Mechanical Forces in Diabetic Kidney Disease: A ... - Semantic Scholar

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Mechanical Forces in Diabetic Kidney Disease: A Trigger for Impaired Glucose Metabolism Luigi Gnudi, Stephen M. Thomas, and Giancarlo Viberti Cardiovascular Division, King’s College London School of Medicine, Guy’s Hospital, London, United Kingdom

ABSTRACT Nephropathy is one of the major microvascular complications of diabetes, and both hemodynamic and metabolic stimuli participate in its development and progression toward ESRD. There is now a greater understanding of the molecular pathways that are activated by high glomerular capillary pressure and hyperglycemia and how they interplay to produce kidney pathology. The observation that overexpression of glucose transporter 1 (GLUT-1) in mesangial cells could induce a “diabetic cellular phenotype” has led to the postulation that the expression of GLUT-1 could be upregulated in glomeruli that are exposed to high pressure. This review suggests a mechanism by which mechanical forces may aggravate a metabolic insult by stimulating excessive cellular glucose uptake. Proposed is the existence of a self-maintaining cycle whereby a hemodynamic stimulus on glomerular cells induces GLUT-1 overexpression followed by greater glucose uptake and activation of intracellular glucose metabolic pathways, resulting in excess TGF-␤1 production. TGF-␤1 in turn, maintains overexpression of GLUT-1, perpetuating a signaling sequence that has, as its ultimate effect, increased extracellular matrix synthesis. This mechanical and metabolic coupling suggests a novel pathophysiologic mechanism of injury in the kidney in diabetes and possibly other glomerular diseases. J Am Soc Nephrol 18: 2226–2232, 2007. doi: 10.1681/ASN.2006121362

THE PROBLEM

The “epidemic” of type 2 diabetes—the burden of diabetic chronic vascular complications, together with improvements in patient care and availability of renal replacement therapy and possibly improved patient survival— has given rise to a public health crisis that is seriously challenging health care resources.1–3 Because hyperglycemia and elevated BP interact in the pathogenesis of diabetic kidney disease,4,5 it is imperative that we understand the nature and mechanism(s) of this interplay to develop novel approaches to prevention and treatment.

PATIENTS WITH DIABETES: CLINICAL OBSERVATIONS

When the correlation between urinary albumin excretion and systolic BP was 2226

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first described in patients with type 2 diabetes,6 the authors made the prescient observation that “the results of hypertension and hyperglycemia combine to increase the degree of albuminuria.” Many investigators have since described the cumulative effect of the parallel perturbations of hypertension and hyperglycemia on the development and progression of diabetes micro- and macrovascular complications. Prospective, randomized, controlled trials have established the risks of hyperglycemia for the development of kidney disease. The Diabetes Control and Complications Trial (DCCT) in patients with type 1 diabetes demonstrated that intensified insulin therapy with improved glycemic control during approximately 7 yr reduced the risk for development of microalbuminuria by 39%.7 The relationship between gly-

cemia and the risk for microalbuminuria was log-linear with no evidence of a threshold below which improved glycemic control could not further reduce the risk for kidney disease.8 In newly diagnosed type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that intensive glycemic control reduced the risk for the development of albuminuria also by approximately 33% over 12 yr.9 Similarly strong evidence exists for the importance of raised arterial BP in the development of diabetic kidney disease. In prospective studies, patients who had diabetes and progressed to albuminuria had higher arterial pressure at baseline,10,11 and in intervention studies, BP lowering slowed kidney disease progression and reduced albuminuria in both type 1 and type 2 diabetes.12,13 The interaction of raised BP and hyperglycemia is therefore important in both the initiation and the progression of kidney disease, potentially trebling the rate of loss of GFR and significantly worsening the degree of albuminuria.14

Published online ahead of print. Publication date available at www.jasn.org. Correspondence: Dr. Luigi Gnudi, Department of Diabetes, Endocrinology and Internal Medicine, 5th Floor Thomas Guy House, Guy’s Hospital, St. Thomas Street, London SE1 9RT, UK. Phone: ⫹4420-7188-1939; Fax: ⫹44-20-7188-0146; E-mail: [email protected] Copyright © 2007 by the American Society of Nephrology

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PATHOPHYSIOLOGY OF KIDNEY DISEASE: METABOLIC ALTERATIONS IMPAIR GLOMERULAR MICROCIRCULATION

Under normal physiologic conditions, autoregulatory mechanisms are in place to protect the glomerular capillaries from changes in systemic arterial BP.15 A greater understanding of the pathophysiologic interaction between hypertension and hyperglycemia in diabetic kidney disease came from the work of Hostetter et al.,16,17 who by direct determination of intraglomerular pressure, using a micropuncture technique of superficial renal cortical glomeruli in the diabetic Munich Wistar rat, demonstrated that hyperglycemia altered the normal process of autoregulation within the glomerulus, reducing afferent and, to a much lesser degree, efferent arteriolar tone. This resulted in ready transmission of systemic pressure to the glomerular capillary and higher glomerular transcapillary hydraulic pressure and contributed to an increase in single-nephron and whole-kidney GFR, which was associated with more severe degrees of structural glomerular damage.16,17 The use of an angiotensin-converting enzyme inhibitor, which lowered glomerular capillary pressure, resulted in reduction of both albuminuria and glomerular extracellular matrix deposition/accumulation.18 Thus, hyperglycemia impairs the physiologic mechanism that maintains normal glomerular capillary pressure. The ways by which hyperglycemia disrupts capillary vasoregulation are complex and beyond the scope of this article. Enhanced production of nitric oxide (NO), leading to both afferent and efferent glomerular arteriolar vasodilation,19 and increased TGF-␤1,20,21 which may act through the production of reactive oxygen species,22 both may be important. In addition, hyperglycemia increases the production of angiotensin II (AngII) particularly by the local tissue renin-angiotensin-aldosterone system (RAAS).23 The efferent glomerular arteriole is 10 to 100 times more sensitive to the vasoconstrictive action of AngII than J Am Soc Nephrol 18: 2226 –2232, 2007

