Kidney International, Vol. 57, Suppl. 75 (2000), pp. S-15–S-21

Glomerular hypertension, abnormal glomerular growth,and progression of renal diseases

AGNES B. FOGO

Vanderbilt University Medical Center, Nashville, Tennessee, USA

Glomerular hypertension, abnormal glomerular growth, and uating vicious cycle, whereby loss of nephrons due toprogression of renal diseases. The development and progres- sclerosis further increased flow and pressures in re-sion of sclerosis is determined by complex interactions of many maining glomeruli, thus augmenting and perpetuatingmechanisms, including direct hemodynamic actions, modula-

injury. We performed serial micropuncture studies intion of glomerular cell injury, and growth factor actions. Thethe same model to investigate whether hemodynamicinterplay of these factors determines the balance of cell growth

and proliferation versus cell death by necrosis or apoptosis, derangement predicted the ultimate severity of sclerosisand the balance of matrix accumulation versus degradation. in those same punctured glomeruli. At sacrifice, theseSclerosis may even be reversed when therapies inhibit these same micropunctured glomeruli were identified, pro-mechanisms and augment matrix degradation processes, both

cessed and histologically assessed for sclerosis. The scle-by directly increasing proteolytic activity and by down-regulat-rosis indices for the individual glomeruli were then corre-ing inhibitors of matrix degradation. We will focus in this review

on the roles of glomerular hemodynamics and growth in the lated with either maximum single nephron glomerularprogression of renal diseases. filtration rate (GFR), glomerular pressure, or average

values for these parameters as assessed by repeated mi-cropuncture in these same glomeruli over the precedingGLOMERULAR HYPERTENSIONweeks [5]. There was no correlation between the degreeAND SCLEROSISof total sclerosis and these hemodynamic variables inHypertension accelerates progression of chronic renalindividual glomeruli, suggesting additional nonhemody-disease in humans, whether it results from, or causes,namic factors contribute to sclerosis.the renal disease. Glomerular pressure can be modulated

Clinical data have shown superior efficacy on progres-differentially from systemic blood pressure. The poten-sion of ACEI over nonspecific antihypertensive therapy,tial impact of these local glomerular hemodynamicnot attributable to blood pressure effects [6]. Cell culturechanges on sclerosis has been extensively studied in thestudies indeed show that angiotensin II (Ang II) canMunich-Wistar rat because it has superficial glomeruli,directly induce mesangial cell hypertrophy and/or prolif-which can be directly punctured to measure glomerulareration, depending on culture conditions, and increaseblood pressures and flows. The remnant kidney model,extracellular matrix (ECM) production [7]. We thereforewhere 5/6 of the total renal parenchyma is removed,examined the possibilities that ACEI in doses higherresults in progressive hypertension, proteinuria and ma-than those required to lower increased blood pressuretrix expansion, culminating in focal segmental glomeru-might have further beneficial effects [8]. The severity oflosclerosis, mimicking key aspects of progressive injuryglomerulosclerosis was assessed by renal biopsy at 8in humans [1–3]. Anderson et al [4] showed superiorweeks after 5/6 nephrectomy. Animals were then dividedprotection against progressive sclerosis in this model withinto groups that received no treatment, usual antihyper-angiotensin I-converting enzyme inhibitor (ACEI) com-tensive dose of ACEI, or a four-fold higher dose ofpared to nonspecific antihypertensive treatment. Al-ACEI. Both systemic and glomerular pressures werethough systemic pressures were normalized with bothnormalized by both ACEI doses, with no further hemo-interventions, glomerular pressures were decreased onlydynamic effects at the higher dose. Progression of sclero-by ACEI, and remained high with nonspecific therapy.sis was seen in all untreated animals from biopsy toThis led to the postulate of increased capillary pressureautopsy. Progression of sclerosis was significantly amel-as a key mediator of progressive sclerosis in a self-perpet-iorated in animals receiving the normal ACEI dose. Re-markably, sclerosis was even further ameliorated and

Key words: glomerular cell injury, proliferation, chronic renal disease. even regressed in response to the four-fold higher ACEIdose, with less sclerosis at autopsy than at biopsy 4 weeks 2000 by the International Society of Nephrology

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Fogo: Glomerular hypertension and abnormal growthS-16

