Renal Prostaglandin Synthesis

Sites of Production and Specific Actions of Prostaglandins

DETLEF SCHLONDORFF, MD Prostaglandins are substances that exert their acts at the site of
Bronx, New York their production. Therefore, the synthesis and effects of prosta-
glandins have to be considered separately for each nephron seg-
ment. In the cortex, major sites of prostaglandin synthesis include
arteries and arterioles as well as the glomerulus. At these sites,
prostaglandins are important in maintaining blood flow and giomer-
ular filtration, especially during conditions of enhanced vasocon-
strictor activity. Vasoconstrictors such as angiotensin II, norepi-
nephrine, and vasopressin increase production of the vasodilator
prostaglandins, thereby preventing an overshoot of their action.
The role of arteriolar-glomerular prostaglandins in maintaining
blood flow and filtration may be even more prominent during renal
diseases. The proximal tubule and the loop of Henle show little abil-
ity to produce prostaglandins, but may generate considerable
amounts of epoxygenase products of arachidonic acid. These
epoxygenase products may play a prostaglandin-independent role
in water and electrolyte transport in the thick ascending loop of
Henle and the collecting tubule. Both the cortical and the medullary
collecting tubules produce large amounts of prostaglandins, pre-
dominantly prostaglandin E2 (PGE2). In these segments, synthesis
of PGE2 is stimulated by bradykinin and to a somewhat more varia-
ble degree by vasopressin. The PGEp generated antagonizes the
hydroosomotic effect of vasopressin both in viva and in vitro, and
may influence electrolyte excretion. Thus, the overall role of PGE2-
and possibly of epoxygenase products of arachidonlc acid-in tu-
bular functions seems to be one of local modulation of water and
electrolyte transport. Finally, interstitial cells are a major site of
medullary prostaglandin production. Prostaglandins generated by
the interstitial cells may play a role in maintaining blood flow to this
poorly oxygenated and hypertonic region of the kidney.

In the kidney, prostaglandins have been implicated in the regulation of a

wide variety of functions (Table I). These range from vasomotor effects at
the level of the afferent-efferent arterioles and the glomerulus to transport
functions of the terminal nephron segment, the collecting tubule [l]. Pros-
From the Renal Division, Department of Medicine, taglandins are, however, considered to be autocoids, i.e., substances
Albert Einstein College of Medicine, Bronx, New that have their predominant action at the site of their production [l]. Since
York. This work was supported in part by a grant the different nephron segments have highly specialized structures and
(AM-22036) from the National Institutes of Health. functions, the synthesis and functions of the various prostaglandins are
Requests for reprints should be addressed to Dr.
Detlef Schlondorff, Department of Medicine, Albert
considered separately for each segment rather than globally for the whole
Einstein College of Medicine, Bronx, New York kidney. Furthermore, arachidonic acid released from membrane phos-
10461. pholipids upon activation of phospholipases can be converted to non-