the afferent arterioles, and this may contribute to the imbalance in arteriolar tone, which results in higher intraglomerular capillary pressure in diabetes.21,24

GLOMERULAR HYPERTENSION IN EXPERIMENTAL ANIMAL MODELS OF KIDNEY DAMAGE

In hypertensive animal models, in which glomerular vasoregulation is lost, such as the Dahl salt-sensitive rat (DSS),25,26 or the one-kidney five-sixths nephrectomy model,27 a rise in intraglomerular pressure results in mesangial matrix expansion and glomerulosclerosis.28 By contrast, in the spontaneously hypertensive rat (SHR), increased preglomerular arteriolar resistance prevents a rise in capillary pressure, protecting the glomerular circulation from systemic hypertension and resulting in delayed damage.29 When preglomerular vasoregulation in the SHR is impaired by uninephrectomy or diabetes, capillary hypertension ensues with accelerated albuminuria, increased TGF-␤1, mesangial expansion, and glomerulosclerosis.4,30 Thus, pathologies that lead to intraglomerular hypertension create the conditions for a mechanical stimulus to induce damage to the glomerular capillary.

EVIDENCE IN HUMANS: GLOMERULAR HYPERTENSION

Intraglomerular pressure is not directly measurable in humans, but glomerular hyperfiltration is common in early diabetes31 and can be reversed to a large extent by better glycemic control.32 It has been suggested that hyperfiltration in diabetes is a significant risk factor for progression to microalbuminuria and advanced kidney disease,31 but the evidence is conflicting.33,34 Nevertheless, individuals with higher filtration fraction (FF ⫽ GFR/renal plasma flow), an indirect measure of glomerular capillary pressure, may be predisposed to the development of diabetic kidney disease.35 Thus, glomerular capillary pressure may be el-

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evated in the presence of hyperglycemia even at supposedly “normal” systemic arterial pressure.36 The prevalence of kidney damage in individuals with essential hypertension is variable. Ethnicity is an important factor: Individuals of African descent seem more at risk for hypertensive kidney damage,37 and those who are of both Asian and African descent and develop diabetes are at higher risk for diabetic kidney disease.38,39 It is speculated that less effective glomerular autoregulation may be a feature of those with higher predisposition to kidney disease.40 Phenotypically, this may be represented by higher salt sensitivity, which some authors have suggested may be a surrogate marker for less effective glomerular autoregulation.41 Certainly, altered response to high salt intake, with a shift of the pressure natriuresis curve to the right, is seen in patients with diabetes and microalbuminuria42,43 and in ethnic groups at higher risk for renal disease, such as those of African descent.39 In salt-sensitive individuals, a salt-rich diet triggers increased RAAS activity, which may lead to increased glomerular capillary pressure.41 These changes are paralleled by greater degrees of left ventricular hypertrophy, microalbuminuria, and lower insulin sensitivity40,44; the last, in turn, could contribute to higher salt sensitivity in both type 1 and type 2 diabetes. It is intriguing that patients who have both type 1 and type 2 diabetes and develop microalbuminuria have reduced insulin sensitivity.42,43 COOPERATIVITY BETWEEN MECHANICAL AND METABOLIC STIMULI AT THE CELLULAR LEVEL

There is much greater understanding of the molecular mechanisms by which high capillary pressure and hyperglycemia independently lead to altered cellular function and pathology. The intriguing question is whether, at a cellular level, these twin insults interact and, more specific, whether the hemodynamic perturbation would aggravate the metabolic one magnifying its deleterious impact on glomerular pathology.

Mechanical Forces in Diabetic Kidney Disease

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The glomerulus is a complex elastic structure, the stability of which depends on the cooperative function of several cell types (endothelial cells, mesangial cells, and podocytes) and the basement membrane. The glomerular volume expands and contracts rapidly as pressure varies. All glomerular cells are hemodynamically responsive, including mesangial cells, which because of their anatomic distribution are exposed to high pressure fluctuations within the capillaries.5,45– 48 In the normal glomerulus, capillary pressure is remarkably constant with only minor fluctuations, but once autoregulation is impaired, pressure variations and cell elongation/stretching is seen to a much greater degree. Calculations suggest that the typical rise in glomerular pressure in diabetes is associated with a cell stretching of approximately 10% as compared with the average 4% elongation seen with normal intraglomerular pressure.49,50 We were intrigued by the hypothesis that a hemodynamic perturbation could affect the sensitivity of the cell to a metabolic stimulus and may be changing the way by which the cell “senses” the extracellular glucose level and “controls” cellular glucose uptake.

