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
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: +44-20-7188-1939; Fax: +44-20-7188-0146; E-mail: luigi.gnudi{at}kcl.ac.uk
Nephropathy is one of the major microvascular complicationsof diabetes, and both hemodynamic and metabolic stimuli participatein its development and progression toward ESRD. There is nowa greater understanding of the molecular pathways that are activatedby high glomerular capillary pressure and hyperglycemia andhow they interplay to produce kidney pathology. The observationthat overexpression of glucose transporter 1 (GLUT-1) in mesangialcells could induce a "diabetic cellular phenotype" has led tothe postulation that the expression of GLUT-1 could be upregulatedin glomeruli that are exposed to high pressure. This reviewsuggests a mechanism by which mechanical forces may aggravatea metabolic insult by stimulating excessive cellular glucoseuptake. Proposed is the existence of a self-maintaining cyclewhereby a hemodynamic stimulus on glomerular cells induces GLUT-1overexpression followed by greater glucose uptake and activationof intracellular glucose metabolic pathways, resulting in excessTGF-1 production. TGF-1 in turn, maintains overexpression ofGLUT-1, perpetuating a signaling sequence that has, as its ultimateeffect, increased extracellular matrix synthesis. This mechanicaland metabolic coupling suggests a novel pathophysiologic mechanismof injury in the kidney in diabetes and possibly other glomerulardiseases.
The "epidemic" of type 2 diabetes—the burden of diabeticchronic vascular complications, together with improvements inpatient care and availability of renal replacement therapy andpossibly improved patient survival—has given rise to apublic health crisis that is seriously challenging health careresources.1–3 Because hyperglycemia and elevated BP interactin the pathogenesis of diabetic kidney disease,4,5 it is imperativethat we understand the nature and mechanism(s) of this interplayto develop novel approaches to prevention and treatment.
When the correlation between urinary albumin excretion and systolicBP was first described in patients with type 2 diabetes,6 theauthors made the prescient observation that "the results ofhypertension and hyperglycemia combine to increase the degreeof albuminuria." Many investigators have since described thecumulative effect of the parallel perturbations of hypertensionand hyperglycemia on the development and progression of diabetesmicro- and macrovascular complications.
Prospective, randomized, controlled trials have establishedthe risks of hyperglycemia for the development of kidney disease.The Diabetes Control and Complications Trial (DCCT) in patientswith type 1 diabetes demonstrated that intensified insulin therapywith improved glycemic control during approximately 7 yr reducedthe risk for development of microalbuminuria by 39%.7 The relationshipbetween glycemia and the risk for microalbuminuria was log-linearwith no evidence of a threshold below which improved glycemiccontrol could not further reduce the risk for kidney disease.8In newly diagnosed type 2 diabetes, the United Kingdom ProspectiveDiabetes Study (UKPDS) demonstrated that intensive glycemiccontrol reduced the risk for the development of albuminuriaalso by approximately 33% over 12 yr.9
Similarly strong evidence exists for the importance of raisedarterial BP in the development of diabetic kidney disease. Inprospective studies, patients who had diabetes and progressedto albuminuria had higher arterial pressure at baseline,10,11and in intervention studies, BP lowering slowed kidney diseaseprogression and reduced albuminuria in both type 1 and type2 diabetes.12,13 The interaction of raised BP and hyperglycemiais therefore important in both the initiation and the progressionof kidney disease, potentially trebling the rate of loss ofGFR and significantly worsening the degree of albuminuria.14
PATHOPHYSIOLOGY OF KIDNEY DISEASE: METABOLIC ALTERATIONS IMPAIR GLOMERULAR MICROCIRCULATION
Under normal physiologic conditions, autoregulatory mechanismsare in place to protect the glomerular capillaries from changesin systemic arterial BP.15 A greater understanding of the pathophysiologicinteraction between hypertension and hyperglycemia in diabetickidney disease came from the work of Hostetter et al.,16,17who by direct determination of intraglomerular pressure, usinga micropuncture technique of superficial renal cortical glomeruliin the diabetic Munich Wistar rat, demonstrated that hyperglycemiaaltered the normal process of autoregulation within the glomerulus,reducing afferent and, to a much lesser degree, efferent arteriolartone. This resulted in ready transmission of systemic pressureto the glomerular capillary and higher glomerular transcapillaryhydraulic pressure and contributed to an increase in single-nephronand whole-kidney GFR, which was associated with more severedegrees of structural glomerular damage.16,17 The use of anangiotensin-converting enzyme inhibitor, which lowered glomerularcapillary pressure, resulted in reduction of both albuminuriaand glomerular extracellular matrix deposition/accumulation.18Thus, hyperglycemia impairs the physiologic mechanism that maintainsnormal glomerular capillary pressure.
