Toxicologic Pathology

Toxicologic Pathology
Kidney Morphology: Update 1985
Ruth Ellen Bulger
Toxicol Pathol 1986 14: 13
DOI: 10.1177/019262338601400103
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Renal Pathology and Toxicity
Volume 14, Number 1. 1986
Copyright 0 1986 by thc Society of Toxicologic Pathologists
Kidney Morphology: Update 1985*
Graduate School of Bioniedical Sciences,
The University of Texas Health Science Center at Hoiuton.
iloirston. Texas 77030
Many new observations havc been made correlating changes in renal morphology with changes in renal
function. These changes have led to a better definition of the various segments which make up the renal
tubule. These morphological patterns vary in different species as is documented by morphologicstudies and
by differences in the patterns of enzymes in various nephron segments. The subdivision of cells located in
the mesangial region of the glomerulus into several types may provide new areas to study with respect to
disease processes.
“. . To all stiiderits for whoin the ever-widenirig
horizons and increasing details of medicine make
the art of healing more diJiciilt and yet more certain
. . .**Homer W.Smith (97).
The relentless drive of scientists to unravel the
complexities of the relationship between renal structure and function has led to a number of important
observations and conceptual advances. First, there
has arisen a better definition of ncphron types classified according to their position and tubular configuration in the kidney. Second, an increasing number ofsubdivisions have bccn and are being identified
in the urinary tubule. Concomitantly, an appreciation of marked species differences of the various
tubular subdivisions in both form and function has
evolved. For example, Morel (74) has graphically
and dramatically demonstrated the difference in
patterns produced by measuring hormonc-dcpcndent adenylate cyclase activity in various nephron
segments. Lastly, the identification ofpreviously undescribed resident cell types within the glomerulus
promises to open new avenues for fruitful investigation in the future.
A synthesis of these “increasing details of medicine” have made it clear that a dynamic interplay
exists between kidney form and function. Disuse can
lead to atrophy (27). Functional stresses can lead to
* Presented at the Fourth International Symposium of thc Society of Toxicologic Pathologists, Junc 5-7, 1985 in Washington, D.C.
Address corrcspondcncc to Dr. Ruth Ellen Bulger, Renal Rcsearch, h1.S.hi.B. 7242, The University ofTexas Medical School,
P.O. BOX20708, Houston, Texas 77225.
hypertrophy, and, some studies indicate that after
a certain degree of nephron loss occurs, nephron
injury progresses (1 6).
The urinary tubule of the long-looped nephrons
is presently divided into the following regions: the
renal corpuscle, the S,, S2,and S3 regions of the
proximal tubule, the upper descending region of the
thin limb, the lower descending region of the thin
limb, the ascending thin limb, the medullary ascending thick (MAT) region of the distal tubule (in
the inner stripe and outer stripe of the outer medulla), the cortical ascending thick (CAT) region of
the distal tubule, the macula densa, the post macula
densa segment ofthc ascending thick limb, the distal
convoluted tubule, the connecting piece, the cortical
collecting duct, the outer medullary collecting duct,
and the inner medullary collecting duct. Short-looped
nephrons have all the same segments except that
they have only one type of thin limb segment and
it comprises a portion of the descending limb of
Henle’s loop. ’
Our understanding of the function of each ofthese
tubular divisions has increased immensely, partly
because of the study of isolated perfused segments.
The whole ofrenal function, however, is greater than
the sum of the individual parts. Recently, we have
learned much about the interrelations between the
elaborate shape of the renal pelvis and the adjacent
renal parenchyma, and suggestions have been made
concerning the role these structures play in the
mechanism of urinary concentration. Furthermore,
the functional interactions of various nephron scgments located in specific zones within the kidney
are now also receiving increased interest.
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FIG.1.-Electron micrograph from a renal.corpuscle showing a capillary loop (C), podocytes (P), and rnesangial cells
(M). ~6,300.
Nephrons are typed as superficial, midcortical, or
juxtamedullary on the basis of the position of their
renal corpuscle within the cortex, and on the anatomy of their postglomerular blood supply (5, 6, 1 1,
12,46, 59). Nephrons are classified as short-looped
if their loops of Henle turn in the outer medulla, or
long-looped if the loops of Henle turn in the inner
medulla. This paper will stress new findings and
assumes that the reader possesses a basic knowledge
of renal anatomy.