FACILITATIVE GLUCOSE TRANSPORTER 1: A POTENTIAL MOLECULAR TARGET OF MECHANICAL-METABOLIC INTERACTION IN (DIABETIC) KIDNEY DISEASE

Glucose transporter 1 (GLUT-1) is one of the members of a family of facilitative glucose transporters—proteins that are involved in glucose uptake into the cell.51,52 GLUT-1 is a ubiquitously expressed molecule, residing mostly on the cell plasma membrane, where it mediates the rate of glucose transport into the cell in basal, non–insulin-stimulated, conditions.52 This is particularly relevant for glucose metabolism of cells in the vessel wall and in the glomerular capillaries, where glucose uptake is relatively insulin independent.53 GLUT-1 is highly expressed in the 2228

glomerulus.53 As with all facilitative glucose transporters, GLUT-1 is a high-affinity, low-capacity transporter and is at or near saturation at physiologic glucose levels. Therefore, an increase in the number of GLUT-1 molecules would be expected to lead to an increase in basal glucose uptake.53,54 The seminal observation by Heilig et al.55 that GLUT-1 overexpression in mesangial cells that were cultured in “normal” glucose concentrations resulted in both increased basal cellular glucose uptake and extracellular matrix protein expression, thus mimicking a “cellular diabetic phenotype,” highlighted the potential importance of GLUT-1 expression modulation in the pathogenesis of diabetic glomerulopathy. In support of this contention, studies of GLUT-1 expression inhibition, with antisense mRNA in mesangial cells in vitro, showed prevention of both basal glucose uptake and glucose-induced extracellular matrix production.56 Moreover, in vivo evidence suggests that an antisense GLUT-1 transgene in diabetic db/db mice protects against the development of diabetic glomerulopathy,57 whereas normoglycemic animals overexpressing GLUT-1 in glomeruli develop more mesangial expansion and albuminuria.58 Many of the molecules involved in the pathophysiology of glomerular capillary damage in diabetes affect GLUT-1 expression; for example, AngII and TGF-␤1 stimulate GLUT-1 protein expression and basal glucose uptake in mesangial cells.5,59 – 61 Thus, there is experimental evidence linking GLUT-1 upregulation with renal damage. To gain further insight into the molecular pathways of this pathophysiologic mechanism, we asked whether and how hemodynamic forces might interact with GLUT-1 expression and cellular glucose uptake. We found that mechanical stretch applied to human mesangial cells in vitro significantly upregulated GLUT-1 protein expression, an event coupled with increased transport capacity (Vmax) and basal glucose uptake at normal glucose concentrations. These effects were pre-

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vented by neutralization of the action of TGF-␤1.5 We then studied whether GLUT-1 expression differed in an animal model of both systemic and glomerular hypertension, the DSS,25,26 as compared with an animal model of systemic hypertension with normal capillary pressure, namely the young SHR.29 DSS that were treated with a high-salt diet developed systemic and glomerular hypertension, with a concomitant 80% increase in glomerular GLUT-1 expression as compared with normotensive DSS (Figure 1).5 By contrast, in the young SHR, a model of normal intraglomerular pressure despite systemic hypertension, GLUT-1 expression was unchanged as compared with the Wistar Kyoto (WKY) normotensive control rat.5 The increased glomerular GLUT-1 upregulation in the hypertensive DSS was associated with a two- to three-fold increase in renal TGF-␤1 expression when compared with their DSS normotensive controls. Renal TGF-␤1 expression was similar in the young SHR and the WKY.5 Importantly in hypertensive DSS, blockade of the RAAS was found to reduce intraglomerular pressure and prevent glomerular TGF-␤1 upregulation.62 Studies in the Milan rat strain also suggest that susceptibility to renal lesions is associated with upregulation of GLUT-1. In this rat model, the normotensive strain with defective afferent arteriolar vasoregulation develops glomerular injury, whereas the hypertensive strain, which maintains the ability to vasoconstrict the afferent arteriole, is protected from renal damage. In the first case, there is increased glomerular GLUT-1 and TGF-␤1 expression that is absent in the hypertensive strain.63 The mechanical GLUT-1–mediated elevated cellular glucose transport would result in activation of different intracellular metabolic pathways: the polyol and hexosamine pathway, increased production of advanced glycation end products, activation of protein kinase C and p38 mitogen-activated protein kinase, and increase in oxidative stress.64 All of these pathways when activated would lead to glomerular TGF-␤1 upregulation with increased glomerular extracellular maJ Am Soc Nephrol 18: 2226 –2232, 2007

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Figure 1. Glomerular hypertension stimulates glucose transporter 1 (GLUT-1) expression in glomeruli. (A) GLUT-1 immunohistochemistry in kidney cortex from Dahl salt-sensitive rats (DSS) on high-salt diet (DSH), DSS on low-salt diet (DSN), spontaneously hypertensive rat (SHR) and Wistar Kyoto (WKY) rats. Intense GLUT-1 staining (brown) was seen in the DSH glomeruli but not in DSN, SHR, or WKY rats. (B) GLUT-1 protein levels in glomeruli isolated from WKY rats, SHR, DSN, and DSH. (Top) Representative Western immunoblotting. (Bottom) Densitometry analysis for GLUT-1 expressed as percentage change over controls (WKY and DSN, respectively). *P ⫽ 0.004, DSH versus DSN (n ⫽ 4 to 5 rats per group). Reprinted with permission from Gnudi et al.: “GLUT-1 Overexpression: Link between Hemodynamic and Metabolic Factors in Glomerular Injury?” Hypertension 42:19 –24, 2003.5