August 25, 1986 The American Journal of Yedlclne Volume 81 (suppl2B) 1

SYMPOSIUM ON RENAL EFFECTS OF NSAIDS-SCHLONDORFF

TABLE I Proposed Roles for Prostaglandins In thermore, renal medullary interstitial cells exhibit cyclo-
Renal Function oxygenase activity [4,1 l-141. The large amounts of pros-
taglandin E2 (PGEP)generated by the renal medulla prob-
Modulationof:
ably result from the large quantities of prostaglandin syn-
Renal blood flow thesized by collecting tubular cells and interstitial cells
Glometular filtration 1151.
Renin release Interlobular Arteries and Afferent and Efferent Arteri-
Renal water excretion
oles. Arteries and arterioles exhibit high cyclo-oxyge-
Renal sodium excretion
Erythropoietin release nase activity both in their smooth muscle and endothelial
layers [4]. They produce predominantly prostacyclin
(PG12) and PGEp [l&17]. Both PGlp and PGE2 can be
considered to be vasodilators, especially under conditions
Membrane Phospholipids of prior vasoconstriction. This has been repeatedly dem-
onstrated in vivo using inhibitors of prostaglandin synthe-
I
Phospholipase sis [18]. Under euvolemic conditions, inhibition of prosta-
glandin production has little effect on renal blood flow.
However, during activation of endogenous pressor sys-
tems or administration of exogenous pressor agents, the
same maneuver results in a considerable reduction in
renal blood flow and the glomerular filtration rate in both
Here’s Prostaflandins !E!EI; 1
human subjects and experimental animals [18]. Further-
more, vasoconstrictors such as norepinephrine, angioten-
sin, and vasopressin stimulate production of PGE2 and
PGIP, thereby closing a feedback loop [18]. Thus, en-
igure 7. Scheme of arachidonic acid metabolism in the
kidney. HETE = hydroxyeicosatetraenoic acid; EET = hanced prostaglandin production under conditions of in-
epoxyeicosatrienoic acid; DHET = dihydrveicosatrienoic creased vasoconstrictor activity contributes significantly to
acid. the maintenance of renal blood flow and the glomerular
filtration rate. This interaction of vasoconstrictors and
prostaglandin has also been demonstrated by Edwards
cycle-oxygenase products (Figure l), which may have [19] in vitro in elegant studies using isolated renal arteri-
their own effects. The lipoxygenase pathway is discussed oles from the rabbit kidney. In these experiments, arachi-
by Ardaillou et al elsewhere in this supplement, whereas donic acid produced a rapid relaxation of norepinephrine-
the production and potential function of epoxygenase induced tone in interlobular arteries and afferent and ef-
products are included in this review. ferent arterioles, an effect that was prevented by co-
incubation with an inhibitor of prostaglandin synthesis
OVERVIEW OF SITES OF PROSTAGLANDIN (Figure 3). In interlobular arteries and afferent arterioles,
SYNTHESIS both PGI:! and PGE2 antagonized the vasoconstrictor ef-
Localization of prostaglandin synthase has been accom- fect of norepinephrine (Figure 3). In contrast to the
plished by histochemical [2,3] and immunofluorescent preglomerular vessels, efferent arterioles responded only
methods [4], as well as by examination of freshly isolated to PG12. PGlp antagonized the vasoconstrictor effects of
nephron segments and cells cultured from specific neph- both norepinephrine and angiotensin II in this vessel seg-
ron sites [l]. The results obtained by the different methods ment. These observations are of great interest since the
are generally in close agreement (Figure 2). In the cortex, afferent and efferent arterioles represent the major sites of
the major sites of prostaglandin synthesis include arteries, resistance to blood flow in the kidney and since their tonus
arterioles, and the glomerulus [4]. Along the nephron, the is of major importance in determining the glomerular filtra-
proximal tubule and the loop of Henle exhibit little capacity tion rate. The specific interactions of PGIB with angio-
for prostaglandin production [4]. The proximal tubule and tensin-induced efferent arteriolar constriction may also
the thick ascending loop of Henle may, however, contain help to explain why PGlp may have a specific role in tu-
considerable P4= cytochrome mono-oxygenase activity bular-glomerular feedback regulation [20]. Furthermore,
[5-lo]. Cells from the thick ascending loop of Henle spe- PGEp and PGlp generated at the glomerular-juxtaglomer-
cifically convert arachidonic acid to products having char- ular site can stimulate the release of renin [21-231 and
acteristics of epoxyeicosatrienoic acids [9]. In the distal thereby influence the local formation of angiotensin II.
tubule, the connecting segment also generates little pros- Most probably the cellular mechanism of action of PGEp
taglandin, whereas the cortical and medullary collecting and PGlp for both the vascular smooth muscle relaxation
tubules are major sources of prostaglandins [4,9,10]. Fur- and the release of renin is via generation of cyclic adeno-

2 August 26, WE6 The Anwican Journal of Mdlclno Votuma 81 (suppl2B)

 SYMPOSIUM ON RENAL EFFECTS OF NSAIDS-SCHLONDORFF

sine monophosphate (CAMP) [21,24]. Activation of ade-

nylate cyclase by PGE2 and PG12has been demonstrated
in vascular smooth muscle, isolated glomeruli, and cul-
tured mesangial cells [25-271. Local production of renin,
angiotensin II, prostaglandins, and CAMP, and their re-
spective interactions, are ideally suited for the regulation
of individual glomerular function.
The Glomerulus. Apart from the arterioles, glomeruli
(Figure 2) are the major source of prostaglandin synthesis
in the renal cortex [4,28-301. Rat glomeruli produce
mainly PGEp and PGF2, and less PG12and thromboxane
B2 (TXB2) [28-301. Human glomeruli synthesize mainly
PGlp (determined as 6-keto-PGF,,), and less PGE2,
TXB*, and PGF2, [31,32].
Localization of prDStaglandin synthesis within the glo-
merulus has been studied using primary cultures of glo-
merular cells. Cultured rat mesangial cells almost exclu-
sively synthesize PGE2 [33,34], whereas mesangial cells
from humans produce predominantly PGl* and PGEp [35],
similar to the isolated human glomerulus [33,34]. Rat glo-
merular epithelial cell cultures seem to have the same
profile as mesangial cells but the amount of prosta-
glandins produced may be smaller [35,36]. Kreisberg et al
[37j have, however, reported considerable and predomi-
nant synthesis of 6-keto-PGF,, by epithelial cells in cul-
ture. Given the difficulty of identifying the cultured cells as
being of glomerular visceral epithelial origin, the possibility igurs 2. SCheIWiC view of cycle-oxygenase and pw
of endothelial contribution has to be considered. mono-oxygenase activities along the nephron.

