograftsite during the course of rejection. Indeed, targeting of chemokinesand/or their receptors has been reported to affect allograftrejection in experimental animals. In humans, associations havebeen reported between organ transplant outcomes and geneticpolymorphisms of specific chemokine receptors. The article bySchroppel et al. describes the expression pattern of key chemokinesand chemokine receptors on islet cells in vitro and in vivoduring the course of rejection. Interestingly, and in contradistinctionto other recent reports in vascularized grafts and even in isletcells, gene targeting of specific receptors did not have a majorimpact on islet allograft survival highlighting the complexityand redundancies of the these pathways. The results emphasizethat chemokine/chemokine receptor targeting will need to involvemultiple 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 withoutcomplete myeloablation is considerably less aggressive thanconventional bone marrow transplantation and offers the advantagethat the graft versus host reaction helps to eliminate tumorcells. One would anticipate that this less aggressive procedurecarries less risk of acute renal failure. Nevertheless the experienceof 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 contributessignificantly to mortality. Several clinical characteristicsdiffer from acute renal failure after conventional bone marrowtransplantation—a new challenge to the nephrologist. Page1868
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 biomarkersand the risk of cardiovascular events among participants inthe Nurses Health Study. They observe that low renal functionand markers of inflammatory stress, including high-sensitivityC-reactive protein, interleukin-6, and tumor necrosis factorreceptors I and II, interact to increase the risk of cardiovascularevents, noted primarily among individuals with creatinine clearancebelow 75 ml/min. It is not clear why the same level of inflammatorystress conferred increased risk of cardiovascular events amongindividuals with impaired but not normal creatinine clearance.As discussed by the authors, chronic kidney disease may be aproatherogenic state that promotes atherosclerotic plaque progressionand rupture. A second possibility is that inflammatory biomarkersare a consequence of subclinical atherosclerotic disease andthat the chronic kidney disease was a consequence of sharedrisk factors for progressive renal injury and atheroscleroticcardiovascular disease. Common risk factors that might accountfor endothelial and renal injury include hypertension, diabetesmellitus, dyslipidemia, smoking, activation of the sympatheticand renin angiotensin systems, and inflammatory stress. Thisreport suggests that understanding the reciprocal roles of earlyatherosclerotic cardiovascular disease and progressive renalinjury might provide important insight into the pathogenesisof 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 patientshave a higher prevalence of dementia than observed in the generalpopulation. The Cardiovascular Heart Study (CHS) is a studyof a representative selection of Medicare patients living infour communities in the United States. Seliger et al. used neurocognitivetesting performed on CHS participants to examine the associationbetween decreased renal function and subsequent risk of dementiain otherwise healthy adults. Healthy CHS participants with moderatelyimpaired renal function had a 37% increased risk of developingdementia compared with individuals with normal renal function.Dementia was categorized using clinical and neuroimaging criteriaas either Alzheimer or vascular dementia, and impaired renalfunction was an independent risk factor for vascular but notAlzheimer dementia. As discussed by the authors, this raisesthe possibility that the increased risk of dementia noted acrossthe spectrum of impaired renal function is related to the generallyincreased risk of atherosclerotic cardiovascular disease. Thisobservation needs to be replicated by other observational studieslike 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 remainsa major problem, limiting successful long-term outcome in renaltransplantation and resulting in end-stage renal disease thatrequires dialysis or retransplantation in a significant numberof kidney transplant recipients. Abnormal renal function anddevelopment of the pathological changes of chronic allograftnephropathy are both late changes; therefore, development ofnovel surrogate markers to predict early disease is very importantfor development of early therapies to halt progression. Thepaper by Poggio et al. described the results of a cross-sectionalstudy comparing T cell and humoral alloreactivity in kidneytransplant recipients with chronic allograft nephropathy. Thestudy is the first to report in the same population on direct,indirect, and humoral alloreactivity. The study confirms thatpatients who have established chronic allograft nephropathyhave heightened alloimmune response, as evidenced by T cellalloreactivity and de novo alloantibody production. Interestingly,others have previously reported that direct T cell anti-donoralloreactivity is suppressed in recipients with chronic allograftnephropathy, a different observation from what is being reportedhere. Nonetheless, the results from this study highlight thatprospective controlled studies are required to monitor the immuneresponse in kidney transplant recipients before and during developmentof chronic allograft nephropathy, and they show that such monitoringassays should be accompanied by clinical trials to evaluatenew immunosuppressive therapies. Page 1952
Receptor Gene-Knockout Mice
