Prevention And Reversal Of Diabetic Nephropathy Lesions
Although prevention of DN lesions in animal models with insulin treatment or reversal of lesions with islet transplantation was known from earlier studies 67-69 , reversibility of lesions in human had been more challenging to document. Diabetic patients who have received renal allografts develop DN lesions at rates similar to those in diabetic patients with native kidneys 58,70 . On the other hand, intensive treatment of hyperglycemia not only reduces incidence of microalbuminuria in type 1...
Pharmacological Blockade of RAGE and Its Impact in Diabetic Nephropathy
Studies demonstrating the enhanced expression of RAGE in the diabetic kidney did not shed light on whether this observation was linked mechanistically to the pathogenesis of nephropathy. To approach this question, pharmacological approaches have been taken to test the role of the RAGE axis in diabetes-associated nephropathy. In the first experiments, we employed the soluble form of the receptor. Soluble RAGE sRAGE was produced and purified from a baculovirus expression system and administered...
REFERENCES Akf
1. Corton JC, Anderson SP, Stauber A. Central role of peroxisome proliferator-activated receptors in the actions of peroxisome proliferators. Annu Rev Pharmacol Toxicol 2000 40 491-518. 2. Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 1990 347 645-650. 3. Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W. Control of the peroxisomal betaoxidation pathway by a novel family of nuclear hormone receptors. Cell...
Bmp Signaling In Kidney Development
Multiple BMPs have been identified in the developing kidney 34 , of which BMP-7 and BMP-4 are the most abundant. BMP-7 is expressed in the ureteric duct at embryonic day 11 postcoitum, and is maintained throughout development in the collecting tubule derivatives of the ureteric duct. BMP-7 is also expressed transiently in the induced mesenchyme, but not the uninduced mesenchyme, and its derivatives. BMP-7 is essential for kidney development as homozygous-null mice have arrested kidney...
Etiology Of The Afferent Arteriolar Dilation Underlying Diabetic Hyperfiltration
Results from the Diabetes Control and Complications Trial 7,8 established that intensive insulin therapy aimed at near normalization of blood glucose levels reduces the occurrence of microalbuminuria and albuminuria by 39 and 54 , respectively, compared with conventional insulin therapy. These benefits were greatest when intensive therapy was initiated soon after onset of T1D, underscoring the importance of early hyperglycemia-induced processes in leading to development of DN. Whereas it seems...
Antiproteinuric Therapies in Diabetic Nephropathy
Mechanistic experimental studies support that proteinuria is a risk factor but growth factor cytokines that are present in proteinuric glomerular ultrafiltrate are culprits in entertaining tubulo-interstitial fibrogenesis. Thus, the goal is to reduce glomerular macromolecule filtration. To this end angiotensin-converting enzyme ACE inhibitors have become the standard of care in DN. Substantial reductions in proteinuria can also be achieved with angiotensin receptor blockers ARBs . In the...
Requirement of OGlycosylation OGT
Fig. 6. High glucose and Glc stimulate the transactivation function of Sp1 via the HBP. A A cDNA coding for the entire transcription factor Sp1 Sp1 Holo or its TAD Sp1 Trans , or the c-Jun TAD Jun , or a portion of the AP-2 TAD was fused to the yeast GAL4 DNA binding domain GAL4 . These cDNAs were cotransfected into mesangial cells with an expression vector for the luciferase reporter gene driven by a promoter containing GAL4 DNA binding sites and exposed to Glc. Glc strongly stimulated the...
Choice Of Modality In Diabetic Esrd Patients Early Nephrology Referral
One of the most interesting parts of the RRT application is to choose the right modality for each diabetic patient. This is partially dependent as with nondiabetic patients on the same factors that include comorbid conditions, independence, and motivation of the patient, home, and social situation, and the patient's hemodynamic stability. The presence of autonomic neuropathy may result in the patient's inability to tolerate volume shifts predisposing to hypotensive episodes during HD sessions....