The renal'corpuscle, the initial part of the nephron, is a eltration device which forms an ultrafiltrate
of plasma (Fig. 1). The double-walled capsule (Bowman's capsule) consists of an outer parietal layer of
flattened cells and an inner visceral layer of epithelial cells, known as podocytes, which possess an
elaborate octopus-like shape; the capillary lining cells
have a fenestrated endothelium consisting of large
pores usually lacking diaphragms. A population of
mesangial cells is located in the hilar region of each
capillary loop in a-position similar to pericytes of
other small vessels. A subpopulation of these mesangal cells which display Ia antigens on their ce1.I
surface can also be identified. Various cxtraccllular
materials contribute to the molecular composition
of the glomcrular basement membrane and mesangial matrix. The glomerular basement membrane
(GBM) is a complex structure consisting of several
type-IV collagens and a type-V (AB2) collagen (82),
collagenous plus noncollagenous glycoproteins, and
proteoglycans. Two glycoproteins, laminin and fibronectin, have been localized in the glomerulus (1,
66). Laminin was localized in the mesangial matrix,
the lamina rara-interna, and adjacent areas of the
lamina densa of the GBM, as well as throughout the
tubular basement membranes. Fibronectin, secmingly involved in mesenchymal cell adhesion, was
found within the mcsangial matrix.
A negatively-charged glycoprotein which coats the
glomerular epithelial cell (the so-called glomerular
polyanion) appears to be involved in podocyte cell
shape maintenance. Seiler et al(95,96) demonstrated podocyte cell shape changes after in vivo administration ofpolycations which appeared to neutralize
the fixed negative charges of this polyanion. Removal of sialic acid by neuraminidase digestion also
resulted in cell shape changes (2). Detachment of
the visceral epithelial cells from the GBM could be
induced by perfusion of neuraminidase or treatment
with puromycin aminonucleoside (52). Concomitant with this detachment, a change in GBM permeability was seen (52). A reduction in glomerular
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FIG.2.-Electron micrograph of a proximal convoluted tubule (S, region). Note the extensive microvillus border and
interdigitated epithelium. x 9,150.
polyanion staining was also seen in certain glomcrular diseases (14), and in aminonucleoside nephrosis
(73). This glomerular polyanion has been identified,
characterized, and named podocalyxin by Kerjaschki et a1 (53). Using aminonucleoside nephrosis as a
model, Kerjaschki et a1 ( 5 5 ) have demonstrated that
the loss of epithelial foot processes and filtration slit
organization is accompanied by a biochemical defect in sialylation of podocalyxin.
Proteoglycans also form an integral part of the
filtration bamer and appear to be important in the
permeability of the GBM. These molecules consist
of a core protein and covalently bound glycosaminoglycans. Using a cationic probe, Kanwar and Farquhar (50) identified a regular lattice-like network
of sulfated glycosaminoglycans with a spacing of 60
nm within the lamina rara of the GBM and in the
mesangial matrix. To assess the role of these molecules in GBM permeability, irz situ vascular perfusion of glycosaminoglycan-degrading enzymes
(heparinase) was done (5 1). Subsequent perfusion
with native fenitin demonstrated that a dramatic
increase in GBM permeability had occurred.
A recent hypothesis suggests that contraction of
intraglomerular mesangial cells can effect glomerular function. Contraction of mesangial cells was
noted in 1969 by Burnick (1 7). Becker (10) suggested
that effects on tuft size and surface area could be
caused by mesangial contraction. More recently,
Ausiello et a1 (3) showed contraction of cultured
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FIG.3.-Electron micrograph of a proximal pars recta tubule (S, region). Note the extensive microvillus border and
the cuboidal epithelium.
mesangial cells in response to either angiotensin I1
or vasopressin. This evidence correlated with the
identification of specific angiotensin I1 receptors on
mesangial cells (98). Angiotensin I1 has been postulated as a regulator of intraglomerular blood flow
by Schor et a1 (89) since both angiotensin I1 and
arginine vasopressin can lead to a decrease in glomerular ultrafiltration coefficient. Streptozotocininduced diabetic rats have a decrease in angiotensin
I1 receptor sites (4)which might underlie the hyperfiltration seen in this situation. Kreisberg (57)
has demonstrated that cultured mesangial cells do
not contract without insulin. Since catecholamines
can influence glomerular hemodynamics, Kreisberg
et a1 (58) exposed mesangial cells in culture to
hi norepinephrine, epinephrine or isoprotcronol.