trix deposition and progressive impairment of glomerular function.47,65–71 Similarly, stretch-induced upregulation of local AngII and the angiotensin type 1 receptor72 will lead to activation of TGF␤1–mediated GLUT-1 upregulation, thus triggering a vicious cycle that results in higher cellular glucose uptake.59,73 Thus, a hemodynamic stimulus, via GLUT-1 upregulation, may magnify intracellular glucose metabolism. Stretching of a mesangial cell would result in higher intracellular glucose concentration relative to actual ambient glucose, in as far as GLUT-1 transporter abundance alone should be sufficient to alter cellular glucose uptake/metabolism, although other mechanisms may also operate. Because all glomerular cells are to some degree capable of responding to hemodynamic stimuli, this process may apply not just to the mesangium. These observations help to explain how a metabolic disturbance is potentiated by a hemodynamic insult.4 Rats with streptozotocin-induced diabetes display a greater abundance of renal cortical GLUT-1 as compared with nondiabetic counterparts.74,75 In diabetes, GLUT-1 overexpression seems peculiar to the kidney, and there are striking dissimilarities with other tissues. In aniJ Am Soc Nephrol 18: 2226 –2232, 2007

mal models of diabetes, GLUT-1 expression is downregulated by 50% in heart tissue76,77 and in the retinal microvasculature.78 High glucose concentrations in mesangial cells counterintuitively increase GLUT-1 expression via a TGF␤1– dependent mechanism.60,79 This may be peculiar to mesangial cells as opposed to other cell types; for example, GLUT-1 levels downregulate in mouse vascular smooth muscle cells when cultured in high-glucose conditions.80 Similarly, in ex vivo work, mesangial cells, obtained from microdissected glomeruli of patients with type 2 diabetes and cultured in vitro, showed enhanced GLUT-1 transporter expression, increased basal glucose uptake, and excessive flux of glucose metabolism through the hexosamine pathway, paralleled by increased extracellular matrix deposition and mesangial cell hypertrophy.81 In contrast skeletal muscle GLUT-1 protein expression as well as basal glucose uptake is reduced in patients with type 2 diabetes.82 Various stimuli may therefore modulate GLUT-1 overexpression in the glomerulus in diabetes, an event that we suggest plays a central role in the sequence of molecular pathways responsible for glomerular damage (Figure 2). It is plausible that mechanical forces

alter intracellular glucose transport/metabolism via GLUT-1 overexpression in other nondiabetic glomerular diseases at “normal” glucose levels. In human obesity, where alterations in plasma glucose are modest and below the “diabetic” range, high arterial pressure and activation of the RAAS are important risk factors for the development of glomerular damage,83 and in obesity-related glomerulopathy, renal cortical GLUT-1 levels are upregulated.84 GENETICS OF GLUT-1 IN DIABETIC KIDNEY DISEASE

Multiple genes have been implicated in the pathogenesis of diabetic kidney disease, including polymorphisms of the angiotensin-converting enzyme and aldose reductase gene.85 Reports have also linked an XbaI polymorphism, located on the second intron of the GLUT-1 gene, with a greater risk for diabetic kidney disease.86 – 88 Data on this polymorphism are conflicting, and a recent metaanalysis was not able to support a clear association between this polymorphism and diabetic kidney disease.86 Two large studies conducted in white patients with type 1 diabetes failed to show an association, whereas two smaller studies (white


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injury in diabetes and possibly other glomerular diseases. Strategies that interrupt pressure-induced metabolic injury may provide new targets for treatment.

DISCLOSURES

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REFERENCES 12. 1. Zimmet P: The burden of type 2 diabetes: Are we doing enough? Diabetes Metab 29: 6S9 – 6S18, 2003 Figure 2. Regulation of glucose entry into mesangial cells 2. Ritz E, Tarng DC: Renal dismediates its response to various external stimuli. Stimuli ease in type 2 diabetes. such as mechanical stretch, high glucose, and angiotensin Nephrol Dial Transplant II upregulate GLUT-1 glucose transporter expression and 16[Suppl 5]: 11–18, 2001 enhance basal glucose transport into mesangial cells. 3. Jones CA, Krolewski AS, Resulting activation of intracellular pathways (protein kiRogus J, Xue JL, Collins A, nase C [PKC], polyol pathway, hexosamine, p38 –mitoWarram JH: Epidemic of gen-activated protein kinase [MAPK], and reactive oxyend-stage renal disease in people with diabetes in the gen species [ROS] formation) with TGF-␤1 upregulation United States population: may mediate and maintain upregulation of GLUT-1 exDo we know the cause? pression, thereby perpetuating a vicious cycle of excess Kidney Int 67: 1684 –1691, extracellular matrix production. 2005 4. Cooper ME: Interaction of patients with type 1 and Asian patients metabolic and haemodynamic factors in mewith type 2 diabetes) claimed a susceptidiating experimental diabetic nephropathy. Diabetologia 44: 1957–1972, 2001 bility effect for diabetic kidney disease. 5. Gnudi L, Viberti G, Raij L, Rodriguez V, Burt The XbaI polymorphism is an intronic D, Cortes P, Hartley B, Thomas S, Maestrini mutation with a questionable functional S, Gruden G: GLUT-1 overexpression: Link significance because it has never been asbetween hemodynamic and metabolic facsociated with changes in GLUT-1 exprestors in glomerular injury? Hypertension 42: sion. It is possible, however, that the 19 –24, 2003 6. Keen H, Chlouverakis C, Fuller J, Jarrett RJ: XbaI polymorphism might be linked The concomitants of raised blood sugar: with a functional locus. However, in Studies in newly-detected hyperglycaemics. linkage studies, the GLUT-1 region II. Urinary albumin excretion, blood pressure 1p35-p31.3 has not, to date, been identiand their relation to blood sugar levels. fied as an important susceptibility locus Guys Hosp Rep 118: 247–254, 1969 in diabetic kidney disease.89 –93 7. The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications CONCLUSION in insulin-dependent diabetes mellitus. Much more is known about the indepenN Engl J Med 329: 977–986, 1993 8. Genuth S: Insights from the Diabetes Condent pathways of both glucose- and prestrol and Complications Trial/Epidemiology sure-induced renal injury; much less is of Diabetes Interventions and Complications known about how they combine. Hemostudy on the use of intensive glycemic treatdynamic–metabolic coupling, whereby a ment to reduce the risk of complications of mechanical stimulus enhances glucose type 1 diabetes. Endocr Pract 12[Suppl 1]: transport and metabolism, suggests a 34 – 41, 2006 9. UK Prospective Diabetes Study (UKPDS) novel pathophysiologic mechanism of