The ways by which hyperglycemia disrupts capillary vasoregulationare complex and beyond the scope of this article. Enhanced productionof nitric oxide (NO), leading to both afferent and efferentglomerular arteriolar vasodilation,19 and increased TGF-1,20,21which may act through the production of reactive oxygen species,22both may be important. In addition, hyperglycemia increasesthe production of angiotensin II (AngII) particularly by thelocal tissue renin-angiotensin-aldosterone system (RAAS).23The efferent glomerular arteriole is 10 to 100 times more sensitiveto the vasoconstrictive action of AngII than the afferent arterioles,and this may contribute to the imbalance in arteriolar tone,which results in higher intraglomerular capillary pressure indiabetes.21,24
GLOMERULAR HYPERTENSION IN EXPERIMENTAL ANIMAL MODELS OF KIDNEY DAMAGE
In hypertensive animal models, in which glomerular vasoregulationis lost, such as the Dahl salt-sensitive rat (DSS),25,26 orthe one-kidney five-sixths nephrectomy model,27 a rise in intraglomerularpressure results in mesangial matrix expansion and glomerulosclerosis.28By contrast, in the spontaneously hypertensive rat (SHR), increasedpreglomerular arteriolar resistance prevents a rise in capillarypressure, protecting the glomerular circulation from systemichypertension and resulting in delayed damage.29 When preglomerularvasoregulation in the SHR is impaired by uninephrectomy or diabetes,capillary hypertension ensues with accelerated albuminuria,increased TGF-1, mesangial expansion, and glomerulosclerosis.4,30Thus, pathologies that lead to intraglomerular hypertensioncreate the conditions for a mechanical stimulus to induce damageto the glomerular capillary.
Intraglomerular pressure is not directly measurable in humans,but glomerular hyperfiltration is common in early diabetes31and can be reversed to a large extent by better glycemic control.32It has been suggested that hyperfiltration in diabetes is asignificant risk factor for progression to microalbuminuriaand advanced kidney disease,31 but the evidence is conflicting.33,34Nevertheless, individuals with higher filtration fraction (FF= GFR/renal plasma flow), an indirect measure of glomerularcapillary pressure, may be predisposed to the development ofdiabetic kidney disease.35 Thus, glomerular capillary pressuremay be elevated in the presence of hyperglycemia even at supposedly"normal" systemic arterial pressure.36
The prevalence of kidney damage in individuals with essentialhypertension is variable. Ethnicity is an important factor:Individuals of African descent seem more at risk for hypertensivekidney damage,37 and those who are of both Asian and Africandescent and develop diabetes are at higher risk for diabetickidney disease.38,39 It is speculated that less effective glomerularautoregulation may be a feature of those with higher predispositionto kidney disease.40 Phenotypically, this may be representedby higher salt sensitivity, which some authors have suggestedmay be a surrogate marker for less effective glomerular autoregulation.41Certainly, altered response to high salt intake, with a shiftof the pressure natriuresis curve to the right, is seen in patientswith diabetes and microalbuminuria42,43 and in ethnic groupsat higher risk for renal disease, such as those of African descent.39In salt-sensitive individuals, a salt-rich diet triggers increasedRAAS activity, which may lead to increased glomerular capillarypressure.41 These changes are paralleled by greater degreesof left ventricular hypertrophy, microalbuminuria, and lowerinsulin sensitivity40,44; the last, in turn, could contributeto higher salt sensitivity in both type 1 and type 2 diabetes.It is intriguing that patients who have both type 1 and type2 diabetes and develop microalbuminuria have reduced insulinsensitivity.42,43
COOPERATIVITY BETWEEN MECHANICAL AND METABOLIC STIMULI AT THE CELLULAR LEVEL
There is much greater understanding of the molecular mechanismsby which high capillary pressure and hyperglycemia independentlylead to altered cellular function and pathology. The intriguingquestion is whether, at a cellular level, these twin insultsinteract and, more specific, whether the hemodynamic perturbationwould aggravate the metabolic one magnifying its deleteriousimpact on glomerular pathology.