FACTORS INFLUENCING GLOMERULAR

PROSTAGLANDIN SYNTHESIS
A number of vasoactive agents can influence glomerular
prostaglandin synthesis (Table II). In vitro, angiotensin II
has been shown to increase PGlp and PGE2 production
by isolated glomeruli [38-401 and by single glomeruli dur-
ing microperfusion [41]. Using a micropuncture technique
in combination with a highly sensitive enzyme immunoas-
say for PGEP,we have been able to demonstrate in vivo
that glomerular PGE2 production is influenced by ahgio-
tensin II [42]. We reasoned that the PGE2 content of mi-
cropuncture samples from the earliest accessible proxi-
mal tubule should reflect predominantly glomerular PGE2
production, when corrected for potentially ultrafiltered
prostaglandins. The enzyme immunoassay employed for
PGE2 determinations does not require a radfoactive
tracer, so single nephron glomerular filtration rates could
be determined at the same time and potentially filtered
PGEp could be calculated using plasma ultrafiltrate PGES
determinations. Measured tubular fluid PGEp always ex-
ceeded potentially filtered PGEp by at least twofold, con-
sistent with glomerular generation of PGE*. In the first se-
ries of studies, rats were fed a high-sodium diet to sup-
press endogenous angiotensin II production. Control mi-
cropuncture samples were collected from early proximal
tubules and urine was collected from both kidneys. Angio-
tensin II was then infused into the left renal artery only,

Inter-lobular Afferent Efferent

Artery Arteriole Arteriole

Norepinephrine Constriction Constriction Constriction

Norepinephrine plus Abolishes Abolishes Attenuates
Arachidonic acid constriction constriction constriction
Norepinephrine Abolishes Abolishes Constriction
constriction Constriction unaffected
Figure 3. Summary of interactions of ii$%ikn II Constriction
vasoconstrictors and prostaglandins on Angiotensln II Abolishes
isolated renal arterioles. Results are from plus PGIP constriction
ml.

Augua 25,lg88 The American Journal of Medlclna Volume 81 (suppl2B) 3

SYMPOSIUM ON RENAL EFFECTS OF NSAIDS-SCHLONDORFF

TABLE ii Agents and Conditions Resulting in
Enhanced Synthesis of Prostaglandins
isolated Giomeruii or Cuitured Giomeruiar
Ceils
Agents or conditions Calcium ionophore
stimulating prostaglandin Angiotensin
synthesis in vitro Vasopressin
Platelet-activating
Bradykinin
Converting
Mercury chloride
Hydrogen
Hypoxia
Endocytosis-phagocytosis
In vivo conditions resulting Renal ablation
in enhanced synthesis of Hypertension
prostaglandin in isolated Unilateral ureteral ligation
glomeruli Streptozotocin-induced
mellitus
Nephrotoxic
Glycerol-induced
failure
which left systemic blood pressure unaltered. The whole
kidney glomeruiar filtration rate decreased only on the
angiotensin ii-infused side as did the single nephron glo-
meruiar filtration rate. Proximal tubular PGE2 increased
significantly from 0.24 pg per 10 minutes to 0.50 pg. We
interpret this as indicating enhanced giomerular PGEP
synthesis in vivo during angiotensin infusion. in a second
group of rats, the renin-angiotensin system was activated
by feeding animals a low-sodium diet for five days and
giving furosemide the night before the study. Rats were
then studied before and after indomethacin administra-
tion. in these volume-contracted rats, indomethacin
caused a significant decline in whole kidney and single
nephron glomeruiar filtration rates. Proximal tubular fluid
PGE2 was 0.87 pg per 10 minutes and dropped to 0.22 pg
after indomethacin administration. These results are con-
sistent with enhanced giomeruiar PGEp generation during
volume contraction, most likely due to increased endoge-
nous levels of angiotensin ii. Overall, these results show
for the first time in vivo that giomeruiar PGEp synthesis is
influenced by both exogenous and endogenous angioten-
sin ii and that suppression of giomeruiar PGE2 during voi-
ume contraction decreases the giomeruiar filtration rate.
These results confirm the importance of vasodiiatqr pros-
taglandins in the maintenance of the giomerular filtration
rate during conditions of activation of vasopressor sys-
tems (Figure 4). The combination of a micropuncture
technique and tubular fluid. prostagiandin determinations
also provides a new approach to the study of giomeruiar
prostagiandin production in vivo. The interaction of vaso-
active agents with prostagiandins and the resulting conse-
quences for giomerular function are discussed in detail by
by Scharschmidt and co-workers in a separate article.
GLOMERULAR PROSTAGLANDINS AND
INFLAMMATION
A 23187
II The role of giomeruiar prostaglandins may not, however,
be restricted to hemodynamic aspects. PGip and PGE2
factor
play active roles during both acute and chronic infiamma-
enzyme inhibitor tory states [43]. in addition, thromboxane can be consid-
ered to be a mediator of inflammation, including that in the
peroxide giomeruius [44]. During acute inflammation, PGI:! and
PGE2 can be pro-inflammatory by contributing to the vas-
cular-exudative component, which may include increased
giomeruiar protein permeability resulting in proteinuria
(see article by Vriesendorp et al). For example, the in-
crease in vascular permeability in response to lipid media-
diabetes
tors of inflammation such as platelet-activating factor and
serum nephritis ieukotrienes is enhanced by prostagiandins [45,46]. in this
acute renal context, it may be of interest that platelet activating factor
increases mesangial prostagiandin production [37,471,
whereas leukotrienes do not [46]. Furthermore, the mem-
brane-attack complex of complement can increase gio-
merular mesangiai prostagiandin synthesis [49]. These
findings may also have significance for the progression of
inflammation at the glomeruiar level. During chronic in-
flammation, both PGE2 and PGip can have anti-infiamma-
tory actions by inhibiting lymphocyte activation and de-
creasing lysosomai enzyme release and chemotaxis of
polymorphonuciear ceils [43]. The contributions of prosta-
glandins to vasoactive inflammatory processes in the gio-
meruius and their interaction with other mediators of in-
flammation is a subject that should continue to attract con-
siderable interest [44].
GLOMERULAR PROSTAGLANDINS AND
ERYTHROPOIETIN
Glomerular, and especially mesangiai cell, prostagiandin
synthesis has also been implicated in the release of eryth-
ropoietin [50-531. According to this hypothesis, mesangiai
hypoxia results in increased PGEp synthesis [52]. PGEp
then causes erythropoietin to be released from mesangiai
cells j53]. in these experiments, cultured mesangiai ceils
were capable of erythropoietin production so that ail eie-
ments for the proposed scheme were present. As the
structure of erythropoietin has been analyzed and a com-
plimentary DNA prepared [54], it should be possible to
examine this possibility in greater detail.
PROXIMAL TUBULE AND LOOP OF HENLE
The proximal tubule and the loop of Henie produce very
little prostagiandin [9,10,28-30,55,56], which is consist-
ent with the absence of detectable histochemicai or immu-
nofluorescent staining for cycio-oxygenase-peroxidaae