2230


13.

14.

15.

16.

17.

18.

19.

20.

Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352: 837– 853, 1998 The Microalbuminuria Collaborative Study Group: Predictors of the development of microalbuminuria in patients with type 1 diabetes mellitus: A seven-year prospective study. Diabet Med 16: 918 –925, 1999 Haneda M, Kikkawa R, Togawa M, Koya D, Kajiwara N, Uzu T, Shigeta Y: High blood pressure is a risk factor for the development of microalbuminuria in Japanese subjects with non-insulin-dependent diabetes mellitus. J Diabetes Complications 6: 181–185, 1992 Lewis JB, Berl T, Bain RP, Rohde RD, Lewis EJ: Effect of intensive blood pressure control on the course of type 1 diabetic nephropathy. Am J Kidney Dis 34: 809 – 817, 1999 Pohl MA, Blumenthal S, Cordonnier DJ, De Alvaro F, Deferrari G, Eisner G, Esmatjes E, Gilbert RE, Hunsicker LG, de Faria JB, Mangili R, Moore J Jr, Reisin E, Ritz E, Schernthaner G, Spitalewitz S, Tindall H, Rodby RA, Lewis EJ: Independent and additive impact of blood pressure control and angiotensin II receptor blockade on renal outcomes in the irbesartan diabetic nephropathy trial: Clinical implications and limitations. J Am Soc Nephrol 16: 3027–3037, 2005 Alaveras AE, Thomas SM, Sagriotis A, Viberti GC: Promoters of progression of diabetic nephropathy: The relative roles of blood glucose and blood pressure control. Nephrol Dial Transplant 12[Suppl 2]: 71–74, 1997 Ito S, Abe K: Contractile properties of afferent and efferent arterioles. Clin Exp Pharmacol Physiol 24: 532–535, 1997 Hostetter TH, Troy JL, Brenner BM: Glomerular hemodynamics in experimental diabetes mellitus. Kidney Int 19: 410 – 415, 1981 Hostetter TH, Rennke HG, Brenner BM: The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies. Am J Med 72: 375–380, 1982 Zatz R, Rentz Dunn B, Mayer TW, Anderson S, Rennke HG, Brenner BM: Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest 77: 1925–1930, 1986 De Vriese AS, Stoenoiu MS, Elger M, Devuyst O, Vanholder R, Kriz W, Lameire NH: Diabetes-induced microvascular dysfunction in the hydronephrotic kidney: Role of nitric oxide. Kidney Int 60: 202–210, 2001 Kagami S, Border WA, Miller DE, Noble NA: Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat

