Altered Glucose Metabolism and CCN

Altered metabolism of glucose, unique in diabetes as opposed to other forms of renal disease, is a critical factor contributing to increased CCN2 and DN. As described earlier, the exposure of a variety of renal cell types, including MCs, to elevated glucose levels has been shown to markedly increase CCN2 activity. This is likely to occur through at least two pathways in vivo. First, high glucose is able to increase protein kinase C, which Fig. 2. Schematic diagram proposing a central role of...

Lipid Lowering Agents

More aggressive lipid-lowering in patients with diabetes has recently become the standard of care, with the National Cholesterol Education Program (NCEP) designating persons with diabetes as having a coronary heart disease equivalent and recommending a low-density lipoprotein (LDL) target of less than 100 mg dL (104). Because of their very high risk for coronary artery disease (12,13) it may well be that the recently recommended lower goal of less than 70 mg dL for LDL cholesterol (105) may be...

Familial Aggregation of ESRD and Heritability of Variation in GFR

Familial aggregation of ESRD and the heritability of a variation in GFR have been examined in the same fashion as proteinuria and a variation in UAE the summary of the studies is shown in Table 2. The first study was by Pettitt et al. (23) who described the familial aggregation of impaired kidney function among diabetic parents and their diabetic offspring in Pima Indians with T2DM. Subsequently, Freedman et al. (24) reported that in families selected through an index case with ESRD caused by...

Classical Proteomics Approach to Define Alterations in Renal Protein Expression in Diabetic Nephropathy Using Animal

The author and colleagues (73-75,95) have performed the classical, gel-based proteomic analysis (using 2D PAGE, SYPRO Ruby staining, quantitative intensity analysis, and MALDI-TOF MS) of DN in the OVE26 transgenic mouse model for type 1 diabetes (96-98) and the db db mouse model for type 2 diabetes (99). Differential pro-teomics has been performed using these two mouse models compared with their respective background strains. A total of 41 (30 identified and 11 unidentified) and 39 (20...

Physiological Effects of HGF in Renal Growth and Repair

In the adult kidney, the number of nephrons remains constant and demonstrate little proliferative activity under physiological conditions. However, the kidney shows great potential for regeneration in order to restore normal size or function once renal mass, morphology, or function are impaired (55). For example, renal regeneration is induced by nephrectomy or cell death caused by toxins. A humoral factor(s) is involved in renal enlargement after unilateral nephrectomy (55), named renotropine....

References

The need for early predictors of diabetic nephropathy risk is albumin excretion rate sufficient Diabetes 2000 49 1399-1408. 2. Chavers BM, Bilous RW, Ellis EN, Steffes MW, Mauer SM. Glomerular lesions and urinary albumin excretion in type I diabetes without overt proteinuria. N Engl J Med 1989 320 966-970. 3. Fioretto P, Steffes MW, Mauer M. Glomerular structure in nonproteinuric IDDM patients with various levels of albuminuria. Diabetes 1994 43 1358-1364. 4....

Anemia As A Progression Promoter In Diabetic Nephropathy

Several studies have shown that anemia is an independent risk factor for progression in both diabetic and nondiabetic renal disease (22). For example, in the Reduction of Endpoints in NIDDM with Angiotensin II Antagonist Losartan Study (RENAAL) study of patients with type 2 diabetes and nephropathy, anemia at the start of the study was a strong predictor of the rate of doubling of serum creatinine or development of ESRD (23). Similarly, the Canadian multicenter cohort study of 313 predialysis...

Glycemic Control

On the one hand, renal failure causes insulin resistance, among others, by cumulation of a (hypothetical) circulating factor interfering with the action of insulin. As a result, patients tend to develop impaired glucose tolerance and hyperglycemia. Because the hypothetical low-molecular-weight circulating insulin inhibitor is apparently dialyzable, insulin resistance is improved after the start of dialysis. On the other hand, the half-life of insulin is prolonged, predisposing to hypoglycemic...

Bmp Function In Animal Models Of Diabetic Nephropathy

A long-term model of streptozotocin-induced DN was developed in order to study the influence of the BMP family on TGF-P and hyperglycemia-mediated injury (Fig. 2) (55). In Sprague-Dawley rats receiving a single injection of streptozotocin, blood sugars were maintained in the 400-500 mL dL range with long-acting insulin. In this model, there is a progressive renal hypertrophy that is near maximally established at 16 wk associated with marked increased in GFR and the development of proteinuria...