These agents elevated intraccllular cyclic AMP levels
nearly threefold. More than half of the cells underwent a shape change with this exposure. PGE, restored or inhibited the cell shape and attenuated the
cyclic AMP generation. .
A subpopulation of glomcrular mesangial cells,
which resemble Kupffer cells, has been recently
identified by Schreiner and Unanue (90) in rats.
These cells are phagocytic, display Ia surface antigens, can take up antigen, and stimulate lympho-
cytes. Total body irradiation induced progressive
loss of these cells after three days; however, the cells
were restored by transplantation of syngeneic bone
marrow (90). The role of these cells in various disease processes has been investigated (9 1).
The nomenclature which divides the proximal tubule into a convoluted and straight portion has been
largely replaced by one using three specific segments
designated S,,S,, and S, (or PI, P,, and P,) on the
basis of cell height; cell shape and organelle content
(71). The part designated as the proximal convoluted tubule includes the entire S, region and the
first part of the S, region (Fig. 2). The pars recta,
seen in the medullary ray and outer stripe of the
outer zone of the medulla, includes the last part of
S, and the entire S3segment (Fig. 3). This new nomenclature is more specific and allows for clearer
definitions of relationships between structure and
function. For example, it has long been known that
the pars recta was involved in para-aminohippuric
acid (PAH) secretion but only recently has it been
shown that the cortical S, segment of the pars recta
is a much more efficient pump then either the S, or
S3 segments (107). There is a marked amount of
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Vol. 14,No. 1, 1986
species variation in morphology seen in the proximal tubule, so cross species generalizations can lead
to erroneous interpretations.
The S , and S , segments are both composed of
cells with. extensive lateral interdigitating projections which contain numerous mitochondria. This
arrangement results in the formation ofan extensive
system of lateral intercellular membranes adjacent
to the cell mitochondria. The cells are held together
by shallow tight junctional regions at their apical
borders. These junctions and the lateral intercellular
spaces form a low resistance shunt pathway. Thus,
it was believed that the proximal tubule reabsorbed
isosmotic fluid by utilizing a standing gradient hypothesis. Newer evidence from several la6oratories
has shown that small but important osmotic gradients develop across the entire proximal tubule,
and that these gradients can drive transepithelial
volume flow (7, 32, 65, 84). The extensive reabsorption of glucose, amino acids and bicarbonate
by the brush border membrane generates a luminal
hypotonicity which serves as an osmotic driving
force for water reabsorption. Kerjaschki et a1 (54),
using a monoclonal antibody for maltase, localized
this glycoprotein to the lateral surface of proximal
tubule microvilli. The Na+K+ATPasein the basolateral membrane maintains the sodium electrochemical gradient.
The proximal tubulc is frequently the site ofinjury
after various insults. A common site within the
proximal tubule is in the S, segment, within the
outer stripe of the medullary outer zone. Agents
which preferentially induce necrosis in this region
include mercuric chloride (1, 19, 3 3 , uranyl nitrate
(28, 37, loo), cis-platinum (22), renal arterial occlusion in rats (30, 31, 103, 104) and hemorrhagic
shock (2 1). With high doses of many of these agents,
necrosis Will extend up the ray and into the proximal
convolutions. One possible explanation for these
findings might be related to blood supply. The majority of the capillary vessels in the outer stripe region have been said to be ascending vasa recta which
contain venous blood from the inner medulla (6,
59). However, recently Yamamoto et a1 (108), using
resin casts instead of silicone rubber casts, has demonstrated a rich capillary network in the outer stripe.
