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*
Department of Medicine, Loyola University Medical Center/Hines VA
Hospital, Maywood, Illinois
Department of Pathology, Loyola University Medical Center/Hines VA
Hospital, Maywood, Illinois
Department of Physiology, Wayne State University, Detroit,
Michigan.
Correspondence to Dr. Karen A. Griffin, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153. Phone: 708-202-8387, extension 24120; Fax: 708-202-7978.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have recently demonstrated that when equivalent approximately 5/6 renal mass reduction (RMR) is achieved by surgical excision (RK-NX) instead of infarction, there is a marked reduction in GS at 6 wk compared to the traditional infarction (RK-I) model (21). The present studies were performed to define the pathogenetic correlates of these striking differences in GS between the two models. Radiotelemetric BP monitoring, single nephron function, glomerular hypertrophy, the temporal expression of renin, TGF-ß and PDGF-B mRNA, and plasma renin concentration were examined in these two models of RMR and compared to sham-operated control rats.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Four sets of studies were performed in separate sets of animals to: (1) characterize the structural and functional adaptations at the whole kidney level at 3 wk as well as for the assessment of morphologic injury; (2) define the determinants of the hyperfiltration response at the single nephron level at 3 to 4 wk; (3) define the temporal expression of mRNA for renin and the growth factors TGF-ß and PDGF-B over the initial 3 wk after RMR; and (4) examine the temporal changes in plasma renin concentration (PRC) after RMR.
Whole Kidney Studies
At the time of renal ablation or sham surgery, radio transmitters (Data
Sciences International, St. Paul, MN) were installed
(21,22,23,24).
The rats were anesthetized with sodium pentobarbital (45 mg/kg,
intraperitoneally), and the sensor's catheter was inserted into the aorta
below the level of the renal arteries. The radio frequency transmitter was
fixed to the peritoneum. The signals from the pressure sensor were converted
and temperature compensated and sent via the radio frequency transmitter to
the telemetry receiver. The receiver was connected to a BCM-100 consolidation
matrix that transmitted the signals to the Dataquest IV acquisition system
(Data Sciences International). Systolic BP in each animal was continuously
recorded at 10-min intervals throughout the course of 3 wk, each reading
representing the average BP during a 5-s sampling period. Tail vein blood
samples were obtained at 3 d for measurement of SCr as an
index of the degree of renal mass reduction. After 3 wk, tail vein
SCr and 24-h urine collections for protein excretion were
obtained. The rats were then anesthetized with intravenous sodium
pentobarbital (40 mg/kg), a tracheostomy was performed using polyethylene
(PE-200) tubing, and the rats were surgically prepared for measurement of
inulin clearance and renal blood flow (RBF) as described previously
(21,22,23,24,25,26).
In brief, a carotid artery was cannulated with PE-50 tubing and connected to a
Windograf (model 40-8474; Gould, Glen Burnie, MD) for continuous recording of
mean arterial pressure. A femoral vein was cannulated with PE-50 tubing and a
priming dose of inulin in 150 mM NaCl was administered, followed by a
continuous maintenance infusion of 150 mM NaCl containing inulin at 0.055
ml/min to maintain the plasma concentration of inulin at approximately 50
mg/dl and for replacement of surgical and ongoing fluid losses. The left
ureter was then cannulated with polyethylene tubing for collection of urine
samples. A 1.0-mm R series flow probe (Transonic Systems, Ithaca, NY) was
placed around the left renal artery for measurement of RBF by a flowmeter
(Transonic Systems), as described previously
(21,22,23,24,25,26).
At the conclusion of the surgery, a 150 mM NaCl bolus equal to 1% of body
weight was administered. Two 20-min clearances of inulin were obtained. Blood
samples were obtained at the midpoint of each urine collection. The kidneys
were then perfusion-fixed at their ambient BP and subsequently processed for
morphologic and morphometric studies.