The glomerulus is a complex elastic structure, the stabilityof which depends on the cooperative function of several celltypes (endothelial cells, mesangial cells, and podocytes) andthe basement membrane. The glomerular volume expands and contractsrapidly as pressure varies. All glomerular cells are hemodynamicallyresponsive, including mesangial cells, which because of theiranatomic distribution are exposed to high pressure fluctuationswithin 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 andcell elongation/stretching is seen to a much greater degree.Calculations suggest that the typical rise in glomerular pressurein diabetes is associated with a cell stretching of approximately10% as compared with the average 4% elongation seen with normalintraglomerular pressure.49,50 We were intrigued by the hypothesisthat a hemodynamic perturbation could affect the sensitivityof the cell to a metabolic stimulus and may be changing theway by which the cell "senses" the extracellular glucose leveland "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 familyof facilitative glucose transporters—proteins that areinvolved in glucose uptake into the cell.51,52 GLUT-1 is a ubiquitouslyexpressed molecule, residing mostly on the cell plasma membrane,where it mediates the rate of glucose transport into the cellin basal, non–insulin-stimulated, conditions.52 This isparticularly relevant for glucose metabolism of cells in thevessel wall and in the glomerular capillaries, where glucoseuptake is relatively insulin independent.53
GLUT-1 is highly expressed in the glomerulus.53 As with allfacilitative glucose transporters, GLUT-1 is a high-affinity,low-capacity transporter and is at or near saturation at physiologicglucose levels. Therefore, an increase in the number of GLUT-1molecules would be expected to lead to an increase in basalglucose uptake.53,54
The seminal observation by Heilig et al.55 that GLUT-1 overexpressionin mesangial cells that were cultured in "normal" glucose concentrationsresulted in both increased basal cellular glucose uptake andextracellular matrix protein expression, thus mimicking a "cellulardiabetic phenotype," highlighted the potential importance ofGLUT-1 expression modulation in the pathogenesis of diabeticglomerulopathy. In support of this contention, studies of GLUT-1expression inhibition, with antisense mRNA in mesangial cellsin vitro, showed prevention of both basal glucose uptake andglucose-induced extracellular matrix production.56 Moreover,in vivo evidence suggests that an antisense GLUT-1 transgenein diabetic db/db mice protects against the development of diabeticglomerulopathy,57 whereas normoglycemic animals overexpressingGLUT-1 in glomeruli develop more mesangial expansion and albuminuria.58
Many of the molecules involved in the pathophysiology of glomerularcapillary damage in diabetes affect GLUT-1 expression; for example,AngII and TGF-1 stimulate GLUT-1 protein expression and basalglucose uptake in mesangial cells.5,59–61 Thus, thereis experimental evidence linking GLUT-1 upregulation with renaldamage. To gain further insight into the molecular pathwaysof this pathophysiologic mechanism, we asked whether and howhemodynamic forces might interact with GLUT-1 expression andcellular glucose uptake.
We found that mechanical stretch applied to human mesangialcells in vitro significantly upregulated GLUT-1 protein expression,an event coupled with increased transport capacity (Vmax) andbasal glucose uptake at normal glucose concentrations. Theseeffects were prevented by neutralization of the action of TGF-1.5We then studied whether GLUT-1 expression differed in an animalmodel of both systemic and glomerular hypertension, the DSS,25,26as compared with an animal model of systemic hypertension withnormal capillary pressure, namely the young SHR.29 DSS thatwere treated with a high-salt diet developed systemic and glomerularhypertension, with a concomitant 80% increase in glomerularGLUT-1 expression as compared with normotensive DSS (Figure 1).5By contrast, in the young SHR, a model of normal intraglomerularpressure despite systemic hypertension, GLUT-1 expression wasunchanged as compared with the Wistar Kyoto (WKY) normotensivecontrol rat.5 The increased glomerular GLUT-1 upregulation inthe hypertensive DSS was associated with a two- to three-foldincrease in renal TGF-1 expression when compared with theirDSS normotensive controls. Renal TGF-1 expression was similarin the young SHR and the WKY.5
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
Importantly in hypertensive DSS, blockade of the RAAS was foundto reduce intraglomerular pressure and prevent glomerular TGF-1upregulation.62 Studies in the Milan rat strain also suggestthat susceptibility to renal lesions is associated with upregulationof GLUT-1. In this rat model, the normotensive strain with defectiveafferent arteriolar vasoregulation develops glomerular injury,whereas the hypertensive strain, which maintains the abilityto vasoconstrict the afferent arteriole, is protected from renaldamage. In the first case, there is increased glomerular GLUT-1and TGF-1 expression that is absent in the hypertensive strain.63