Therapy With Soluble Tgfp Typeiii Receptor
In addition to TPRII, the type-III receptor also called betaglycan binds to the TGF-P ligand. Betaglycan presents TGF-P directly to the type-II receptor, facilitating TGF-P signaling 127 . It has been shown that the effects of TGF-P are strongly inhibited by a recombinant, soluble type-III receptor that binds TGF-P but is unable to shepherd the ligand to the type-II receptor 128-130 . Without resorting to the competitive binding strategy of soluble receptors, one novel way to inhibit TGF-P...
Rage Signaling And Implications For Diabetic Nephropathy
The signaling cascades activated on ligand-engagement of RAGE are diverse and reflect the cell type and duration of stimulation by ligand. We and others have shown that RAGE signaling triggers recruitment of p21ras, erk1 2 p44 p42 MAP kinases, p38 and SAPK JNK MAP kinases, rho GTPases, phosphoinositol-3 kinase, and the JAK STAT pathway. Key downstream consequences such as activation of the key transcription factors nuclear factor NF -kB and CREB have also been reported 28,36,53-61 . Recent...
INTRODUCTION Gtg
This chapter outlines the histopathology of human diabetic nephropathy DN . The classical structural changes of DN have been well described and demonstrated in general renal and renal pathology textbooks. The emphasis here is on current and evolving studies and concepts in this field. As renal lesions in type 1 diabetes are believed to be more unique to DN and more uniform and as lesions in type 2 diabetes are more heterogeneous and, perhaps, more frequently complicated by renal diseases other...
Podocyte Detachment From GBM
Detachment of podocytes has been reported in glomerulopathies with severe podocyte damage. We have documented obvious and substantial podocyte foot process detachment from GBM in proteinuric type 1 diabetic patients 31 . We also found that a small but measurable fraction of GBM is denuded of podocyte foot processes in normoalbuminuric and microalbuminuric longstanding type 1 diabetic patients. Podocyte foot process detachment correlates inversely with GFR and directly with AER. Podocyte...
Of Nephropathy
Diabetic nephropathy is characterized pathologically by glomerular changes including basement membrane thickening, mesangial expansion consisting of extracellular matrix ECM protein accumulation, occasionally the classical Kimmelstiel-Wilson nodules, and, in advanced disease, glomerular sclerosis with obliteration of capillaries 26-28 . It has been proposed that the critical event leading to progressive renal failure is the unrelenting accumulation of ECM proteins such as fibronectin, laminin,...
Anemia and Diabetic Nephropathy
George Jerums, mbbs, md, fracp, Richard MacIsaac, phd, md, fracp, Sianna Panagiotopoulos, phd, and Merlin Thomas, mb, chb, phd Erythropoietin and the Anemia of Diabetic Nephropathy Anemia as a Progression Promoter in Diabetic Nephropathy Anemia and Extra-Renal Microvascular Disease Epidemiology of Anemia in Diabetes Community and Clinic-Based Studies Anemia, Cardiac Failure, and Cardiovascular Outcomes in Renal Disease The Potential Utility of Anemia Correction in Patients With Diabetes...
Tgfp Superfamily And Signal Transduction
The TGF-P family encodes several secreted factors that regulate a wide variety of cellular processes. The members include TGF-P 1-3, activins, inhibins, BMPs, and growth and differentiation factors GDFs 16,17 . These secreted proteins bind to type-I and type-II receptors expressed on the cell surface Fig. 1 . There are seven type I, also termed activin receptor-like kinases Alk , and five type-II receptors, with specific ligand-binding specificity 16 . The receptors contain intracellular...
Diabetic Glomerulosclerosis
DN is the most common cause of progression of CKD to ESRD 1 , as well as morbidity and mortality in patients with DM. DN is characterized early by glomerular hemodynamic abnormalities that will eventually lead to glomerular hyperfiltration and then to glomerular structural changes see Fig. 2 5-8 . These changes progress to MAU and an eventual CKD and CVD if preventative measures are not taken. Renal morphological changes in the initial stages involve hyperfiltration that is evidenced by...
Contributors
Joseph P. Bast, md Department of Medicine, Loyola University Stritch School of Medicine, Chicago, IL Geoffrey Boner, mbbcii Department of Internal Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel and Danielle Alberti Memorial Centre for Diabetes Complications, Vascular Division, Wynn Domain, Baker Medical Research Institute, Melbourne, Australia Erwin Bottinger, md Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, Dorrace Hamilton...