Morphologic Methods. Transverse sections of the kidney through the papilla were fixed in situ by perfusion for 5 min at the measured BP with 1.25% glutaraldehyde in 0.1 M cacodylate buffer. Sections were cut at a thickness of 2 µm and stained with hematoxylin and eosin and periodic acid-Schiff. Sections were evaluated systematically in each kidney for evidence of glomerular injury in a blinded manner by standard morphologic methods (21,22,23,24). At least 100 glomeruli in each animal, and usually more, were evaluated for the presence of lesions of segmental sclerosis (collapsed capillaries with obliteration of the capillary lumina, frequently accompanied by a fibrous adhesion between the glomerular tuft and Bowman's capsule) and/or necrosis (fibrinoid necrosis of part or all of the glomerular tuft with loss of architecture often accompanied by capillary thrombosis, karyorrhexis, fibrin leakage into the Bowman space, and proliferation of the parietal epithelium of Bowman's capsule). The severity of glomerulosclerosis was expressed as the percentage of glomeruli exhibiting such injury.
Morphometric Methods. Glomerular volume was measured by area
perimeter analysis (Bioquant System IV software; R&M Biometrics,
Nashville, TN). The cross-sectional area (AG) of 75
consecutive glomerular profiles contained in one kidney section for each
animal was measured using a digitizing pad as described previously
(21,
23,
24). The mean glomerular
volume (VG) was then calculated from the respective mean
AG as VG = ß/
(AG3/2), where ß = 1.38 is the size
distribution coefficient and = 1.1 is the shape coefficient for
glomeruli idealized as spheres
(27,
28).
Micropuncture Studies to Define the Determinants of Single Nephron
Hyperfiltration
These rats underwent sham or RMR surgery as described above, but without
the placement of radio transmitters. At 3 to 4 wk, the rats were anesthetized
with inactin (100 mg/kg, intraperitoneally) and placed on a
temperature-regulated (37°C) micropuncture table and prepared for
micropuncture studies as described previously
(29). Left kidney GFR,
proximal tubular pressure (PT), stop flow pressures
(PSF), peritubular capillary (first order) pressures
(PPC), and SNGFR were determined using 3H
inulin. Nephrons were mapped by injection of 0.9% NaCl stained with fast green
dye. Only nephrons clearly within the normal remnant parenchyma and well away
from scar areas were selected for micropuncture. Three to five proximal
tubular collections were obtained in each rat. Similarly, 3 to 4
PSF measurements with a continuously recording Servonull
system were made in each rat. Simultaneous femoral arterial and renal vein
collections were obtained to determine inulin extraction and whole kidney
filtration fraction (17,
30). Afferent arterial colloid
oncotic pressure (
A) was calculated using the femoral arterial
plasma protein concentration and the Landis—Pappenheimer equation.
PGC was calculated as PSF + A. Other
equations used were: glomerular plasma flow (QA) =
SNGFR/FF; glomerular blood flow (GBF) = QA/1 — Hct;
efferent arteriolar blood flow (EABF) = GBF — SNGFR; afferent, efferent,
and total renal arteriolar resistance (RA=AP —
PGC/GBF x (7.982 x 1010);
RE = PGC —
PPC/EABF x (7.982 x 1010);
(RTA = RA + RE),
respectively; net ultrafiltration pressure (PUF) =
PGC — PT —
A; and ultrafiltration coefficient (Kf) =
SNGFR/PUF
(29,30,31).
Temporal Expression of Growth Factors
These rats underwent sham or RMR surgery and installation of radio
transmitters for BP radiotelemetry as described for rats undergoing renal
hemodynamic studies. Separate sets of sham (n = 8), RK-NX (n
= 9), and RK-I (n = 9) rats each were sacrificed at 3, 7, and 21 d,
and the kidneys were harvested for Northern blot analysis for renin,
TGF-ß, and PDGF-B mRNA expression. The infarcted areas (scars) and the
immediately adjacent areas were excised quickly, and the remaining kidney
tissue was placed into liquid nitrogen.