4 Augurt 25,1986 The Am&can Journal oi Modklne Volunm 81 (8uppl28)

 SYMPOSIUM ON RENAL EFFECTS OF NSAIDS-SCHLONDORFF

activity in these segments [2-41. The possibility of prosta-

glandins interfering with fluid, electrolyte, and, especially,
phosphate handling by the proximal tubule has been
raised [l], but will not be discussed further in this article.
Cells from the thick ascending loop of Henle may have
some ability to generate PGEp and PGF*,, but this ability
is limited in comparison to that of, for example, the collect-
ing tubules, [9,10,56]. According to stop-flow studies,
however, the loop of Henle may be a major source of uri-
nary prostaglandins [57,58]. This may be due to the en-
trance of prostaglandins generated by medullary intersti-
tial cells adjacent to Henle’s loop into the tubular lumen.
Medullary interstitial cells are in close contact with both
the vasa recta and the ascending loop of Henle [59]. Con-
ceivably, PGE2 generated by interstitial cells could influ-
I
ence sodium chloride transport by the thick ascending
Figure 4. Sites of interactions for prostaglandins and vast
limb of Henle’s loop. A role for prostaglandins in renal constrictors at the glomerulus. All = angiotensin II.
sodium chloride handling has been long proposed, but still
remains controversial [60,61]. Similarly, inhibition of so-
dium chloride transport by PGE2 in the thick ascending sorption and potassium secretion in isolated perfused rab-
loop of Henle has not been uniformly demonstrated [61- bit cortical collecting tubules, whereas 14,15-eico-
64]. The reasons for these discrepancies remain unclear. satrienoic acid had no effect.
In this segment, vasopressin stimulates adenylate cyclase We examined the effects of three epoxyeicosatrienoic
and enhances sodium chloride reabsorption via genera- acids (EETs) (5,6-EET, 11 ,lBEET, and 14,1&EET) on
tion of CAMP. PGE2, in turn, inhibits the activation of ade- osmotic water flow across the toad urinary bladder as a
nylate cyclase and sodium chloride reabsorption in re- model of a transporting, vasopressin-responsive epithe-
sponse to vasopressin [65,66]. These results would be lium [69,70]. All three compounds inhibited vasopressin-
consistent with PGEp interfering with sodium chloride stimulated osmotic water flow, with 5,6-EET and 11 ,12-
transport in this segment. The possibility that metabolites EET being the most potent (Figure 5). This inhibition was
of arachidonic acid, other than prostaglandins, are gener- reversible, and was demonstrable in bladders pre-stimu-
ated and influence the function of this nephron unit now
has to be considered [9,67]. Recently, it has been demon-
strated that the kidney can also metabolize arachidonic
acid by reduced nicotinamide-adenine dinucleotide phos-
phate (NADPH)-dependent cytochrome P450 enzymes
through epoxygenation at the double bonds [7,8]. This
yields the epoxyeicosatrienoic acids, which can then be
hydrolyzed to their respective vicinal diols, the dihydro-
eicosatrienoic acids [7,8]. Cytochrome P4s0mono-oxyge-
nase activity is located in the proximal tubule [5,8]. In ad-
dition, isolated cells from the thick ascending loop of
Henle transform arachiodonic acid into products that have
been partially identified as 5,6- and 11 ,lPdihydro-
eicosatrienoic acids [9,67]. The formation of these prod-
ucts by the thick ascending loop cells could be enhanced
by vasopressin and calcitonin [67], hormones known to
stimulate generation of CAMP in this segment.
The product co-eluting with 11 ,12-dihydroeicosatrienoic
acid on high-pressure liquid chromatography also inhib- BASAL AVP 20m u/ml
ited Na+-K+-ATPase in vitro [67], leading the authors to + NAPROXEN
speculate that these arachidonic acid metabolites could Lure 5. Effect of 5,&epoxyeicosatrienoic acid (5,6-EE7
alter the function of the thick ascending loop of Henle. on osmotic water flow across toad bladder in response to
Jacobson et al [68] have indeed demonstrated that 5,6- arginine-vasopressin (AVP) in the presence of the cyclo-
eicosatrienoic acid significantly decreased sodium reab- oxygenase inhibitor naproxen (10m5 M).