Contents
Series Editor's Part I Basic Pathophysiology and Biochemistry of Diabetic Nephropathy 1. Angiotensin II and Its Receptors in the Pathogenesis of Diabetic David J. Leehey, Ashok K. Singh, and Rekha Singh 2. Altered Renal Microvascular Function in Early Diabetes 23 Pamela K. Carmines, Joseph P. Bast, and Naohito Ishii 3. Proteinuria and Interstitial Fibrogenesis in Diabetic 4. Podocytes and Diabetic George Jerums, Sianna Panagiotopoulos, and Richard MacIsaac, 5. Altered Glucose Transport and Its...
George Jerums mbbs md Sianna Panagiotopoulos phd and Richard MacIsaac phd md
Podocyte Ultrastructure in Type 1 Diabetes Podocyte Ultrastructure in Type 2 Diabetes Podocyte and Nephrin Expression in Experimental Diabetes Nephrin Expression in Human Diabetes Alterations of Podocyte Function in Diabetes Podocyte Density in Diabetic Nephropathy Interaction of Proteins and Other Plasma Factors With Podocytes and Tubules in Diabetic Nephropathy Summary References
Treatment Strategies In The Treatment Of Hypertension In Diabetes
Current knowledge of the pathophysiological mechanisms of DN and advancing kidney disease occurring with insulin resistance and HTN in patients with diabetes will enable physicians to make rational choices in therapy. The initial evaluation of the hypertensive, diabetic patient should include a careful history and physical examination, focusing on his or her overall CVD risk. The degree of glucose control, presence of microvascular and macrovascular complications, and existence of end-organ...
INTRODUCTION Jpl
Over a nearly 25-yr period beginning in 1979, four diabetic renal-retinal syndrome meetings were held in New York City. They were led by Eli Friedman and Francis L'Esperance, who brought together epidemiologists, bench scientists, clinicians, nephrologists, and ophthalmologists involved in research and clinical care of persons with diabetic retinopathy and nephropathy 1-4 . The renal-retinal syndrome was defined in these meetings as coincident kidney and eye diseases resulting from diabetic...
HGF Ewu
Fig. 8. Putative mechanisms for therapeutic effects of HGF against tissue fibrosis. There are sequential steps for pathogenesis of tissue fibrosis 1 under chronic injuries, interstitial macrophages M j are activated and overproduce TGF- 3, then peri-tubular fibroblasts converts to ECM-producing myofibroblasts MyoFB 2 the myofibroblasts show overgrowth in response to PDGF, followed by hyperplasia of myofibroblasts so called, myofibroblas-tosis and 3 under such fibrotic conditions, CTGF and TGF-...
Effects of PPARy Ligands Independent of Changes in Blood Glucose Levels
TZD treatment could ameliorate renal abnormalities in streptozotocin STZ -induced diabetic rats, a type 1 model of diabetes, without changing blood glucose levels 84,85 . This finding suggests that the beneficial effects of PPAR-y ligands in preventing diabetes-induced renal dysfunction are independent of their insulin-sensitizing properties. Multiple biochemical mechanisms have been proposed to explain the adverse effects of hyperglycemia including activation of the diacylglycerol DAG -protein...
Diabetes And Sglts
GLUT, facilitative glucose transporter SGLT, sodium glucose cotransporter N A, information not available. GLUT, facilitative glucose transporter SGLT, sodium glucose cotransporter N A, information not available. family i.e., SGLT, SLC5A , has allowed their investigation in the kidney and a beginning assessment of their roles in normal and diabetic kidneys. The explosion of information that is now occurring in the glucose transporter field is allowing renal researchers many new opportunities to...
A Mmr
ABCD. See Appropriate Blood Pressure Control in Diabetes ACE. See Angiotensin-converting enzyme inhibitors Acute myocardial infarction, 508 ACE inhibitors, 446 ARBs, 446 prevention, 508 valsortan, 443 ADEMEX, 458 Adenosine monophosphate kinase AMPk , 106 Adenosine triphosphate ATP sensitive potassium channels impact on afferent arteriolar tone in T1D, 30-31 Advanced glycosylation endproducts AGE , 353, 458 diabetic kidney disease, 138 glucose auto-oxidation, 156-157 GLUT, 87 inhibition, 162-164...