Northern Blot Analysis. RNA isolation was performed by a modification of the method of Chirgwin et al. (32). One hundred micrograms of this "non-scar" renal tissue was homogenized with guanidinium isothiocyanate. The RNA was isolated by isopycnic centrifugation over CsCl, and its concentration was measured spectrophotometrically at 260/280 nm using the molar extinction coefficient of nucleic acids. A standardized aliquot of RNA (20 µg) was separated by electrophoresis on a formaldehyde agarose denaturing gel and transferred to a Nytran® membrane by capillary transfer. Lanes were loaded with pooled RNA from each of the three groups of rats sacrificed at each of the three separate time points. The RNA was immobilized to the membrane by ultraviolet cross-linking.
The membrane was successively hybridized with four parts (15 ml of Formamide, 0.6 ml Denhardt's solution, 1.5 ml of 1 M phosphate buffer, 7.5 ml of 20x SSC, 1.5 ml of 205 SDS, 2.4 ml of diethylpyrocarbonate water, and 1.5 ml of salmon sperm DNA)/blot and one part 50 dextran sulfate solution with 32P-dCTP-labeled cDNA probes (renin [gift of Kevin R. Lynch, University of Virginia, Charlottesville, VA], TGF-ß, PDGF-B, and GAPDH, which was used as the house-keeping gene [American Type Culture Collection, Manassas, VA]). The cDNA was radiolabeled using a random prime labeling kit (Pharmacia, Piscataway, NJ). After each hybridization, the membrane was washed and placed in an x-ray cassette for the requisite exposure time. Autoradiograms were quantified using computerized densitometry (Bioquant Systems IV software; R&M Biometrics) and corrected for protein loading. This was accomplished by factoring the relative density of the various mRNA autoradiograms by the GAPDH mRNA autoradiogram (the values in sham controls were arbitrarily assigned a value of 1).
Temporal Changes in PRC
PRC measurements were performed at 3 and 21 d after RMR. These rats
underwent sham or RMR surgery and installation of radio transmitters for BP
radiotelemetry as described for rats undergoing renal hemodynamic studies. For
rats that were to undergo PRC measurements at 3 d, the right or left femoral
artery was catheterized with flexible Tygon® tubing at the time of RMR
surgery. The distal end of the catheter was tunneled through the subcutaneous
tissue and exteriorized at the back of the neck. The catheter was flushed and
filled with a heparin dextrose solution and plugged with a straight blunted
pin. For the rats undergoing PRC measurements at 21 d, the placement of the
femoral artery catheter was performed 2 d earlier under sodium pentobarbital
(45 mg/kg, intravenously) anesthesia. Blood samples were obtained from rats
resting quietly in restrainers. Blood was drawn into prechilled ice-cold
heparinized plastic syringes
(25,26).
Blood samples were centrifuged at 4°C, and the plasma was stored at
-20°C until analyzed. The rats were sacrificed after blood samples were
obtained.
Laboratory Analyses
Urinary protein was measured by the quantitative sulfosalicylic acid method
with human serum albumin serving as standard. Serum creatinine was measured
using a creatinine analyzer (Beckman Instruments, Fullerton, CA)
(21,24).
Inulin in urine and plasma filtrates was determined spectrophotometrically by
the diphenylamine method as described previously
(21,22,23,24,25,26).
GFR was calculated using standard formulas. PRC was determined by incubating
plasma with excess homologous renin substrate, in the presence of inhibitors
of converting enzyme and angiotensinase, and determining the amount of AngI
generated during the incubation period, as described previously
(25,26).
PRC was expressed in units of nanograms of AngI per milliliter plasma per hour
incubation with substrate (i.e., ng AngI/ml per h).
Statistical Analyses
All results are expressed as mean ± SEM. Statistical analysis was
performed using ANOVA followed by Student-Newman-Keuls test or by
Kruskal-Wallis nonparametric ANOVA followed by Dunn multiple comparison test
as appropriate (33). A
P value of <0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Figure 1, A and B, provides the data for the functional and structural indices of the renal hypertrophy response at 3 wk after RMR. Kidney weight and glomerular volume (Figure 1A) were significantly increased in the two RMR groups compared to the sham rats but were not significantly different from each other. By 3 wk after RMR, the RBF and GFR of the remnant left kidneys of both RMR groups had increased such that no significant differences were seen between them and the intact left kidney of the sham-operated controls (Figure 1B).