August 25, 1986 The American Journal of Medicine Volume 81 (suppl 28) 5
SYMPOSIUM ON RENAL EFFECTS OF NSAIDS-SCHLONDORFF
60-
2 ron segments.
- 250
1 -L)
-;q~~~&!,~,~~,~M,~
&$040
Figure 6. Effect of meclofenamate infusion on urinary osma
lalify (solid line) and urinary excretion (broken line) in rats.
Reproduced with permission from [82].
lated with vasopressin. The inhibition persisted in tissues
incubated with inhibitors of prostaglandin synthesis and
also in tissues incubated with high concentrations of
PGEP,suggesting that the effects of epoxyeicosatrienoic
acids occur independent of prostaglandins.
Epoxyeicosatrienoic acids inhibited the water flow re-
sponse to forskolin but not (with the exception of 11 ,12-
EET) the response to CAMP or 8-bromo-CAMP, which is
consistent with an effect on CAMP generation. For 11,12-
EET, the possibility of additional inhibition at a site beyond
cyclic AMP or independent of CAMP has to be considered.
To determine whether these effects were due to the
epoxyeicosatrienoic acids themselves or to products of
their metabolism, we also examined the conversion of
epoxyeicosatrienoic acids and the effects of the vicinal
diol hydrolysis products, the dihydroeicosatrienoic acids
[70]. Non-enzymatic conversion of labeled 5,8-EET to its
vicinal diol occurred rapidly in buffer as demonstrated by
high-performance liquid chromatography. The dihydro-
eicosatrienoic acids formed inhibited water flow in a man-
ner paralleling that of the epoxyeicosatrienoic acids. Fi-
nally, 11,12-dihydroeicosatrienoic acid inhibited vaso-
pressin- and forskolin-stimulated adenylate cyclase,
whereas 14,15-dihydroei&satrienoic acid had no effect
[70]. These results are in agreement with the rank order of
their inhibition of water flow, suggesting a site of action at
the adenylate cyclase or one of its nucleotide regulatory
subunits.
Our data support the hypothesis that epoxyeicosa-
trienoic acids, probably via conversion to physiologically
active dihydroeicosatrienoic acid metabolites, inhibit vaso-
6 Augusl25, lg66 The American Journal of Medicine
pressin-stimulated water flow predominantly via inhibition
of adenylate cyclase. This mechanism may also be re-
sponsible for the inhibition of electrolyte transport ob-
served with 5,8-EET in the perfused cortical collecting
tubule [SS]. Taken together, these results raise the possi-
bility that metabolites of arachidonic acid via the
epoxygenase pathway could independently of prosta-
glandins influence water and electrolyte handling by the
loop of Henle and the distal tubule. This hypothesis will,
however, require further study, including proper identifica-
B
tion of epoxygenase products generated by various neph-
DISTAL TUBULE AND COLLECTING DUCT
Prostaglandin synthesis in the connecting tubule is rela-
tively low, but progressively increases towards very high
levels in the cortical and medullary collecting tubules (Fig-
ure 2). This has been demonstrated by immunofluores-
cent studies of cycle-oxygenase activity [4] and by deter-
mination of prdstaglandin synthesis in microdissected tu-
bules [71]. Furthermore, these results are in agreement
with observations of isolated and cultured cells of collect-
ing tubular origin. In both the microdissected collecting
tubules and the isolated and cultured collecting tubule
cells, the predominant prostaglandin generated is PGE:,
[10,15,55,56,71-731.
INTERACTIONS OF PROSTAGLANDIN WITH
VASOPRESSIN
Since the original observation that PGE, inhibits the effect
of antidiuretic hormone in the toad urinary bladder [74]
and in the mammalian collecting tubule [75], the interac-
tion of vasopressin with prostaglandin has attracted much
interest. Multiple studies have confirmed that PGE, and
PGE2 antagonize the antidiuretic action of vasopressin
both in vitro in isolated perfused rabbit collecting tubules
and the toad urinary bladder, and in vivo in experimental
animals and man (for review see [76-781).
The major effect of prostaglandin in the concentrating
mechanism is its interference with the cellular mechanism
of action of vasopressin. Studies in the toad urinary blad-
der [79-801, in segments of the thick ascending loop of
Henle, in isolated collecting tubules [65,66,81], and in vivo
[82,83] (Figure 6) have shown that PGE;! interferes with
the vasopressin-induced generation of CAMP probably via
an inhibitory subunit of the adenylate cyclase [84]. Al-
though this effect can be shown in intact tissue, an inhibi-
tory action of prostaglandin on vasopressin-stimulated
adenylate cyclase in broken cell preparations has not
been uniformly found [77]. Furthermore, PGEp at concen-
trations of 1Om6M and upward may even increase cellular
CAMP concentrations [79,80,85]. Therefore, we have
raised the possibility of an additional inhibitory action of
prostaglandin at a site distal to, or independent of, the
generation of CAMP [80].
Our recent studies with the epoxygenation products of
Volume 61 (auppl2B)
 SYMPOSIUM ON RENAL EFFECTS OF NSAIDS-SCHLONDORFF