Table 1. Conditions with glomerular hypertrophy and sclerosispreviously in three of the five rats. An angiotensin type1 receptor antagonist (AIIRA) was similarly effective, Animal Models Human Diseasesachieving regression in half of the rats. This regression Remnant kidney FSGS

Puromycin nephropathy Unilateral renal agenesiswas associated with marked inhibition of plasminogenBcl22/2 mice Extensive loss of renal massactivator inhibitor-1 (PAI-1) protein expression (see be-Os1/1/Rop mice Oligomeganephronia

low) (abstract; Nakamura et al, J Am Soc Nephrol Diabetic modelsa DiabetesHigh protein diet Reflux nephropathy10:665A, 1999). Similar reversal of sclerosis by ACEI orAngiotensin infusion Sickle cell diseaseAIIRA was observed in the nonhypertensive puromycinGrowth hormone or IGF-1 Eclampsia

aminonucleoside model of glomerulosclerosis by us and administration Cyanotic heart diseaseObesity/sleep apneaothers [9, 10].

The impact of hemodynamic vs. other factors on pro- aAssociated with mesangial expansion, not sclerosis, in rodent modelsAbbreviations: Os, oligosyndactyly mouse; FSGS, focal segmental glomerulo-gressive injury at the single glomerular level was investi-

sclerosis; IGF-1, insulin-like growth factor-1.gated in the ureteral diversion model [11]. The ureterof one kidney was diverted into the peritoneum withpartial ablation of the contralateral kidney, resulting inmarked glomerular hyperperfusion and hyperfiltration well as growth. The tight linkage of glomerular enlarge-and increased glomerular pressure. These changes, how- ment with glomerulosclerosis is thus postulated to beever, were accompanied by only minimal glomeruloscle- due to the actions of multiple factors on the glomerularrosis, and only minimal glomerular enlargement oc- cells with a response of matrix, hypertrophy and prolifer-curred. In contrast, in the 5/6 nephrectomy model, ation often occurring in concert (Fig. 1). Recent in vitromarked glomerular enlargement occurred and was data based on sophisticated microchip gene array analy-closely associated with glomerulosclerosis. Glomerular sis indeed show that the early fibroblast response toenlargement and sclerosis were also closely correlated at growth factors includes not only genes implicated in cellan individual glomerular level in a biphasic distribution, division, but also genes involved in wound healing andwith positive correlation of glomerular enlargement and angiogenesis [13]. These findings indicate tight linkagesclerosis at early phases of sclerosis (i.e., up to 50% between growth, differentiation and wound healing/re-of the tuft involved) and a negative correlation as the modeling responses.glomeruli became smaller as progressive sclerosis devel-oped until obsolescence occurred [12]. The ACEI effect

GLOMERULAR HYPERTROPHY INin ameliorating sclerosis in the remnant kidney modelEXPERIMENTAL MODELSwas associated with inhibition of glomerular growth,

Stimuli that have been shown in experimental condi-while maintaining the correlation of sclerosis and glo-tions to promote growth and glomerulosclerosis includemerular size. Of note, ACEI was not equally effectiveloss of renal mass, high protein or high salt diet, variousat all stages of fibrosis; progressive deterioration contin-hormones such as growth hormone, insulin-like growthued in glomeruli with more advanced sclerosis despitefactor (IGF), androgens, and glucocorticoids; and vaso-ACEI, whereas progression was inhibited in glomeruliactive molecules such as angiotensin or endothelin [14].at earlier stages of sclerosis. These findings suggest thatHypertrophic stimuli accelerate sclerosis, while interven-different mechanisms of sclerosis were active among thetions that dampen glomerular hypertrophy often alsoheterogeneously affected glomeruli, with different po-ameliorate glomerulosclerosis. The latter include lowtentials for response to treatment and remodeling. Theseprotein or low salt or low phosphate diet, ablation ofdata indicate that abnormal glomerular growth is associ-androgen effects by castration, antagonism of growthated with, and may be a marker of mechanisms leadinghormone with octreotide, a somatostatin analog, geneticto sclerosis. These experiments also indicate that hyper-defects in growth hormone or inhibition of angiotensinfiltration alone is insufficient to induce pathogenic glo-or endothelin.merular hypertrophy and subsequent sclerosis.