CONCLUSIONS Hmb
The development of diabetic glomerulosclerosis and subsequent MAU in concert with insulin resistance creates a state of ED resulting from an overall proinflammatory state. This places patients at risk for CVD and increased CVD outcomes as well as progression of CKD. Treatment with traditional RAAS blockade cannot only reduce progression of DN, but can also improve CV outcomes. However, clinicians must note the beneficial effects on CV outcomes of diuretics, CCBs, and P-blockade in the...
C
Fig. 1. mRNA and ribosome, essential components involved in mRNA translation. A Organization of mRNA showing the cap at 5' end, 5' and 3' UTRs, coding region and the polyA tail. B 80S ribosome consisting of 405 and 60S subunits, bound to mRNA. C Polyribosome or polysome consists of several ribosomes bound to an mRNA transcript. Internal Ribosomal Entry Site-Driven Translation Translation of cellular mRNAs can continue even when the cap-dependent translation mechanism is inhibited. It is...
Antifibrotic Mechanisms Common To Parenchymal Organs
Thus far, we have discussed how HGF prevents or improves renal fibrosis in DN and other CRDs. We have also accumulated evidence that HGF is anti-fibrotic in other chronic nonrenal diseases, such as liver cirrhosis 66,105 , pulmonary fibrosis 67,103 , cardiomyopathy 108 , and scleroderma 109 , thus suggesting common mechanisms of fibrosis and its counteraction. Hyperplasia of interstitial myofibroblasts is the common denominator in multiple tissues, and the degree of myofibroblast hyperplasia...
REFERENCES Psj
1. Andersen AR, Christiansen JS, Andersen JK, et al. Diabetic nephropathy in Type 1 insulin-dependent diabetes an epidemiological study. Diabetologia 1983 25 496-501. 2. Krolewski AS, Warram JH, Christlieb AR, et al. The changing natural history of nephropathy in type I diabetes. Am J Med 1985 78 785-794. 3. Rossing P, Rossing K, Jacobsen P, et al. Unchanged incidence of diabetic nephropathy in IDDM patients. Diabetes 1995 44 739-743. 4. Krolewski M, Eggers PW, Warram JH. Magnitude of end-stage...
Renal Failure and Macular Edema
There are anecdotal reports that treatment of renal failure will reduce macular edema in patients who have both 125 . However, hemodialysis failed to reduce fluorescein leakage in the eyes of type 2 diabetic patients with renal failure and macular edema 126 . There are no epidemiological studies or clinical trials that have demonstrated that reduction of microalbuminuria and prevention of overt diabetic nephropathy manifest by clinical proteinuria will result in reduction of risk of...
Interaction Of Proteins And Other Plasma Factors With Podocytes And Tubules In
Although the glomerular slit diaphragm is the major site for size-selective filtration of proteins, several studies indicate that additional cellular processing of proteins occurs during their renal passage through the glomerulus and renal tubules. In the proximal tubule, albumin is reabsorbed by endocytosis, mediated by two receptors, cubilin and megalin, acting in concert 68 . In human diabetes, filtered albumin is subject to lysosomal degradation and albumin-derived fragments are returned to...
Depletion of Endogenous Antioxidants and Altered Activity of Antioxidant Enzymes
Depletion of endogenous antioxidants and free radical scavengers may occur in diabetes 28,96-101 . In plasma or serum, lower levels of vitamins C, E, and A, lycopene, and lipoic acid have been reported in human diabetics compared with non-diabetic controls 28,96-99,102-104 . Similarly, impaired total serum antioxidant capacity and reduced antioxidant properties of serum albumin and high-density lipoprotein have been described in human diabetics 102,105-109 . In experimental diabetes, depletion...