arachidonic acid (discussed earlier) also indicate that in

certain nephron segments, non-cycle-oxygenase prod-
ucts of arachidonic acid can interfere with vasopressin-
induced CAMP generation [69,70]. Based on studies in the
toad urinary bladder, Zusman et al [86] proposed that
vasopressin directly enhances the synthesis of prosta-
glandins in its target organ, thereby closing a negative
feedback loop. Some seemingly contradictory answers
have been obtained. In the toad urinary bladder, stimula-
tion of PGEp and thromboxane synthesis after vasopres-
sin has been reported [86,871. Other groups were unable
to detect a significant effect of vasopressin on PGEPsyn-
thesis in the toad bladder or in toad bladder epithelial cells oxygenore
[80-901. Currently, it appears that the reason for the dif- -. - . _
Figure 7. HypOthetrCal Scheme for the interactions of va-
ferences may in part relate to technical differences in the sopressin (VP), CAMP, arachidonic acid (AA), and prosta-
preparation of the tissue [87,91]. glandin (PG) in vasopressin-responsive epithelia. Repro-
In studies with mammalian tissue, interstitial cells in cul- duced with permission from [91].
ture, medullary slices and cell suspensions, collecting tu-
bule cells in culture, and microdissected collecting tubules
have been employed. In medullary slices and cell suspen-
sions, vasopressin usually stimulates PGEs synthesis to I Distal And Collecting Tubule
some extent [71,85]. These preparations do, however,
contain both interstitial and collecting tubule cells and thus
do not allow one to attribute an increase in PGE2 synthe- Capillary
sis to a specific cell. In primary cultures of medullary col-
lecting tubule cells, vasopressin increased the concentra-
tion of CAMP but did not stimulate PGE2 synthesis [72].
On the other hand, in cultures of cortical collecting tubules
from dogs, vasopressin increased PGE:! synthesis [73],
but failed to do so in cultures from rabbit [92]. Similarly,
vasopressin and 1-deamino-8-D-arginine vasopressin
were found to increase PGE synthesis in isolated cortical Figure 8. Interactions of kallikrein (KK) with kininogen to
collecting tubules [55]. Studies carried out in our labora- generate lysyl-bradykinin (Lys-BK) or bradykinin (SK) in the
distal tubule and capillaries. The lysyl-bradykinin can then in
tory indicate that some of the differences may be due to turn stimulate PGE, synthesis by collecting tubular and inter-
the in vitro incubation conditions and that under certain stitial cells.
conditions vasopressin can increase PGE2 synthesis in
both cortical and medullary collecting tubules [71]. It has
to be kept in mind, though, that even in cultured collecting
tubular cells and in microdissected tubules, contamination CAMP. On the other hand, the increase in CAMP would
with interstitial cells cannot be fully excluded. Medullary inhibit phospholipase activation and the resulting synthe-
interstitial cells have been found to increase PGE* synthe- sis of PGE2, representing a second feedback loop that
sis in response to vasopressin [13,93]. would tend to prevent an overshoot of both the vasopres-
Demonstration of vasopressin-induced PGE2 synthesis sin and PGEp effect in either direction.
may be further complicated by the fact that CAMP can
decrease prostaglandin production, probably by inhibiting INTERACTION OF BRADYKININ, PROSTAGLANDIN,
AND VASOPRESSIN
phospholipase activation (Figure 7). Based on the obser-
vation that 8-bromo-CAMP can inhibit PGEp synthesis in The interaction of vasopressin and prostaglandin in col-
renal medullary cells and in toad bladder epithelial cells lecting tubular function can also be influenced by brady-
under basal and vasopressin-stimulated conditions, we kinin. In vivo kinin administration results in increased uri-
recently proposed that vasopressin and PGE2 may inter- nary sodium excretion and in a resistance to the antidiu-
act in a dual feedback loop [91]. In this scheme, vasopres- retie action of vasopressin [94,95]. Interpretation of these
sin would increase PGEP synthesis by activating phos- results is, however, complicated by concomitant in-
pholipases in a CAMP-independent manner as originally creases in renal blood flow, glomerular filtration rate, and
proposed by Zusman et al [86]. The resulting increase of renal prostaglandin production [94,95]. Direct interactions
PGE2 will, in turn, inhibit vasopressin’s hydroosmotic ef- between vasopressin, prostaglandin, and kinin to alter
fect, to a large extent by interfering with generation of epithelial function (Figure 8) are suggested by their com-