The mechanical GLUT-1–mediated elevated cellular glucosetransport would result in activation of different intracellularmetabolic pathways: the polyol and hexosamine pathway, increasedproduction of advanced glycation end products, activation ofprotein kinase C and p38 mitogen-activated protein kinase, andincrease in oxidative stress.64 All of these pathways when activatedwould lead to glomerular TGF-1 upregulation with increased glomerularextracellular matrix deposition and progressive impairment ofglomerular function.47,65–71 Similarly, stretch-inducedupregulation of local AngII and the angiotensin type 1 receptor72will lead to activation of TGF-1–mediated GLUT-1 upregulation,thus triggering a vicious cycle that results in higher cellularglucose uptake.59,73 Thus, a hemodynamic stimulus, via GLUT-1upregulation, may magnify intracellular glucose metabolism.Stretching of a mesangial cell would result in higher intracellularglucose concentration relative to actual ambient glucose, inas far as GLUT-1 transporter abundance alone should be sufficientto alter cellular glucose uptake/metabolism, although othermechanisms may also operate. Because all glomerular cells areto some degree capable of responding to hemodynamic stimuli,this process may apply not just to the mesangium. These observationshelp to explain how a metabolic disturbance is potentiated bya hemodynamic insult.4
Rats with streptozotocin-induced diabetes display a greaterabundance of renal cortical GLUT-1 as compared with nondiabeticcounterparts.74,75 In diabetes, GLUT-1 overexpression seemspeculiar to the kidney, and there are striking dissimilaritieswith other tissues. In animal models of diabetes, GLUT-1 expressionis downregulated by 50% in heart tissue76,77 and in the retinalmicrovasculature.78 High glucose concentrations in mesangialcells counterintuitively increase GLUT-1 expression via a TGF-1–dependentmechanism.60,79 This may be peculiar to mesangial cells as opposedto other cell types; for example, GLUT-1 levels downregulatein mouse vascular smooth muscle cells when cultured in high-glucoseconditions.80 Similarly, in ex vivo work, mesangial cells, obtainedfrom microdissected glomeruli of patients with type 2 diabetesand cultured in vitro, showed enhanced GLUT-1 transporter expression,increased basal glucose uptake, and excessive flux of glucosemetabolism through the hexosamine pathway, paralleled by increasedextracellular matrix deposition and mesangial cell hypertrophy.81In contrast skeletal muscle GLUT-1 protein expression as wellas basal glucose uptake is reduced in patients with type 2 diabetes.82Various stimuli may therefore modulate GLUT-1 overexpressionin the glomerulus in diabetes, an event that we suggest playsa central role in the sequence of molecular pathways responsiblefor glomerular damage (Figure 2).
Figure 2. Regulation of glucose entry into mesangial cells mediates its response to various external stimuli. Stimuli such as mechanical stretch, high glucose, and angiotensin II upregulate GLUT-1 glucose transporter expression and enhance basal glucose transport into mesangial cells. Resulting activation of intracellular pathways (protein kinase C [PKC], polyol pathway, hexosamine, p38–mitogen-activated protein kinase [MAPK], and reactive oxygen species [ROS] formation) with TGF-1 upregulation may mediate and maintain upregulation of GLUT-1 expression, thereby perpetuating a vicious cycle of excess extracellular matrix production.
It is plausible that mechanical forces alter intracellular glucosetransport/metabolism via GLUT-1 overexpression in other nondiabeticglomerular 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 theRAAS are important risk factors for the development of glomerulardamage,83 and in obesity-related glomerulopathy, renal corticalGLUT-1 levels are upregulated.84
Multiple genes have been implicated in the pathogenesis of diabetickidney disease, including polymorphisms of the angiotensin-convertingenzyme and aldose reductase gene.85 Reports have also linkedan XbaI polymorphism, located on the second intron of the GLUT-1gene, with a greater risk for diabetic kidney disease.86–88Data on this polymorphism are conflicting, and a recent meta-analysiswas not able to support a clear association between this polymorphismand diabetic kidney disease.86 Two large studies conducted inwhite patients with type 1 diabetes failed to show an association,whereas two smaller studies (white patients with type 1 andAsian patients with type 2 diabetes) claimed a susceptibilityeffect for diabetic kidney disease. The XbaI polymorphism isan intronic mutation with a questionable functional significancebecause it has never been associated with changes in GLUT-1expression. It is possible, however, that the XbaI polymorphismmight be linked with a functional locus. However, in linkagestudies, the GLUT-1 region 1p35-p31.3 has not, to date, beenidentified as an important susceptibility locus in diabetickidney disease.89–93
Much more is known about the independent pathways of both glucose-and pressure-induced renal injury; much less is known abouthow they combine. Hemodynamic–metabolic coupling, wherebya mechanical stimulus enhances glucose transport and metabolism,suggests a novel pathophysiologic mechanism of injury in diabetesand possibly other glomerular diseases. Strategies that interruptpressure-induced metabolic injury may provide new targets fortreatment.
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1 production. TGF-
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Abstract
THE PROBLEM