Podocyte Changes In Diabetic Nephropathy

Podocyte injury is putatively the main culprit in many progressive glomerulopathies 21 including DN. Using conventional methods, perhaps, the first recognizable podocyte alteration in DN is foot process effacement. It is known that foot process effacement is accompanied by excess filtration of protein in ultrafiltrate. However, this may not be detectable in the terminal urine until the capacity of tubular protein reabsorption is surpassed. Foot processes are interconnected by slit diaphragm...

Dialysis In Esrd Diabetic Patients

Thirty years ago, RRT could provide only a limited benefit to most diabetic patients with ESRD. In 1966, Avram et al. 5 reported that diabetic patients who started on HD Potential Advantages of Peritoneal Dialysis in the Treatment of Diabetic Patients No need for vascular access No need for systemic anticoagulation Continuous therapy Gradual ultrafiltration Fewer episodes of hypotension Better preservation of renal function Better blood pressure control Better control of anemia More liberal...

Cdci in cdczd

Schematic representation of basic CCN2 structure. Five exons encode a signal peptide SP , an insulin-like growth factor-binding protein domain, a VWC, a thrombospondin type-1 repeat, and a C-terminal CT module. At the junction between the domains II and III is a region proposed to act as a hinge. Reprinted by permission of author, B. Perbal et al., University of Paris, from Lancet, 363, 2004. of at least six related genes, recently named the CCN family 2 . The letters, C-C-N, arise from...

Podocyte Density In Diabetic Nephropathy

At least three processes may explain a decrease in podocyte density in patients with DN Fig. 3 . First, it is possible that glomerular enlargement caused by glucose, intra-glomerular hypertension, and or growth factors leads to separation of podocyte foot processes without a decrease in podocyte number. As the podocyte is a terminally differentiated cell, any acquired increase in glomerular size induced by diabetes result in increases in endothelial cell and MC number but not in podocyte...

Epidemiology Of Anemia In Diabetes Community And Clinicbased Studies

Diabetes is responsible for 45 of new patients entering ESRD programs in the United States, 36 in Germany, and 22 in Australia. The majority of these patients will have anemia, although this represents the tip of a much larger problem. Most patients with DN will not survive to reach ESRD, succumbing instead to comorbid vascular complications and infection. It is not yet clear how anemia contributes to their morbidity or mortality, as there have been comparatively few studies in early diabetes....

Introduction

Cd2 Podocin Nephrin

The glomerular capillary wall comprises three major components the fenestrated endothelium surrounded by glycocalyx, the glomerular basement membrane, and the podocyte layer. Podocytes are specialized epithelial cells that form a network of interdigitating foot processes. The predominant filtration pathway for macromole-cules is through slit diaphragms bounded by podocyte foot processes. Nephrin is a key component of the slit diaphragm in association with other intracellular proteins, including...

VEGF Levels in Plasma Serum or Urine

In a group of patients with both types of diabetes, serum VEGF concentrations were found to be increased, especially in those with proliferative retinopathy Table 1 . Furthermore, levels of VEGF were higher in patients with macroalbuminuria than in those with lesser degrees of albuminuria 58 . Indeed, there was a significant correlation between serum VEGF concentrations and albuminuria. Similar findings have been reported in a group of type-2 diabetic subjects with serum creatinine...

Info

Adjusted end-stage renal disease ESRD incident rates, by primary diagnosis, and diabetes in the general population. Incident ESRD patients rates adjusted for age, gender, and race. Data on the prevalence of diabetes in the general population obtained from the CDC's behavioral risk factor surveillance system. The data reported here have been supplied by the US Renal Data System. The interpretation and reporting of these data are the responsibility of the author s and in no way should be...

Tubules

TBM thickening is an early abnormality in type 1 diabetes that parallels GBM thickening and can be detected in normoalbuminuric patients using stereological methods 4 . TBM width correlates with GBM width and Vv Mes glom and more specifically with Vv MM glom , consistent with the idea that the TBM changes are part of a broad accumulation of basement membrane ECM material in the diabetic kidney 8 and arguing against the hypothesis that glomerular hemodynamic abnormalities are causally related to...

Erythropoietin And The Anemia Of Diabetic Nephropathy

Although a number of mechanisms potentially contribute to the development of anemia in diabetes, damage to the renal mechanisms that normal control Hb levels appears to be an essential component. Consistent with this paradigm, at moderate levels of renal impairment, with glomerular filtration rate GFR in the range 30-60 mL min 1.73 m2, anemia is present in more than one-third of patients with diabetes. Once GFR is below 30 mL min 1.73 m2, anemia is more common, affecting up to half of all...