Charles W Heilig md
Glomerular Glucose Transporters Implications of High-Glucose-Induced Alterations of Mesangial Cell Glucose Transporter Expression for Diabetic Nephropathy Glomerular Glucose Metabolism Mesangial Cell-Signaling Pathways From Glucose Transporters to Extracellular Matrix Production Renal Tubular Glucose Transporters Genetic Studies of GLUTI Alleles and the Risk for Diabetic Nephropathy Effects of Antidiabetic Drugs on Mesangial Cell Glucose Transporters Inhibitors of GLUTI Conclusions References
Renal Tubular Glucose Transporters
The renal tubules appear to have much higher expression of glucose transporters than the glomeruli. This may be due in part to the substantial energy requirement for solute reabsorption 53 . The renal tubules express both facilitative GLUTs and sodium-glucose cotransporters Fig. 2 . The GLUTs identified in the tubules to date include GLUT1-5 and -8. The sodium-linked glucose transporters reported in the tubules to date include SGLT1-3, and NaGLT1 63,64 . SGLT1 is a high-affinity, low-capacity...
INTRODUCTION Ign
Type 2 diabetes mellitus DM is increasing exponentially more than 18 million Americans are currently diagnosed, of which more than approx 73 have concomitant hypertension HTN 1 . Notably, at the time of diagnosis of diabetes, HTN is present in 50 of diabetic patients 2 . The presence of diabetic nephropathy DN and its clinical hallmark, microalbuminuria MAU , with concommittant HTN accelerates progression to renal and cardiovascular disease CVD . CVD risk progresses as DN progresses into...
Tuft To Bowmans Capsule Adhesions
TBCA are rare findings in normoalbuminuric and microalbuminuric type 1 diabetic patients 55 . TBCA are frequent in proteinuric patients, and show marked predilection for the area of the glomerulotubular junction 56 , equivalent to tip lesions . These Fig. 1. Three glomeruli with tuft to Bowman's capsule adhesions bold arrows and glomerulotubu-lar junction abnormalities the middle and right glomeruli from a proteinuric type 1 diabetic patient. Presumed paraglomerular filtration thin arrows...
Cdj Introduction
Over many years of investigation it has been found that the mechanisms contributing to the development of diabetic nephropathy DN are both varied and complex 1-8 . A key finding, however, was that hyperglycemia plays an important role in the development of diabetic tissue complications, including nephropathy. A substantial amount of effort has been expended in identifying glucose-induced pathways in the kidney, which contribute to the production of excessive extracellular matrix ECM , which...
Podocytes And Rage
Expression of RAGE is enhanced in the diabetic kidney both in animals and in man 58 . In the glomerulus, RAGE is expressed especially at the base of podocytes but not in mesangium or endothelium 58 . As mentioned, a recent study tested the hypothesis that activation of RAGE contributed to increased excretion of urinary albumin and attraction of mononuclear phagocytes to diabetic glomeruli, driven by enhanced expression of podocyte VEGF and expansion of mesangial matrix mediated by TGF-P 47 . It...
REFERENCES Lkb
1. McFarlane S, Gizycki HV, Winer N, et al. Control of cardiovascular risk factors in patients with diabetes and hypertension at urban academic medical centers. Diabetes Care 2002 25 718-723. 2. American diabetes association national diabetes fact sheet. Accessed http www.diabetes.org on 3 14 05. 3. McFarlane SI, Banerji M, Sowers JR. Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab 2001 86 2 713-718. 4. Couser WG, Johnson RJ. Mechanisms of progressive renal disease in...
Glomerular Proteinuria And The Renal Interstitium
The nephrotic syndrome in ouvert DN is associated with nonselective proteinuria i.e., 50-60 of the urinary protein excretion consists of albumin with the balance including proteins of lower as well as high molecular weights . Diabetic microalbuminuria From Contemporary Diabetes The Diabetic Kidney Edited by P. Cortes and C. E. Mogensen Humana Press Inc., Totowa, NJ Fig. 1. Activation of nuclear factor NF -kB by proteasomal degradation of its inhibitor, I-kB, in tubular cells occurs in response...
REFERENCES Lgt
1. Inomata S, Itoh M, Imai H, Sato T. Serum levels of erythropoietin as a novel marker reflecting the severity of diabetic nephropathy. Nephron 1997 75 426-430. 2. Bosman DR, Winkler AS, Marsden JT, Macdougall IC, Watkins PJ. Anemia with erythropoietin deficiency occurs early in diabetic nephropathy. Diabetes Care 2001 24 495-499. 3. Silverberg D. Outcomes of anemia management in renal insufficiency and cardiac disease. Nephrol Dial Transplant 2003 18 2 ii7-ii12. 4. Koury ST, Koury MJ,...