The hypertrophic response and subsequent develop-ment of sclerosis are dependent on the genetic back-

ABNORMAL GLOMERULAR GROWTH ground, suggesting that complex genetic traits modulateAND SCLEROSIS the response of glomerular cells to pathogenic stimuli.

Mice with reduced nephron number due to a radiation-Glomerular hypertrophy and sclerosis are linked innumerous diseases in humans and in experimental ani- induced mutation that results in ,50% nephron reduc-

tion in association with oligosyndactyly (Os1/1) devel-mal models (Table 1). In vivo and in vitro experimentalevidence point to the capability of many cytokines to oped severe glomerular enlargement and sclerosis when

this abnormality occurred on the sclerosis-prone ROPpromote growth of glomerular cells and also to enhanceextracellular matrix release, thus promoting sclerosis as genetic background, but not in C57 mice [15]. Glomeru-

Fogo: Glomerular hypertension and abnormal growth S-17

Fig. 1. Glomerular hypertrophy is postulatedto be associated with glomerulosclerosis basedon the linked responses of glomerular cells togrowth stimuli. Hypertrophy and proliferationthus typically occur in concert with increasedECM release. ECM accumulation is the cor-nerstone of sclerosis.

lar hypertrophy was proportional to reduction of neph- course and re-biopsy consistent with this diagnosis werecompared to patients with similar initial biopsies butron mass in the former strain. In contrast, a threshold

for glomerular size was observed in the C57 mice. The who subsequently developed overt focal segmental glo-merulosclerosis. These biopsies were then compared tointerplay of genetic background and response to injury

is also well recognized in humans, where only ,40% of age-matched controls [17]. Whereas patients with mini-mal change disease showed normal glomerular size, ini-patients with type 1 diabetes mellitus develop diabetic

nephropathy (see below). tial biopsies in patients with progression to focal segmen-tal glomerulosclerosis revealed significant glomerularThe age of injury also modifies the growth response

to renal ablation. In young animals where maturational enlargement. Similarly, in adults with focal segmentalglomerulosclerosis, glomeruli were larger than in thosegrowth is occurring, injury after renal ablation was more

severe than in adults [16]. Hemodynamic factors were with minimal change disease [18]. The association ofincreased glomerular size and subsequent evolution ofnot different among the two age groups. Although glo-

merular enlargement occurred to greater degree in the glomerular sclerosis was also seen in the setting of recur-rent FSGS in the transplant. Thus, in cases of nephroticyoung compared to the adult rat after renal ablation,

glomerular enlargement occurred proportionally in both syndrome without evident segmental glomerular sclero-sis, patients with normal glomerular size appear to have asuperficial and deep nephron populations, with more

severe glomerulosclerosis in deep nephrons in young good prognosis. In contrast, those patients with markedlyenlarged glomerular size have a high risk of subsequentanimals. This increased sclerosis was postulated to be

related to factors unique in the young growing kidney, progression to overt FSGS. A recent genetic analysis ofchildren with nephrotic syndrome found FSGS patientswhich is characterized by centripetal growth and differ-

entiation. to have a higher prevalence of the ACE deletion (D)polymorphism, compared to the insertion (I) polymor-phism, when compared to minimal change disease pa-

GLOMERULAR HYPERTROPHY AND tients [19]. This D allele has been associated with higherHUMAN DISEASE activity of the renin angiotensin system (RAS), which

Glomerular hypertrophy is linked with development may influence both renal growth and scarring responses.of sclerosis in human disease [14]. Stimuli to abnormalgrowth noted in humans include hypoxia, as seen in

LOSS OF RENAL MASS IN HUMANScyanotic heart disease, sickle cell disease and obesity-associated sleep apnea; and limited renal mass, as in Response to decreased renal mass in humans varies

according to age at loss, underlying condition and extenttransplantation, extensive removal of renal mass andunilateral renal agenesis. All of these conditions have of tissue loss. Several follow-up studies conducted on

renal transplant donors as well as individuals nephrecto-also been associated with lesions of focal segmental glo-merulosclerosis (FSGS). In human diabetes and FSGS, mized secondary to trauma and unilateral diseases sug-

gest a relatively benign course after unilateral nephrec-increased glomerular size precedes development of thesclerotic lesions. Patients with initial biopsies consistent tomy [14, 20]. In contrast, patients with nephrectomy for

unilateral disease show a surprisingly high incidence ofwith minimal change disease and with subsequent clinical