T I i I N Llh1B.S
Four kinds of thin limb regions have been identified (8, 9, 20, 24, 59, 61, 93, 94): descending thin
limbs of short-looped ncphrons, upper descending
thin limbs of long-looped nephrons, lower descending thin limbs of long-looped nephrons, and ascending thin limbs of long-looped'nephrons. Their
characteristics differ from each other in the following ways: 1) the number of intramembranous par-
ticles in the cell membranes (94), since the density
of these particles is thought to be related to transepithelial water flux; 2) the depth (number ofstrands)
of the tight junction is perhaps related to ion permeability; 3) the degree ofcell interdigitation which
is related to the overall length of the paracellular
pathway and presumably to ion permeability; 4) the
cellular organelles which will influence cell function
such as the number of mitochondria being related
to the degree of energy production, the amount of
basolateral cell membrane to the number of
Na+K+ATPasesites, and the number of microvilli
related to some aspect of surface transport.
The descending thin limb of short-looped nephrons from all species studied has a relatively small
diameter and is lined by flat, simple non-interdigitating cells with few microvilli, few mitochondria,
a tight junction with several strands (94), and few
intramembranous particles. Such an epithelium
would be expected to have a low permeability to
sodium chloride and water, and be fairly inactive
in transport processes. The small diameter would
be consistent with a low flow per nephron. In some
species which are good concentrators such as rat
(60), mouse (62), Psantnionzys (48), and Perognathus (73,the descending thin limbs of short-looped
nephrons lie in the vascular bundles in close approximation to ascending vasa recta where exchange
of substances such as urea could easily occur. In
other species, they surround the vascular bundles or
lie in the interbundle region,
Morphologic differences have been reported in thc
upper descending thin limb of long-looped nephrons of various species. In the rat, mouse, and desert
rodents (8,9, 20, 62, 75, 93, 94), the epithelial cells
which line this segment are joined by shallow tight
junctions and have extensive intercellular interdigitations, numerous microvilli, and many mitochondria (Fig. 4). They run in the interbundle region.
This region stains positively for Na+K+ATPase(69),
and carbonic anhydrase in mouse (23). The cells
have a high density-of intramembranous particles
(94). This region of the thin limb epithelium would
be expected to have an extensive paracellular shunt
pathway, the ability to transport solutes, and a high
water permeability. In other species, such as the
rabbit (46), a less interdigitated epithelium containing fewer organelles and a deeper tight junctional
region is seen. Carbonic anhydrase activity was seen
fa-intly in the lumen (23).
As the long-looped thin limb descends into thc
inner medulla it assumes a simplified form lined by
flat, less interdigitating cells with multiple strands
in the tight junction, few microvilli, and an intermediate number of intramembranous particles. This
morphology would bc consistent with a relatively
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FIG. 4.-Electron micrograph of an upper descending thin limb segment characterized by an elaborately-shaped
epithelium with interdigitating processes. x 13,100.
FIG.5.-EElectron micrograph ofa medullary thick segment from the distal tubule. x 12,600.
high permeability to water, but a decreased passage
of sodium chloride. In animals on reduced dietary
protein, Schmidt-Nielsen et a1 (88) showed a significant thinning in the wall of the descending limbs
of long-looped nephrons. The ascending thin limb,
present only in long-looped nephrons, usually begins
just prior to the bend in the loop and is lined by a
highly interdigitated epithelium containing few mi-
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Vol. 14, No. 1, 1986
tochondria and joined by relatively shallow but tight
junctions with single thick strands. It is similar in
all species studied. The prominent paracellular
pathway of this epithelium would indicate a high
ion permeability but not with extensive active transport. This would be consistent with the passive efflux of sodium chloride postulated for this region.
The distal tubule is now generally divided into an
MAT which runs through the inner and outcr stripe
regions of the outer medulla, a CAT, and a distal
convoluted tubule (DCT). The macula densa is a
specialized region near the end of the CAT. It is
continuous with a short post-macula densa segment
which converts to the distal convoluted tubule (46).
The MAT and the CAT differ both in morphology
and function. The MAT, especially in the inner
stripe, is characterized by tall cells which are highly
interdigitated and have shallow tight junctions (Fig.
5). Numerous mitochondria fill the interdigitating
cell projections. The MAT traverses the inner stripe
region, gradually decreases in cell height in the outer
stripe region, and becomes the CAT in the medullary ray. The CAT therefore has a lower cell height
and more simplified cell shape. The MAT and CAT
demonstrate several physiological differences, especially with respect to hormone responsiveness (1 5 ,
18,38,39, 102). The MAT region has a high density
of Na+K+ATPase(72). Hebert et al(42) have shown
that ADH increased the transepithelial voltage and
net chloride absorption in the MAT (but not CAT)
of the mouse. Kone et a1 (56) has quantitated the
morphology of the ascending thick limb in the inner
stripe, outer stripe, and inner cortex in rat kidney.