August 25, 1988 The American Journal of Medicine Volume 81 (suppl 28) 7
SYMPOSIUM ON RENAL EFFECTS OF NSAIDS-SCHLONDORFF
mon effector-generation site in the distal and collecting
tubules [94,95]. Bradykinin has been found to stimulate
PGEp synthesis in microdissected cortical and medullary
collecting tubules from rabbits [71] and in cells cultured
from collecting tubules [72,92,96,97]. In isolated perfused
rabbit cortical collecting tubules, Schuster et al [98] re-
cently demonstrated that bradykinin antagonizes the in-
crease in luminal water permeability normally occurring
with vasopressin. This effect was only observed when
bradykinin was added to the basolateral side of the tubule.
Pre-incubation of the collecting tubules with inhibitors of
prostaglandin synthesis overcame this effect of brady-
kinin. These results indicate that in the collecting tubule
bradykinin predominantly interferes with vasopressin’s
action by stimulating PGEp synthesis. The PGE2 gener-
ated then, in turn, interferes with the cellular action of
vasopressin (see previous section). Non-PGE,-mediated
actions of bradykinin on the collecting tubule are not fully
excluded and could potentially be related to phos-
phatidylinositide turnover and activation of calcium-
phospholipid-dependent, diglyceride-stimulatable protein
kinase C [96]. The possibility of a prostaglandin-inde-
pendent action of bradykinin has been suggested on the
basis of experiments in the toad urinary bladder [99].
INDIRECT EFFECTS OF PROSTAGLANDIN ON
URINARY CONCENTRATING MECHANISM
In addition to directly interfering with vasopressin’s action
at the collecting tubule, prostaglandin could also alter the
renal concentrating mechanism by increasing renal med-
ullary blood flow, leading to washout of solute and dissipa-
tion of the usmotic gradient required for water reabsorp-
tion. Prostaglandin may also influence medullary solute
composition by decreasing sodium transport and urea
accumulation in the medulla. Both of these effects could
be independent of vasopressin. Consistent with this for-
mulation, medullary sodium chloride concentration in-
creases after inhibition of prostaglandin synthesis and
decreases after administration of PGE2 [lOO,lOl]. Also,
urea permeability of the toad urinary bladder (1021 and the
mammalian collecting tubule [103] increases after inhibi-
tion of prostaglandin synthesis, whereas exogenous pros-
taglandin decreases urea permeability. Thus, prostaglan-
din could influence medullary solute composition and
hence urinary concentrating ability even in the absence of
vasopressin [104].
CONTRIBUTION OF PROSTAGLANDIN TO RENAL
SODIUM CHLORIDE EXCRETION
Despite a considerable amount of experimental data from
both in vivo and in vitro studies, the evidence for a blood-
flow-independent role for prostaglandins in renal sodium
chloride excretion remains controversial. In vivo, depend-
ing on the experimental conditions (e.g., prior sodium
chloride content of diet, volume status, water diuresis or
antidiuresis, awake state or anesthesia), intrarenal admin-
8 August 25,1986 The American Journal of Medicine
istration of PGE or inhibition of renal prostaglandin pro-
duction has provided results that indicate renal prosta-
glandins do not influence renal sodium chloride excretion;
prostaglandins inhibit sodium chloride excretion; or pros-
taglandins increase renal sodium chloride excretion (for
review see [SO]). These conflicting results are not overly
surprising as the physiologic status of the animal can alter
the effect of prostaglandins on renal blood flow and its
distribution. Though some studies have attempted to mini-
mize or exclude changes in blood flow, it remains doubtful
whether this factor can ever be adequately eliminated dur-
ing in vivo studies. Studies using urinary PGE2 excretion
as an index of renal prostaglandin synthesis have occa-
sionally, but not always, shown a correlation between
urinary prostaglandin and sodium chloride excretion
WI.
Microperfusion of isolated tubules has similarly resulted
in conflicting results [61]. Although several groups have
shown inhibition of sodium chloride transport by PGEp or
PGlp in the cortical collecting tubule [105-l 071 or the thick
ascending loop of Henle [62] from rabbits, another group
has been unable to show such an effect [63,64]. The rea-
son for these discrepancies remains unclear and cannot
easily be explained by differences in hormonal status,
basal sodium chloride transport, or buffers used. If PGEp
produced by the collecting tubule inhibits sodium chloride
transport, it remains unclear why inhibition of collecting
tubular prostaglandin synthesis does not result in en-
hancement of sodium chloride transport. Furthermore, the
recent microperfusion studies with bradykinin argue
against PGE*-mediated inhibition of sodium chloride
transport [108]. Although inhibition of prostaglandin syn-
thesis abolished the antagonism of bradykinin on the
hydroosmotic effect of vasopressin, it did not influence
sodium transport [108]. Holt and Lechene [log] did, how-
ever, report that prostaglandin inhibition prevented the
vasopressininduced changes in sodium ion transport in
cortical collecting tubules, but again this finding has been
challenged [108]. Also, it is possible that non-cyclo-oxyge-
nase products of arachidonic acid, such as the epoxides,
can influence sodium chloride transport (see earlier).
RENAL MEDULLARY INTERSTITIAL CELLS
Apart from the collecting tubules, renomedullary interstitial
cells are the second major source of prostaglandin syn-
thesis in the renal medulla [4,15]. Cultured interstitial cells
produce predominantly PGEp [l l-141. PGEp synthesis
can be stimulated by angiotensin II, vasopressin, and bra-
dykinin. In addition, rendering the medium hypertonic will
increase prostaglandin synthesis [l lo]. This may be of
significance with changes in renomedullary tonicity occur-
ring during diuresis-antidiuresis. Prostaglandin synthesis
by medullary interstitial cells may be important in main-
taining blood flow to this poorly oxygenated and hyper-
tonic region of the kidney. This may be illustrated by the
preferential decrease in renomedullary blood flow ob-
Volume 81 (suppl2B)
 SYMPOSIUM ON RENAL EFFECTS OF NSAIDS-SCHLONDORFF