J Am Soc Nephrol 18: 2226 –2232, 2007

www.jasn.org

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

glomerular mesangial cells. J Clin Invest 93: 2431–2437, 1994 Raij L: The pathophysiologic basis for blocking the renin-angiotensin system in hypertensive patients with renal disease. Am J Hypertens 18: 95S–99S, 2005 Sharma K, Cook A, Smith M, Valancius C, Inscho EW: TGF-beta impairs renal autoregulation via generation of ROS. Am J Physiol Renal Physiol 288: F1069 –F1077, 2005 Anderson S, Vora JP: Current concepts of renal hemodynamics in diabetes. J Diabetes Complications 9: 304 –307, 1995 Maddox DA, Brenner BM: Glomerular ultrafiltration. In: The Kidney, 6th Ed., edited by Brenner BM, Rector FC Jr, Philadelphia, W.B. Saunders Co., 2000, pp 319 –374 Azar S, Limas C, Iway J, Weller D: Single nephron dynamics during high sodium intake and early hypertension in Dahl rats. Jpn Heart J 20[Suppl 1]: 138 –140, 1979 Takenaka T, Forster H, De Micheli A, Epstein M: Impaired myogenic responsiveness of renal microvessels in Dahl salt-sensitive rats. Circ Res 71: 471– 480, 1992 Faraj AH, Morley AR: Remnant kidney pathology after five-sixth nephrectomy in rat. I. A biochemical and morphological study. APMIS 100: 1097–1105, 1992 Hayakawa H, Raij L: Nitric oxide synthase activity and renal injury in genetic hypertension. Hypertension 31: 266 –270, 1998 Arendshorst WJ: Autoregulation of renal blood flow in spontaneously hypertensive rats. Circ Res 44: 344 –349, 1979 Raij L, Azar S, Keane WF: Role of hypertension in progressive glomerular immune injury. Hypertension 7: 398 – 404, 1985 Mogensen CE: Early glomerular hyperfiltration in insulin-dependent diabetics and late nephropathy. Scand J Clin Lab Invest 46: 201–206, 1986 Wiseman MJ, Saunders AJ, Keen H, Viberti G: Effect of blood glucose control on increased glomerular filtration rate and kidney size in insulin-dependent diabetes. N Engl J Med 312: 617– 621, 1985 Yip JW, Jones SL, Wiseman MJ, Hill C, Viberti G: Glomerular hyperfiltration in the prediction of nephropathy in IDDM: A 10-year follow-up study. Diabetes 45: 1729 –1733, 1996 Zerbini G, Bonfanti R, Meschi F, Bognetti E, Paesano PL, Gianolli L, Querques M, Maestroni A, Calori G, Del MA, Fazio F, Luzi L, Chiumello G: Persistent renal hypertrophy and faster decline of glomerular filtration rate precede the development of microalbuminuria in type 1 diabetes. Diabetes 55: 2620 –2625, 2006 Berg UB, Torbjornsdotter TB, Jaremko G, Thalme B: Kidney morphological changes in relation to long-term renal function and metabolic control in adolescents with IDDM. Diabetologia 41: 1047–1056, 1998 Lurbe E, Redon J, Kesani A, Pascual JM,

J Am Soc Nephrol 18: 2226 –2232, 2007

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

Tacons J, Alvarez V, Batlle D: Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes. N Engl J Med 347: 797– 805, 2002 Barri YM: Hypertension and kidney disease: A deadly connection. Curr Cardiol Rep 8: 411– 417, 2006 Crook ED, Patel SR: Diabetic nephropathy in African-American patients. Curr Diab Rep 4: 455– 461, 2004 Powers DR, Wallin JD: End-stage renal disease in specific ethnic and racial groups: Risk factors and benefits of antihypertensive therapy. Arch Intern Med 158: 793– 800, 1998 Campese VM: Salt sensitivity in hypertension. Renal and cardiovascular implications. Hypertension 23: 531–550, 1994 Weir MR: Impact of salt intake on blood pressure and proteinuria in diabetes: Importance of the renin-angiotensin system. Miner Electrolyte Metab 24: 438 – 445, 1998 Trevisan R, Bruttomesso D, Vedovato M, Brocco S, Pianta A, Mazzon C, Girardi C, Jori E, Semplicini A, Tiengo A, Del Prato S: Enhanced responsiveness of blood pressure to sodium intake and to angiotensin II is associated with insulin resistance in IDDM patients with microalbuminuria. Diabetes 47: 1347–1353, 1998 Vedovato M, Lepore G, Coracina A, Dodesini AR, Jori E, Tiengo A, Del Prato S, Trevisan R: Effect of sodium intake on blood pressure and albuminuria in type 2 diabetic patients: The role of insulin resistance. Diabetologia 47: 300 –303, 2004 Giner V, Coca A, de la Sierra A: Increased insulin resistance in salt sensitive essential hypertension. J Hum Hypertens 15: 481– 485, 2001 Endlich N, Kress KR, Reiser J, Uttenweiler D, Kriz W, Mundel P, Endlich K: Podocytes respond to mechanical stress in vitro. J Am Soc Nephrol 12: 413– 422, 2001 Eng E, Ballermann BJ: Diminished NF-kappaB activation and PDGF-B expression in glomerular endothelial cells subjected to chronic shear stress. Microvasc Res 65: 137– 144, 2003 Gruden G, Zonca S, Hayward A, Thomas S, Maestrini S, Gnudi L, Viberti GC: Mechanical stretch-induced fibronectin and transforming growth factor-beta1 production in human mesangial cells is p38 mitogen-activated protein kinase-dependent. Diabetes 49: 655– 661, 2000 Cortes P, Mendez M, Riser BL, Guerin CJ, Rodriguez-Barbero A, Hassett C, Yee J: Factin fiber distribution in glomerular cells: Structural and functional implications. Kidney Int 58: 2452–2461, 2000 Cortes P, Riser BL, Zhao X, Narins RG: Glomerular volume expansion and mesangial cell mechanical strain: mediators of glomerular pressure injury. Kidney Int Suppl 45: S11–S16, 1994