Fogo: Glomerular hypertension and abnormal growthS-18

glomerular sclerosis developing in these remnant kid- wards normal after injury. Renal growth occurs by bothhyperplasia (increase in cell number) and hypertrophyneys. The reason for this apparent difference between

response to these two forms of nephrectomy may be (increase in cell size). Increases in renal mass primarilyreflect tubular growth. However, glomerular growth alsomultifactorial, including recurrence of the primary dis-

ease in the therapeutically nephrectomized patients and occurs in response to some injuries or reduced nephronmass. The glomerular growth occurs primarily by length-selection of individuals without risk factors for renal

disease as kidney donors. In contrast, more extensive loss ening of the capillaries without significant increase indiameter after loss of renal parenchyma or in childrenof renal mass in patients with bilateral tumors resulted in

an increased incidence of FSGS in the remnant kidney with reflux nephropathy [27, 28]. In contrast, growth isaccomplished by new capillary branching in experimen-[21]. Age at loss of renal mass influences the renal re-

sponse in humans. In patients undergoing unilateral ne- tal diabetes and in toxic nephropathy due to lithium [29,30]. With more extreme hemodynamic abnormalities,phrectomy for Wilms’ tumor, renal growth was most

marked in those who had surgery at a younger age, dilatation of capillaries may occur and contribute to in-creased glomerular size [31].and this increased kidney growth was associated with

microalbuminuria that developed in 11 of 34 patients So-called glomerular hypertrophy, that is an increasein glomerular size, represents both cellular hypertrophy[22]. In 157 patients with unilateral renal agenesis, there

was significantly increased risk for proteinuria (in 19%), and hyperplasia. Glomerular hypertrophy can be de-tected biochemically and morphologically by electronhypertension (47%) and renal insufficiency (13%), with

death due to renal disease in 6 patients [23]. The worse microscopy as early as 2 days after 5/6 nephrectomy.Increased glomerular volume at 2 days was attributableprognosis in these patients compared to the benign out-

comes following unilateral nephrectomy for trauma or to increased glomerular visceral epithelial cell expansion,likely hypertrophy in view of this cell’s limited mitogenicin donors suggests that the number of remnant nephrons

in the congenital solitary kidney may, in fact, be de- capacity (see below) [32]. Later increases in glomerularvolume were contributed to by mesangial cell increase,creased (i.e., hypogenesis), thereby representing a morelikely both hypertrophy and hyperplasia. Hyperplasiasevere form of reduction in nephron population thanpredominated after 5/6 nephrectomy, whereas hypertro-surgical unilateral nephrectomy. The possibility that thephy was the major growth response after uninephrec-remnant glomeruli of congenital solitary kidney are un-tomy. The resulting glomerular growth was more markedder greater hypertrophic stress is indeed supported byafter 5/6 nephrectomy, and was associated with laterquantitative morphometric studies. The volume of eachsclerosis.glomerulus in solitary kidneys was found to be 5–6 times

The precise trigger(s) for initiation of growth responsenormal, a value closer to that found in oligomega-remain undetermined. Early work proposed that renalnephronia than that seen in postnephrectomized adultsgrowth after uninephrectomy was merely in response to[24]. Oligomeganephronia is another congenital condi-increased work load. In the early 1970s the concept oftion in humans characterized by few but markedly en-“renotropic” factor(s) was formulated as the alternativelarged nephrons, and perhaps increased risk of FSGS.explanation based on observations of renal growth inLower nephron number may be associated with in-normal animals connected by parabiosis with an anephriccreased risk of renal disease in the population with twopartner, resurrecting observations made by Sacerdottiapparent normal kidneys as well. Glomerular size inover a hundred years ago [14, 33]. Most recently, a possi-normal African Americans is larger than in Caucasians,ble quantitative trait locus (QTL) linked to genetic mod-and could possibly reflect smaller nephron number [25].ulation of the compensatory growth response has beenDecreased nephron number has been postulated to occuridentified in the mouse on chromosome 11. This markersecondary to low birth weight [26]. The latter is associ-maps near the genes for ACE, growth hormone andated with increased risk for progressive renal disease inneural growth factor receptor (NGFR), all of which haveadulthood. Other possible mechanisms that could under-known influences on growth responses in the kidney [34].lie these differences in normal glomerular growth andHypertrophy of remnant glomeruli was also postulatedalso relate to the well-documented increased incidenceto be the consequence of the abnormal hemodynamicsof end stage renal disease in the African American popu-developing within these glomeruli or merely representlation include polymorphisms of genes involved both inengorgement. However, the increased growth in the rem-renal/glomerular development and in scarring mecha-nant kidney model in the rat occurred before increasesnisms, such as the renin angiotensin system.in single nephron GFR [14].