The ascending thick region functions in the flowdependent absorption of sodium chloride in which
there is co-transport of Na+2CI K+ (33, 34). The
MAT and CAT vary in basal transport rates and
susceptibility to hormone stimulation. Sasaki and
Imai (83), and Hebert et a1 (42) have shown that
sodium chloridc reabsorption is stimulated by antidiuretic hormone.
The DCT (Fig. 6) can reabsorb sodium chloride
against a steep chemical gradient. It contains the
greatest amount of Na+K+ATPase(72, 85), which
is present on its basolateral plasma membrane (26).
This region does not appear to be sensitive to ADH
(36, 44, 106). Recent work indicates that the DCT
does not respond to aldosterone (25, 70).
Proliferation of the DCT has been shown to correlate with an increase in active sodium reabsorption (45). Recently, Kaissling et a1 (49) demonstrated a marked structural adaptation of the distal
convoluted tubule to an increased sodium load produced by furosemide administration over a 6-day
period. The kidney responded by enlargement of the
cortex, proliferation of the distal convoluted tubules, and an increase in DCT basolateral cell membrane volume.
A well-dcfined connecting tubule (CnT) has been
identified between the DCT and the cortical collecting duct (CCT) in the rabbit kidney (46). Similar
segments appear to be present, although less well
demarcated, in other species. Each superficial nephron empties directly into a cortical collecting duct
via a connecting tubulc. The arcades formed by
deeper nephrons are also considered to be connecting tubules. Two cell types comprise this segment.
The connecting tubule cell is characterized by extensive true infoldings of the basal cell membrane
which extend deep into the cells separated by the
mitochondria. The intercalated cell of the connecting tubule is similar to its namesake seen in the
collecting duct system.
There is controversy as to whether the connecting
tubule is part of the DCT of thc nephron (derived
from metanephric blastema) or part of the collecting
duct system (derived from the ureteric bud). Oliver
(77), Potter (80), and Neiss (76) support the metanephric blastema as the source, while Peter (78) believes that the arcades arise from the ureteric bud.
The morphology of the CnT, however, more closely
resembles the collecting duct. Morel (74) demonstrated differences between argininc vasopressinsensitive, parathyroid-sensitive, and synthetic calcitonin-sensitive adenyl cyclase activity in the rabbit
between the DCT and CnT.
The CnT cell displays an amplification of basolateral cell membrane area in situations with a low
sodium and high potassium intake and a high plasma aldosterone level. Stanton et al (99) using rats
and Kaissling and Le Hir (47) using rabbits have
shown an increase in membrane arca of the CnT.
When an inhibitor of aldosterone production (canrenoatc K) was administered in the rabbit experiment cited above, the membrane amplification was
still present in the beginning of the CnT but not near
the end.
The collecting ducts are divided into cortical collecting ducts, outer medullary collecting ducts, and
inner medullary collecting ducts. The cortical collecting ducts are lined by principal (light) cells and
intercalated (dark) cells (Fig. 7). The collecting ducts.
are the final regulators of fluid and electrolyte balance and play key roles in the handling of sodium,
chloride, potassium and acid-base balance. The collectingduct system is a major site ofaction for ADH,
and hence plays a critical role in urine concentration.
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F ~ G6.-Electron
micrograph from a distal convoluted tubule. This segment contains abundant mitochondria, and
intcrdigitating epithelial cells. x 7,750.
FIG.7.-Electron micrograph of a collecting duct lined by intercalated cells (I) and principal cells (P). x 8,000.
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Vol. 14, No. 1, 1986
The cortical collecting duct is the targct tissue for
aldosterone (70).
The principal (light) cell is most numcrous. It has
pale cytoplasm with a few oval mitochondria, frequent infoldings of the basal cell membrane, short
apical microvilli, and relatively long tight junctions.