Sulfonylureas

The sulfonylurea medications have been in use for decades to manage hyper-glycemia in type 2 diabetic patients, however, even patients with well-controlled blood glucose levels may develop DN. It is of interest, therefore, that studies of the sulfonylurea derivative tolazemide have demonstrated that it increases MC glucose uptake 76 , despite its beneficial effect to improve glycemia in diabetics by increasing peripheral glucose disposal. The increase in glucose uptake into MCs appears to be...

Regression of Albuminuria Important Clinical Significance A New Paradigm Shift By ACE Inhibitor and ARBS and AHT

It is well known to all diabetologists that patients with proteinuria or albuminuria carry a poor prognosis. The same is the case for microalbuminuria, but to a lesser extent. Indeed, the higher the level of albuminuria, the greater the risk of renal progression and the risk of all complications including early mortality. These results derive from studies of the so-called natural history of diabetic nephropathy, both in type 1 and 2. The next question is, of course, to ask whether regression or...

Vegf In Diabetic Nephropathy In Humans

In spite of the large amount of experimental evidence implicating VEGF in the development of experimental diabetic nephropathy, there is a lack of convincing evidence of a pivotal role for VEGF in human diabetic nephropathy. Of interest is a patient described by Baba et al. 56 . This patient had a syndrome known as POEMS polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes and type 2 diabetes for 30 yr, when he died from cardiac failure. Plasma levels of VEGF...

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...

Etiology Of The Afferent Arteriolar Dilation Underlying Diabetic Hyperfiltration

H2o2 Redutcion

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...

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....

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...

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...

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

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 Mac Isaac 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...

HGF

Met Hgf Angiogenesis

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

Transcription Factors Ppar

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...

Mmr

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

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...

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 Diabetic Nephropathy

Lysosome Ros

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

Proximal Tubule Kidney 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...

Ign Kidney Disease

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

Proteinuria Patients

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

Diabetic 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...

Jama J. Am. Med. Assoc. 2002 288 2579.

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

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...

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

Familial Aggregation

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...

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,...

Slowing Progression Delaying ESRD and Preventing Cardiovascular Mortality

Once DN is established, therapeutic efforts should focus on slowing the rate of progression of kidney disease and delaying ESRD. Although early referral to a nephrologist may be an ideal way to care for patients with established DN 116,117 , economic reality suggests that primary care providers are often the sole providers of care for members of transitional and disadvantaged populations. Fortunately, therapy may be simplified so that nurses 125 or even low-skilled workers can implement it...

Alterations Of Podocyte Function In Diabetes

Both metabolic hyperglycemia and hemodynamic stretch and systemic hypertension mechanisms are important mediators of podocyte dysfunction in diabetic nephropathy. Podocytes are the principal cell type involved in the formation of the glomerular basement membrane 31 . Podocytes also secrete matrix metalloproteinases MMPs that modulate matrix remodeling 32 . Recent studies in cultured human podocytes have shown that glucose decreases MMP activity and enhances tissue inhibitor of matrix...

Regulation of mRNA Translation by Glucose and Insulin

We have recently explored the role of hyperglycemia and hyperinsulinemia in general protein synthesis hypertrophy and in synthesis of extracellular matrix protein, laminin, in renal cells. Whereas hyperglycemia is a pathogenic factor common to both types of diabetes, hyperinsulinemia is of relevance to type 2 diabetes. Hyperinsulinemia precedes clinical expression of diabetes during the phase of insulin resistance. Fasting plasma insulin levels and insulin levels between meals remain higher...

Evolution Of The Structural Changes Of Diabetic Nephropathy

The sequence of structural changes in DN can be considered along either chronological or functional time scales. The functional alterations are expressed as the evolution of events related to clinical findings such as progression from normoalbuminuria to From Contemporary Diabetes The Diabetic Kidney Edited by P. Cortes and C. E. Mogensen Humana Press Inc., Totowa, NJ microalbuminuria and to proteinuria or from hyperfiltration to progressive glomerular filtration rate GFR decline and end-stage...

Glucose Auto Oxidation and Formation of AGE

Pyrraline Age

AGE, predominantly NG- carboxymethyl lysine CML , pentosidine, and pyrraline, can arise in excess in diabetes from sequential glycation and oxidation reactions termed glycooxidation or auto-oxidative glycosylation 30,34,47,48,88,89 . Formation of CML and pentosidine in particular depend on oxidative processes 31 . Glucose and other reducing sugars can be auto-oxidized by metal-catalyzed oxida-tive processes that generate ROS and the reactive intermediate dicarbonyl, glyoxal Fig. 2 . The latter...