Altered gene expressions in pathophysiologic settingsFACTORS MEDIATING GROWTH implicate many factors in glomerular growth and en-

Adaptations to increase renal mass and function pre- hanced ECM release, including the following: plateletderived growth factor (PDGF), transforming growthsumably occur in attempts to restore renal function to-

Fogo: Glomerular hypertension and abnormal growth S-19

factor-b (TGF-b), TGF-a, IGF-1, growth hormone, epi- well as proliferation and migration occur in several ani-mal models of glomerular injury. The balance betweendermal growth factor, interleukins 1 and 6, tumor necro-

sis factor-a (TNF-a), Ang II, hepatocyte growth factor endothelial cell growth and death appear to be crucialfor determining whether healing or scarring will resultand its receptor c-myc, and endothelin. Several growth

factors are now considered to play key causal roles in after injury [37]. Normally, endothelial cells inhibitsmooth muscle cell migration and proliferation. Endo-glomerulosclerosis, including Ang II, PDGF and TGF-b,

based on results of infusion, transfection and inhibition thelial cells produce numerous factors that modulatemesangial or vascular smooth muscle cell growth (e.g.,of these factors. Studies in human renal diseases have

begun to map some of these key growth factors, showing vascular endothelial growth factor, VEGF; nitric oxide;endothelin and PDGF) [18]. Some endothelial-derivedup-regulation in some settings. Interpretation must takefactors act in synergy with heparin-like substances.into account that a given growth promoter may affectVEGF is an endothelial cell-specific mitogen that withindifferent cells differently, inducing proliferation, hyper-the kidney originates largely from epithelial cells, andtrophy or even inhibiting growth, depending on the hostmay mediate physiologic and pathologic angiogenesis.cells’ milieu, genotype and phenotype.Recent evidence implicates VEGF as a necessary sur-vival factor for cells in vivo (abstract; Suga et al, J Am

METABOLIC FACTORS PROMOTING Soc Nephrol 10:561A, 1999). Endothelin, a powerful va-RENAL GROWTH soconstrictor, is released from endothelial cells in re-

Abnormal renal growth precedes development of scle- sponse to a variety of stimuli and also after injury [38].rosis in diabetic nephropathy. IGF-1 is one key growth Endothelin results in the adaptive responses of hyperpla-factor altered in progressive renal diseases, including sia, hypertrophy and increased matrix in mesangial cellsdiabetes. Several other growth factors including basic in culture [18, 38]. Plasminogen activator-inhibitor-1,fibroblastic growth factor (bFGF), PDGF and epidermal PAI-1, which is produced by endothelial cells amonggrowth factor, may be altered in diabetes and affect other sources, has been linked to not only thrombosis,glomerular growth and sclerosis. Patients with diabetic but also fibrosis through its effects to inhibit matrix deg-nephropathy showed significantly larger mean glomeru- radation [39]. PAI-1 induction occurs in response to sev-lar size and mesangial volume compared to both normal eral growth factors and cytokines that play key roles incontrols and diabetics without nephropathy [35]. In addi- renal growth and fibrotic responses, including TGF-btion, there was a strong correlation between severity of and angiotensin. These data indicate that PAI-1 may beglomerular sclerosis and glomerular hypertrophy. The an additional target for antifibrotic therapies.potential importance of the diabetic milieu in promoting The glomerular visceral epithelial cell is part of the