BRIEF REVIEW

50. Cortes P, Zhao X, Riser BL, Narins RG: Regulation of glomerular volume in normal and partially nephrectomized rats. Am J Physiol 270: F356 –F370, 1996 51. Joost HG, Bell GI, Best JD, Birnbaum MJ, Charron MJ, Chen YT, Doege H, James DE, Lodish HF, Moley KH, Moley JF, Mueckler M, Rogers S, Schurmann A, Seino S, Thorens B: Nomenclature of the GLUT/SLC2A family of sugar/polyol transport facilitators. Am J Physiol Endocrinol Metab 282: E974 –E976, 2002 52. Mueckler M: Facilitative glucose transporters. Eur J Biochem 219: 713–725, 1994 53. Heilig CW, Brosius FC, Henry DN: Glucose transporters of the glomerulus and the implications for diabetic nephropathy. Kidney Int 52[Suppl 60]: S91–S99, 1997 54. Li Y, Liu Z, Liu D, Zhang J, Chen Z, Li L: Identification and function of glucose transporter 1 in human mesangial cells. Chin Med J (Engl) 114: 824 – 828, 2001 55. Heilig CW, Concepcion LA, Riser BL, Freytag SO, Zhu M, Cortes P: Overexpression of glucose transporters in rat mesangial cells cultured in a normal glucose milieu mimics the diabetic phenotype. J Clin Invest 96: 1802–1814, 1995 56. Heilig CW, Kreisberg JI, Freytag S, Murakami T, Ebina Y, Guo L, Heilig K, Loberg R, Qu X, Jin Y, Henry D, Brosius FC 3rd: Antisense GLUT-1 protects mesangial cells from glucose induction of GLUT-1 and fibronectin expression. Am J Physiol Renal Physiol 280: F657–F666, 2001 57. Chen S, Heilig KO, Brosius FC 3rd, Heilig CW: Diabetes increases glomerular Glut1, and antisense-Glut1 protects against diabetic glomerulosclerosis [Abstract]. J Am Soc Nephrol 14: 46A, 2003 58. Heilig KO, Chen S, Xiang M, Brosius FC, Heilig CW: Transgenic overexpression of Glut1 in glomeruli produces feature of diabetic nephropathy in mice [Abstract]. J Am Soc Nephrol 15: 263A, 2004 59. Inoki K, Haneda M, Maeda S, Koya D, Kikkawa R: TGF-beta 1 stimulates glucose uptake by enhancing GLUT1 expression in mesangial cells. Kidney Int 55: 1704 –1712, 1999 60. Zhang J, Liu Z, Liu H, Li Y, Li L: Regulation of the expression and function of glucose transporter-1 by TGF-beta 1 and high glucose in mesangial cells. Chin Med J (Engl) 113: 508 –513, 2000 61. Nose A, Mori Y, Uchiyama-Tanaka Y, Kishimoto N, Maruyama K, Matsubara H, Iwasaka T: Regulation of glucose transporter (GLUT1) gene expression by angiotensin II in mesangial cells: Involvement of HB-EGF and EGF receptor transactivation. Hypertens Res 26: 67–73, 2003 62. Otsuka F, Yamauchi T, Kataoka H, Mimura Y, Ogura T, Makino H: Effects of chronic inhibition of ACE and AT1 receptors on glomer-


2231

BRIEF REVIEW

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

www.jasn.org

ular injury in Dahl salt-sensitive rats. Am J Physiol 274: R1797–R1806, 1998 Ricci C, Iacobini C, Oddi G, Amadio L, Menini S, Rastaldi MP, Frasheri A, Pricci F, Pugliese F, Pugliese G: Role of TGF-beta/ GLUT1 axis in susceptibility vs resistance to diabetic glomerulopathy in the Milan rat model. Nephrol Dial Transplant 21: 1514 – 1524, 2006 Brownlee M: Biochemistry and molecular cell biology of diabetic complications. Nature 414: 813– 820, 2001 King GL, Kunisaki M, Nishio Y, Inoguchi T, Shiba T, Xia P: Biochemical and molecular mechanisms in the development of diabetic vascular complications. Diabetes 45[Suppl 3]: S105–108, 1996 Kolm-Litty V, Sauer U, Nerlich A, Lehmann R, Schleicher ED: High glucose induced transforming growth factor beta 1 production is mediated by the hexosamine pathway in porcine glomerular mesangial cell. J Clin Invest 101: 160 –169, 1998 Adhikary L, Chow F, Nikolic-Paterson DJ, Stambe C, Dowling J, Atkins RC, Tesch GH: Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy. Diabetologia 47: 1210 –1222, 2004 Burt DJ, Gruden G, Thomas SM, Tutt P, Dell’Anna C, Viberti GC, Gnudi L: P38 mitogen-activated protein kinase mediates hexosamine-induced TGFbeta1 mRNA expression in human mesangial cells. Diabetologia 46: 531–537, 2003 Igarashi M, Wakasaki H, Takahara N, Ishii H, Jiang ZY, Yamauchi T, Kuboki K, Meier M, Rhodes CJ, King GL: Glucose or diabetes activates p38 mitogen-activated protein kinase via different pathways. J Clin Invest 103: 185–195, 1999 Koya D, King GL: Protein kinase C activation and the development of diabetic complications. Diabetes 47: 859 – 866, 1998 Henry DN, Busik JV, Brosius FC 3rd, Heilig CW: Glucose transporters control gene expression of aldose reductase, PKCalpha, and GLUT1 in mesangial cells in vitro. Am J Physiol 277: F97–F104, 1999 Becker BN, Yasuda T, Kondo S, Vaikunth S, Homma T, Harris RC: Mechanical stretch/ relaxation stimulates a cellular renin-angiotensin system in cultured rat mesangial cells. Exp Nephrol 6: 57– 66, 1998 Weigert C, Brodbeck K, Klopfer K, Haring

2232

74.