Podocyte Number vs Number Density
Podocyte damage, if severe enough, leads to podocyte loss. Increased urinary excretion of podocytes has been detected in microalbuminuric and proteinuric type 2 diabetic patients 23 . There has been a debate concerning whether reduction in podocyte number or reduction in podocyte number density is a better correlate or predictor of renal dysfunction in DN 24-27 . Studies of Pima Indian patients with type 2 diabetes showed marked reduction in both the number N PC glom and the number density of...
Preventing Microalbuminuria in Diabetes
Patients with normoalbuminuria have been examined, first in type 2 diabetes, with an ACE inhibitor by Ravid and coworkers 12 . The ACE inhibitor prevented development of microalbuminuria. Kvetny et al. 13 showed the same for type 1 diabetes using Perindopril. The Bergamo Nephrologic Diabetes Complications Trial BENEDICT was recently published 14 . Indeed, it is important to distinguish between normo- and microalbuminuria and renal insufficiency, as confirmed by Adler and coworkers in the United...
Familial Aggregation Of Phenotypes Of Diabetic Nephropathy
Proteinuria and kidney function impairment are two phenotypes that are the major hallmarks of DN. Several studies demonstrated that both aggregate in families of diabetic as well as nondiabetic individuals as heritable traits. Before we discuss these results, a few comments are necessary about the ways the studies were designed. Two different but complementary study designs are used to examine familial aggregation of complex diseases such as DN. Usually, conventional epidemiological designs and...
CONCLUSIONS Hwr
Patients with diabetes who are at high risk of developing ESRD can now be identified at a point very early in the course of their development of this complication. A number of therapies summarized in Table 2 have been identified that can slow progression of this Summary of Therapeutic Interventions in Early Diabetic Kidney Disease Summary of Therapeutic Interventions in Early Diabetic Kidney Disease
Info Rds
CSME, clinically significant macular edema. CSME, clinically significant macular edema. Fig. 9. The prevalence of retinopathy and nephropathy severity by duration of diabetes in younger onset type 1 diabetes group in the Wisconsin Epidemiologic Study of Diabetic Retinopathy, 1980-1982. CSME, clinically significant macular edema. - Gross proteinuria - Dialysis or renal
Podocyte Ultrastructure In Type Diabetes
There have been several studies of glomerular ultrastructure in patients with type 1 diabetes spanning the spectrum from normoalbuminuria through microalbuminuria to overt nephropathy Table 2 . Using light microscopy, comparisons of renal ultrastructural changes in microalbuminuric patients and healthy controls have focused on basement membrane thickening and matrix glomerular volume fraction. In some studies, microalbuminuric patients were shown to have significantly increased glomerular The...
Role of RAAS in CVD and Renal Disease
HTN in DM is characterized by reduced NO-mediated vasorelaxation, reduced baroreflex sensitivity, and enhanced sympathetic activity, abnormalities that are promoted by aldosterone 31 . Changes in aldosterone secretion in response to changes in volume status or alteration in salt intake are mediated primarily by Ang-II. Although, patients with DM have usually normal Ang-II regulation of aldosterone and normal circulating levels of this hormone there may be increased tissue levels 30 . However,...
INTRODUCTION Rha
Prolonged hyperglycemia is the critical etiological factor in the development of the microvascular complications of diabetes including diabetic nephropathy 1-3 . The tissues subject to these complications appear to be susceptible by virtue of abundant expression of cell surface facilitative glucose transporters resulting in the transport of glucose down its concentration gradient. The fact that increased glucose uptake and metabolism promotes the pathological changes leading to tissue damage...
Info Pdh
Fig. 6. Summary of novel therapeutic targets in DN. Potentially useful therapeutic principles are depicted in light gray lettering. See text in Emerging, Novel Therapeutic Targets and Strategies Section for explanations. TGF-P in the renal interstitium, and fibroblasts are the primary target. Transcriptional upregulation of C-C chemokines appears to be NF-kB-dependent which, in turn, is activated by proteasomal degradation of its endogenous inhibitor, I-kB. Indeed, inhibition of MCP-1 with 7ND...