capillary wall barrier, and produces ECM. Glomerularthe glomerular hypertrophy and mesangial matrix expan-visceral epithelial cells have limited capacity for hyper-sion of diabetic nephropathy was evident in a study ofplasia. The exciting recent discoveries of specific cyclin-diabetic patients with renal and pancreas transplants.dependent kinase inhibitors expressed in mature, but notPatients with the combined transplants, who achieved aimmature glomerular visceral epithelial cells suggest ametabolic cure of their diabetes, had only minimal mesan-possible mechanism for this limitation of this highly spe-gial expansion in their transplant kidneys. Long-termcialized cell [40]. Manipulations of one of these inhibi-follow-up even showed reversal of sclerosis in some oftors, p27Kip-1, in experimental mice models illustratedthese patients [36]. The pancreas transplant patients alsothat abnormal glomerular visceral epithelial cell prolifer-had smaller mean glomerular volume and mesangial vol-ation, whether too little or too much, resulted in aug-umes than control patients. In contrast, diabetic patientsmented glomerular injury [40]. Epithelial cells frequentlyreceiving only kidney transplant who thus remained dia-are detached from the underlying basement membranebetic, showed more severe diabetic renal lesions.in settings of glomerular hypertrophy and sclerosis, per-haps due to their limited growth. These epithelial cell

CELL-SPECIFIC GROWTH RESPONSES defects are postulated to play an important role in adhe-Glomerular growth may occur due to increase in any sions and hyalinosis, leading to progressive scarring [41].

of its cellular components. These alterations in response Glomerular visceral epithelial cells also interact withto either the initial injury or to a decrease in remaining other glomerular cells and modulate cell growth andrenal mass after initial injury contribute to maintaining matrix synthesis/degradation by elaboration of growthrenal function in the short term. However, in the long factors and cytokines, such as heparan (inhibits mesan-term these adaptive changes promote matrix accumula- gial cell growth) and VEGF. Injured glomerular visceraltion and thereby renal malfunction. epithelial cells also change phenotype. The Wilms’ tumor

The glomerular endothelial cell has a long half-life, gene WT-1, normally expressed in glomerular visceralepithelial cells, is decreased or lost in injured glomerularapproximately 100 days. Endothelial cell apoptosis as

Fogo: Glomerular hypertension and abnormal growthS-20

visceral epithelial cells in the severe collapsing form of creased growth factors, which may be induced in re-sponse to various stimuli. The final result of these pro-FSGS, a dedifferentiation phenotype [42]. WT-1 has

been implicated in a wide spectrum of functions in the cesses is increased matrix accumulation, the root causeof sclerosis. The particular growth factors and the roleskidney, including renal development, glomerular perm-

selectivity and sclerosis. they play may differ at the various stages of injury. Thecontribution of angiotensin II is particularly relevantThe mesangial cell responds to many growth factors by

proliferation and increased ECM synthesis. After initial since it can be inhibited by currently clinically availableagents. The potential regression of glomerular sclerosisinjury, the activated mesangial cell changes phenotype,

expressing fibroblast-like myosin [43]. This wound heal- has now been shown in human diabetic nephropathy.Animal studies point to PAI-1 as a key target in achievinging phenotype is associated with increased matrix gener-this remodeling of matrix, however, the specific factorsation. a-actin expression is also increased after injury,that could optimize regeneration of open capillary loopsalong with increased PDGF-B, recapitulating their de-have not been identified. Further study is necessary tovelopmental patterns of expressions in mesangial cells.determine the specific role each of these factors plays inAng II induces mesangial cell hypertrophy and increasesvarying settings of renal growth to maximize beneficialmatrix production from mesangial cells in vitro. TGF-bgrowth responses and inhibit those deleterious to kidneyincreases both collagen and proteoglycan production byfunction and structure.mesangial cells, and depending on the cell cycle stage,

acts synergistically with other growth factors. bFGF mayReprint requests to Agnes B. Fogo, M.D. MCN C3310, Department of

initiate mesangial cell injury response. Mesangial cells Pathology, Vanderbilt University Medical Center, Nashville, Tennessee,37232, USA.in culture release both interleukin-1 and a PDGF-likeE-mail: Agnes.Fogo@mcmail.vanderbilt.edufactor, and proliferate and produce ECM in response to

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