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Single Nephron Studies
The body weights, SCr, and urine protein excretion data
of the rats undergoing micropuncture studies are presented in
Table 2 and were essentially
similar to Table 1. Also
provided are the whole kidney RBF and GFR data for these groups.
Table 3 presents the renal
functional data at the single nephron level for the sham control and the two
RMR groups. Both single nephron plasma flow and GFR were significantly greater
in the two RMR groups compared with the sham controls but were not
significantly different from each other. Mean arterial pressure (AP) under
anesthesia was significantly greater in the RK-I compared with the RK-NX and
sham rats, consistent with the average systolic BP recorded in the
unanesthetized rats of the three groups during the whole kidney studies. All
components of renal vascular resistance (total, afferent, and efferent) were
reduced in both RMR groups compared to sham controls; however, the reduction
in RA in the RK-I group did not reach statistical
significance. However, it should be noted that the RA in
the RK-I group is expected to be somewhat elevated due to the superimposition
of autoregulatory afferent vasoconstriction, albeit impaired, in response to
the significantly higher AP in this group. The PGC and
PUF were significantly greater in both RMR groups compared
to the sham controls, but the increase was significantly greater in the RK-I
compared to the RK-NX group. By contrast, the increase in
Kf in the two RMR groups compared to the sham rats was
statistically significant only for the RK-NX rats.
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Studies of Temporal Expression of mRNA for Renin, TGF-ß, and
PDGF-B
Figure 2 illustrates the
average systolic BP in the rats that underwent Northern blot analysis at each
time point (3, 7, and 21 d). The RK-I rats had significantly increased
systolic BP at all time points compared to both the sham and RK-NX rats. By
contrast, no significant differences were seen in systolic BP between the
RK-NX and sham rats at any of the time points. Northern blot analysis was used
to measure the temporal expression of renin, TGF-ß, and PDGF-B at 3, 7,
and 21 d. Figure 3 shows the
relative density units/sham controls for the mRNA expression of renin,
TGF-ß, and PDGF-B. Renin mRNA expression was increased in the RK-I rats
at 3 and 7 d compared to the sham and RK-NX rats but was subsequently
suppressed at 21 d. By contrast, the RK-NX rats exhibited no increase in renin
mRNA expression at any time point, but rather a temporary suppression on day
7. The temporal pattern of TGF-ß and PDGF-B mRNA expression was
characterized by a marked increase in both at 21 d in only the RK-I group in
whom glomerular injury had started to develop, whereas only a modest increase
in TGF-ß but not PDGF-B mRNA expression was noted at all time points in
the RK-NX rats.
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Temporal Changes in PRC after RMR
Table 4 presents the
radiotelemetrically measured average systolic BP and the PRC data for the
separate sets of sham, RK-NX, and RK-I rats, each of whom underwent PRC
measurements at 3 and 21 d. As can be noted, changes in PRC after RMR were
directionally similar to the changes in tissue renin mRNA expression. PRC was
significantly increased in the RK-I rats at 3 d compared to both the sham and
the RK-NX rats. At 21 d, PRC of RK-I rats was not significantly different than
sham rats but was still significantly higher than that of the RK-NX rats.