75.

76.

77.

78.

79.

80.

81.

82.

HU, Schleicher ED: Angiotensin II induces human TGF-beta 1 promoter activation: Similarity to hyperglycaemia. Diabetologia 45: 890 – 898, 2002 D’Agord SB, Lacchini S, Bertoluci MC, Irigoyen MC, Machado UF, Schmid H: Increased renal GLUT1 abundance and urinary TGF-beta 1 in streptozotocin-induced diabetic rats: Implications for the development of nephropathy complicating diabetes. Horm Metab Res 33: 664 – 669, 2001 D’Agord Schaan B, Lacchini S, Bertoluci MC, Irigoyen MC, Machado UF, Schmid H: Impact of renal denervation on renal content of GLUT1, albuminuria and urinary TGF-beta1 in streptozotocin-induced diabetic rats. Auton Neurosci 104: 88 –94, 2003 Depre C, Young ME, Ying J, Ahuja HS, Han Q, Garza N, Davies PJ, Taegtmeyer H: Streptozotocin-induced changes in cardiac gene expression in the absence of severe contractile dysfunction. J Mol Cell Cardiol 32: 985–996, 2000 Hirsch B, Rosen P: Diabetes mellitus induces long lasting changes in the glucose transporter of rat heart endothelial cells. Horm Metab Res 31: 645– 652, 1999 Badr GA, Tang J, Ismail-Beigi F, Kern TS: Diabetes downregulates GLUT1 expression in the retina and its microvessels but not in the cerebral cortex or its microvessels. Diabetes 49: 1016 –1021, 2000 Heilig CW, Liu Y, England RL, Freytag SO, Gilbert JD, Heilig KO, Zhu M, Concepcion LA, Brosius FC 3rd: D-glucose stimulates mesangial cell Glut1 expression and basal and IGF-I-sensitive glucose uptake in rat mesangial cell. Diabetes 46: 1030 –1039, 1997 Howard RL: Down-regulation of glucose transport by elevated extracellular glucose concentrations in cultured rat aortic smooth muscle cells does not normalize intracellular glucose concentrations. J Lab Clin Med 127: 504 –515, 1996 Liu Z, Chen Z, Li Y: Phenotypic and functional alterations of mesangial cells in patients with diabetic nephropathy. Zhonghua Yi Xue Za Zhi 81: 1369 –1373, 2001 Ciaraldi TP, Mudaliar S, Barzin A, Macievic JA, Edelman SV, Park KS, Henry RR: Skeletal muscle GLUT1 transporter protein expression and basal leg glucose uptake are reduced in type 2 diabetes. J Clin Endocrinol Metab 90: 352–358, 2005


83. Praga M, Morales E: Obesity, proteinuria and progression of renal failure. Curr Opin Nephrol Hypertens 15: 481– 486, 2006 84. Wu Y, Liu Z, Xiang Z, Zeng C, Chen Z, Ma X, Li L: Obesity-related glomerulopathy: Insights from gene expression profiles of the glomeruli derived from renal biopsy samples. Endocrinology 147: 44 –50, 2006 85. Rich SS: Genetics of diabetes and its complications. J Am Soc Nephrol 17: 353–360, 2006 86. Zintzaras E, Stefanidis I: Association between the GLUT1 gene polymorphism and the risk of diabetic nephropathy: A metaanalysis. J Hum Genet 50: 84 –91, 2005 87. Hodgkinson AD, Page T, Millward BA, Demaine AG: A novel polymorphism in the 5⬘ flanking region of the glucose transporter (GLUT1) gene is strongly associated with diabetic nephropathy in patients with type 1 diabetes mellitus. J Diabetes Complications 19: 65– 69, 2005 88. Liu Z, Guan T, Chen Z: Insulin receptor substrate-1 and glucose transporter gene polymorphisms in noninsulin-dependent diabetes mellitus. Zhonghua Yi Xue Za Zhi 78: 662– 665, 1998 89. Imperatore G, Hanson RL, Pettitt DJ, Kobes S, Bennett PH, Knowler WC: Sib-pair linkage analysis for susceptibility genes for microvascular complications among Pima Indians with type 2 diabetes. Pima Diabetes Genes Group. Diabetes 47: 821– 830, 1998 90. Iyengar SK, Fox KA, Schachere M, Manzoor F, Slaughter ME, Covic AM, Orloff SM, Hayden PS, Olson JM, Schelling JR, Sedor JR: Linkage analysis of candidate loci for endstage renal disease due to diabetic nephropathy. J Am Soc Nephrol 14[Suppl]: S195–S201, 2003 91. Lindner TH, Monks D, Wanner C, Berger M: Genetic aspects of diabetic nephropathy. Kidney Int Suppl 84: S186 –S191, 2003 92. Moczulski DK, Rogus JJ, Antonellis A, Warram JH, Krolewski AS: Major susceptibility locus for nephropathy in type 1 diabetes on chromosome 3q: Results of novel discordant sib-pair analysis. Diabetes 47: 1164 –1169, 1998 93. Vardarli I, Baier LJ, Hanson RL, Akkoyun I, Fischer C, Rohmeiss P, Basci A, Bartram CR, van der Woude FJ, Janssen B: Gene for susceptibility to diabetic nephropathy in type 2 diabetes maps to 18q22.3-23. Kidney Int 62: 2176 –2183, 2002

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