Dramatic increascs in basolatcral membrane surface
density have bcen measured in principal cells after
potassium adaptation or by high endogenous or cxogenous mincralocorticoid levels which increase potassium sccretion along the collecting ducts (47, 81,
99, 105).The second cell type called the intercalated
cell is prescnt in both the CnT and CCT. Thcy are
mainly seen in cortical and outer medullary regions
of the collecting duct system; however, occasional
dark cells arc present even in the inner medulla of
some species. Kaissling and Kritz (46) estimate 33%
intercalated cells in the rabbit cortical collecting duct,
and 50% in the outer medullary collecting duct. The
intercalated cells generally are characterized by lum i n d extensions (microvilli or microplicac), a cytoplasm with more ribosomes, and more mitochondria than seen in the light cells, which leads to their
darker staining characteristics. Two morphological
variants of the intercalated cell have been identified
(46,60) in the rabbit. The grey manifestation stained
lighter and contained many spherical or flat cytoplasmic vesicles while the black manifestation
stained more densely.
Medullary intercalated cells in rats on a high potassium diet have a small luminal membrane area
and the cell apcx contains numerous vesicles (8 1).
However, when rats are fed a low potassium diet
there is an increase in luminal membrane area and
fewer apical vesicles (101). These changes would be
consistent with a function for some of the intcrcalated cells of potassium reabsorption. The intercalated cells ofthe cortcx, however, respond to dietary
potassium in a different manner (47). Similar increases in the amount of apical plasma membrane
with a decrease in tubulovesicular profiles within
the apical cytoplasm were seen in intercalated cells
of the outer medulla in acute respiratory acidosis
(67) and in chronic metabolic acidosis (68) in rats.
These authors postulated that hydrogen ion pumps
were inscrtcd into the luminal membrane by the
fusion of thc apical vesicles with the apical cell
The inner collecting duct is lined almost entirely
by light cells which contain fcw mitochondria and
only a fcw small basal intcrdigitations. In spite of
this rather simple structure, inner medullary collccting ducts can reabsorb ions from the urine and
secrete potassium and hydrogen ions against high
concentration gradients (1 3, 43).
A dose-related increase in the number of clusters
of intramembrane particles has bcen dcmonstratcd,
using freezc-etch tcchniqucs, in the luminal membrane of the papillary collecting duct after antidiuretic hormone treatment (40, 41).
The renal pelvis, major and minor calyces, and
their blind ending fornices have been viewed mainly
as passive receptacles, but it is becoming clear that
they play a vital rolc in renal concentrating me’chanisms. Pfeiffer (79) divided animals into those with
renal pelves of simple and complex shape. Species
with complex shaped renal pelves had the ability to
increasc urine concentration in response to dietary
protein. This complex shape was associated with
the increase in surface area of rcnal medulla exposed
to thc pelvic urine. In fact, Lacy (63) has demonstrated that the area of pelvic surface in a variety of
rodents correlates with the urine concentrating ability. Although the functional significance to the concentration process is not yet clearly understood, a
variety of investigators are involved in research
aimed at understanding these interrelationships (29,
64,86,87,92). Studies combining morphology with
altered physiological state should continue to refinc
our knowledge of how thc kidney functions.
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2. Andrews PM (1 979). Glomcrular epithelial alterations resulting from sialic acid surface coat removal. Kidticy irit. 15: 376-385.
3. Ausiello DA, Krcisberg JI, Roy C, and Karnovsky
MJ (1980). Contraction of cultured rat glomemlar
cells of apparent mesangial origin after stimulation
with Angiotensin I1 and argininc vasopressin. J. Clin.
Itivcst. 65: 754-760.
4. Ballermann BJ. Skorecki KL, and Brcnner BM
(1 984). Reduced glomcrular Angiotensin I1 receptor
density in early untreated diabetes mellitus in the
rat. Atner. J . Pliysiol. 16: FllO-FI16.
5. Bankir L, Kaissling B, dc Roufignac C, and Kriz W
(1979). Vascular organization of thc kidney of
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9. Barrett JM, Kriz W, Kaissling B, and dc Roufignac
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(1979). Potassium secretion along the inner mcdullary collecting duct. Ant. J. Physiol. 236: F278F282.
14. Blau EB and Haas JE (1973). Glomerular sialic acid
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15. Bourdeau JEL and Burg MB (1980). Effect of PTH
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