served during inhibition of prostaglandin formation
[l 11 ;112]. The close anatomic association of the intersti-
tial cells with the vas recta, the thin limb of Henle’s loop,
and the inner medullary collecting tubule makes it attrac-
tive to speculate that prostaglandin generated by these
cells could directly influence the function of these struc-
tures. PGE2 via its vasodilator properties could increase
blood flow through the vasa recta and could directly alter
transport parameters of Henle’s loop and the collecting
tubule (as discussed earlier). Finally, long-term inhibition
of prostaglandin synthesis could result in renomedullary
ischemia, eventually leading to papillary necrosis, as ob-
served in chronic analgesic abuse.
maintaining local, rather than systemic, homeostasis.
Thus, prostaglandins can be envisioned as serving a cyto-
protective role. This hypothesis is consistent with the ob-
servation that during normal euvolemic conditions, inhibi-
tion of prostaglandin formation has little effect on renal
function. When, however, renal function is stressed by
fluid or electrolyte depletion or overload, or by kidney dis-
ease, the local generation and action of prostaglandins
becomes an important factor in protecting the respective
renal compartment from injury. This concept is supported
by the clinical observation that untoward renal effects of
nonsteroidal anti-inflammatory agents have been reported
predominantly under conditions of “renal stress.”

COMMENTS
ACKNOWLEDGMENT
Prostaglandin synthesis follows a specific pattern along
the nephron. This allows prostaglandins to act as modula- My thanks to Mrs. D. Nieves who provided superb secre-
tors of different nephron functions with the overall goal of tarial support.

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August 25, 1955 The American Journal of Medlclne Volume 81 (suppl 2B) 11