Average systolic BP showed an excellent correlation with PRC at 3 d
(Figure 4) (r = 0.84,
P < 0.0001), but not at 21 d (r = 0.36 P >
0.09).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Based on the initial micropuncture studies in the RK-I model, it had been suggested that the compensatory increase in single-nephron GFR (SNGFR) after RMR per se may be maladaptive, eventually resulting in glomerular injury and sclerosis (2,3). Subsequent studies have indicated that of the individual hemodynamic determinants of this augmentation in SNGFR, an increased PGC is the parameter of primary importance in the pathogenesis of the "hyperfiltration" glomerular injury (3,15,16). The micropuncture data in the present study indicate that even marked increases in single nephron glomerular blood flow and filtration rate after severe approximately 5/6 RMR may not per se be sufficient to result in GS. These data additionally indicate that only modest increases in PGC, as seen in the RK-NX rats, are sufficient to achieve substantial single nephron hyperfiltration. No significant differences in pre- and postglomerular resistances were observed between the two groups. These data are therefore consistent with the interpretation that the greater PGC increase observed in the RK-I rats reflects glomerular transmission of the higher systemic pressures present in the RK-I rats, rather than being intrinsic to the hemodynamic adaptations that follow RMR. Moreover, our data indicate that such modest increases in PGC as seen in the RK-NX rats may not be pathologic, at least over the short term. These interpretations are additionally supported by our previous observations in the WKY strain of rats, which fail to develop HTN even after 5/6 renal ablation by infarction (29). These rats also exhibited modest elevations in PGC (approximately 5 mmHg) comparable to those observed in RK-NX rats in the present study and did not develop significant GS despite substantial single nephron hyperfiltration for up to 16 wk. Therefore, increases in PGC sufficient to be pathologic seem to be a superimposed consequence of systemic hypertension on the intrinsic adaptive changes of RMR. A similar conclusion was reached by Meyer and Rennke (41) after more limited RMR (41). Significantly greater systemic and glomerular HTN was noted in rats that had undergone 40% RMR by segmental renal infarction despite greater compensatory hyperfiltration in the normotensive uninephrectomized rats (50% RMR).
Some investigators have suggested that structural glomerular hypertrophy (and the associated cellular responses), rather than glomerular hyperfiltration (and the associated hemodynamic changes), may be the maladaptive process that eventually causes GS (11,12,13,14). Our data do not support such a postulate. Both RK-I and RK-NX rats exhibit comparable glomerular hypertrophy, despite the differences in GS that are observed by 6 wk between the two groups (21). However, these data do not exclude the potential of long-term adverse effects of glomerular hypertrophy because of the associated increases in glomerular capillary wall tension as predicted by the Laplace Law (Tension = Pressure x Radius) (28,29,30,42,43). Nevertheless, these data do suggest that glomerular hypertrophy per se may also be of limited pathologic import in the absence of pathologic glomerular hypertension. Additionally, the similarity of glomerular hypertrophy responses between the RK-NX and RK-I rats despite the early differences in renin mRNA expression and PRC do not support a primary role for AngII as a determinant of the glomerular hypertrophy response after RMR.
Our data similarly do not support a primary role for TGF-ß and PGDF-B in the renal hypertrophy response after RMR. Although a modest increase in TGF-ß mRNA was observed in RK-NX rats at all time periods, its relationship to compensatory hypertrophy is not clear. Comparable renal and glomerular hypertrophy was observed in the RK-I rats without an increase in TGF-ß at 3 and 7 d after RMR. The marked increase in PDGF-B and TGF-ß observed at 21 d in the present study in the RK-I group in whom glomerular injury has started to develop, but not in the RK-NX rats, suggests that such increased expression may be a consequence of glomerular hypertension and/or may be initiated by the early increases in renin (and AngII) at 3 and 7 d in the RK-I rats. Significant in vitro and in vivo evidence supports the potential of AngII to directly cause an increase in the expression of PDGF-B and TGF-ß in the RK-I model through its "growth effects" on mesangial cells analogous to those on vascular smooth muscle cells (8,9,10,11,12,14,44). AngII is thought to initiate a molecular cascade by activating the immediate early genes c-fos and c-myc, followed by increases in the growth factors PDGF-B and TGF-ß with resulting increases in extracellular matrix accumulation and GS. However, the present study does not allow a direct and independent evaluation of the role of increased AngII and/or aldosterone in the absence of glomerular hypertension, because the mechanical stress generated by glomerular capillary hypertension per se has the potential to alter glomerular mesangial and/or endothelial function and to initiate increased generation of cytokines, collagen synthesis, and GS (40,44,45,46,47). It is also possible that infarction per se may result in the generation of local factors other than AngII that may lead to increased PDGF-B and TGF-ß expression and eventual GS in the absence of systemic and/or glomerular HTN. However, the absence of such GS in normotensive WKY rats despite infarction argues against such a possibility (29). Therefore, although the present data are consistent with the postulated roles of PDGF-B and TGF-ß as mediators of glomerulosclerosis (6,7,10,11,12,14), they do not provide evidence that these growth factors are the primary initiators of the renal hypertrophy and/or GS in the absence of pathologic glomerular hypertension and/or increased AngII after 5/6 RMR. However, such interpretations regarding the role of TGF-ß and PDGF-B in glomerular hypertrophy and injury are not definitive due to the limitations of the methods used in our study. Only pooled kidney tissue from rats from each group was used for the message expression studies. Moreover, the message expression was not localized within the kidney. Because the message from the glomeruli is only a small part of the total message in the whole kidney isolates, it is quite possible that specific time-dependent patterns of glomerular expression of TGF-ß and PDGF-B after RMR may be different and therefore may not be detected by the methods used in the present study. Nevertheless, the temporal pattern of TGF-ß and PDGF-B mRNA expression in the RK-I group with marked increases in both at 21 d is consistent with previous reports in the RK-I group (9,11,45). Increased glomerular endothelial TGF expression using in situ reverse transcription was observed by Lee et al. at 23 to 25 d, but not at 6 to 14 d after 5/6 renal ablation in rats fed a standard protein diet (45). However, modest increases in PDGF-B glomerular expression have been noted as early as 1 wk after 5/6 ablation by some investigators (9,11).
Collectively, these data support the hypothesis that pathologic glomerular hypertension is likely to be the primary initiator of intraglomerular cellular events such as increased PDGF-B and/or TGF-ß expression, which eventually culminate in glomerulosclerosis. Furthermore, these data support the postulate that such pathologic glomerular hypertension is a consequence of enhanced transmission of systemic hypertension and is not intrinsic to the glomerular hemodynamic adaptations that follow severe RMR. Renal autoregulatory mechanisms that normally serve to protect glomerular capillaries from transmission of systemic hypertension have been demonstrated to be impaired in rats with remnant kidneys (24,25,48,49), and although renal autoregulation is comparably impaired in both RK-I and RK-NX rats (21), it should be noted that recent studies using continuous radiotelemetry in awake unanesthetized rats have demonstrated a marked exaggeration in the amplitude of BP fluctuations in hypertensive RK-I rats (22,23,24). Therefore, the impact of impaired autoregulation on glomerular pressures is likely to be much greater in the hypertensive RK-I rats than the normotensive RK-NX rats, and the relatively modest but significant differences in PGC observed between RK-I and RK-NX rats under anesthesia are likely to significantly underestimate the ambient glomerular capillary exposure to hypertension in unanesthetized RK-I rats. The excellent correlation between radiotelemetrically measured BP and GS in individual RK-I rats provides additional support for the dominant role of hypertensive mechanisms in the pathogenesis of GS after RMR (21,22,23,24,48). Therefore, the striking difference in the severity of glomerulosclerosis after comparable RMR by infarction or surgical excision appears largely to be a consequence of the presence or absence of systemic hypertension in these two models and is independent of the compensatory functional and structural adaptations after RMR.
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Acknowledgments |
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This work was supported in part by National Institutes of Health Grant DK40426. The authors gratefully acknowledge the technical assistance of Jue Ouyang, Lisa Kelly, and Wanda Plott and the secretarial assistance of Martha Prado.
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Footnotes |
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References |
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), 5/6
renal ablation by infarction (RK-I) (
), and 5/6 renal mass reduction by
surgical excision (RK-NX) ([UNK]) rats at 3 wk after sham ablation or 5/6
renal ablation. *P < 0.01 versus sham. (B)
Renal blood flow (RBF) and GFR for the left kidney of the same three groups of
rats sacrificed at 21 d. There were no significant differences between the
groups. The mean arterial pressure under anesthesia for the three groups was
as follows: sham, 120.8 ± 2.8 mmHg; RK-NX, 115.3 ± 5.1 mmHg;
RK-I, 132.9 ± 4.9 mmHg. P < 0.05 RK-NX versus
RK-I.
