Primary Role of Renal Homografts in Setting Chronic
Blood Pressure Levels in Rats
By Lewis K. Dahl and Martha Heine
ABSTRACT
The genotype of homograft kidneys plays the primary role in determining chronic blood
pressure levels in two strains of rats with opposite genetically controlled propensities for
hypertension. In hypertensive rats from the hypertension-prone (S) strain, a renal
homograft from the same strain resulted in a slight rise in blood pressure to a level that
was equivalent to that in appropriate uninephrectomized S controls. In contrast, a renal
homograft from the hypertension-resistant (R) strain led to a sharp fall in blood pressure
in hypertensive S recipients. Opposite results were found when the host came from the R
strain: R homografts maintained the same low pressure as that seen in controls, whereas S
homografts resulted in hypertension. We concluded that genetically controlled factors
operating through the kidney can chronically modify the blood pressure up or down. The
central role of the kidney in hypertension is thus further documented.
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KEY WORDS
genetic hypertension
experimental hypertension
kidney transplant
• In two earlier papers (1, 2), we used interstrain
renal transplants to study the influence of the
kidney on blood pressure in two strains of rats that
have opposite genetically determined propensities
for hypertension. We found that the genotype of
the renal homograft was more influential in determining the subsequent blood pressure development
than was the genotype of the host rat, and we
concluded that the kidneys of the hypertensionprone (S) strain had a greater hypertensinogenic
and a lesser antihypertensive effect than did the
kidneys of the hypertension-resistant (R) strain. In
those studies, the course of blood pressure development was followed in initially normotensive young
rats from both strains. In the present work, many of
the rats from the S strain were allowed to become
moderately hypertensive by consuming a high-salt
(NaCl) chow for 4-5 weeks prior to the insertion of
the renal homograft. We wanted to see whether the
antihypertensive and hypertensinogenic qualities
of the kidneys from these two strains would be
demonstrable in the presence of hypertension.
Methods
Rats.—The rats came from one of two SpragueDawley strains that were originally established from a
From the Medical Department, Brookhaven National Laboratory, Upton, New York 11973.
This work was principally supported by U. S. Public Health
Service Grants HL-13408 and HL-14913 from the National
Heart and Lung Institute, by American Heart Association Grant
73-739, and by the U. S. Atomic Energy Commission.
Received December 30, 1974. Accepted for publication February 28, 1975.
692
salt
heredity
renal genotype
single strain on the basis of their different blood pressure
responses to the same NaCl intake: one strain was resistant (R strain) and the other was sensitive (S strain)
to the hypertensinogenic effects of NaCl (3, 4). Later we
found that the two strains had similar disparate responses to most hypertensinogenic stimuli (5, 6).
Details on rat care and blood pressure measurement
have appeared in earlier papers (7-12). Special chows
made to order (Agway Inc., Country Foods Division,
Syracuse, N. Y.) containing either 0.3% NaCl (low-salt
chow) or 8% NaCl (high-salt chow) were fed ad libitum as
specified. The low-salt chow contained adequate
amounts of NaCl for normal growth and development.
Tap water containing 0.5-0.7 mEq sodium/liter was
allowed ad libitum. Rats fed the high-salt chow were
given this diet for the first 4-5 weeks after weaning; they
were then fed low-salt chow until the end of the experiment. Rats were observed as long as they remained in
good health as evidenced primarily by maintenance of
normal weight gain; however, observations on the rats
with homografts ceased if their uninephrectomized controls became ill and vice versa. Survival ranged from 5 to
52 weeks with a median of 32 weeks. Only male rats were
used. The rats were 8-9 weeks old at the time of surgery;
at this time the S rats had been hypertensive about 3
weeks.
Kidney Transplantation.—The kidney transplantation procedure has been described in a previous paper
(2). Briefly, it was a modification of the technique of
Fisher and Lee (13) and of Lee (14). After the homograft
had been inserted, the opposite (right) kidney was
removed so that renal function was dependent solely on
the single homograft kidney. Immunosuppressives and
antibiotics were not used, but rejection was not a
problem; failures were due to errors in technique and
occurred approximately once in five operations, with
failure being defined as death within 4 weeks after
surgery.
Protocol.—Transplants were reciprocal as described
earlier (1, 2). Four siblings from each of two litters were
Circulation Research, Vol. 36, June 1975
693
RENAL HOMOGRAFTS AND CHRONIC BLOOD PRESSURE
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used; one member from each litter was the host, one the
donor, the third a uninephrectomized control, and the
fourth an intact control. The uninephrectomized control
and the host rat were of primary interest, and death or
illness of either one was considered the end of the
observation period for that pair. The intact control was
essentially a control on its uninephrectomized sibling
and proved unnecessary.
Systolic blood pressures were measured under light
ether anesthesia by the microphonic method (7) prior to
surgery and at 1-4-week intervals thereafter. Blood urea
nitrogen was measured routinely as described previously
(2). Weights were measured at each blood pressure
determination. A weight loss in excess of 10 g was
considered evidence of illness and only observations prior
to such evidence were used in our calculations. Statistical comparisons between means were made by analysis of
variance; data with P values < 0.05 were considered
significant, and all P values < 0.01 were assigned that
nominal value. The following symbols are used to identify the rats: "R" or " S " identifies the strain of the
recipient, "r" or "s" denotes the strain of the donor, and
"uni" indicates a control right uninephrectomized rat
with its left kidney intact. Therefore, R,, R r , S r , and Ss
indicate the combinations of recipient and donor in this
study, and Runl and S uni indicate the uninephrectomized
controls.
The following questions were asked. (1) Would S rats
with various degrees of hypertension that received a
renal homograft from normotensive R rats have significantly lower blood pressures than their uninephrectomized sibling controls? (2) Would the opposite hold true,
namely, would R rats with normal blood pressure that
received a renal homograft from hypertensive S rats have
significantly higher blood pressures than their uninephrectomized sibling controls?
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There were ten S r rats; the recipient S rats had
an average blood pressure of 167.8 ± 3.13 (SE) mm
Hg prior to surgery, whereas the rats from which
the donor R kidney came averaged 107.2 ± 3.54
mm Hg. The average pressure of the S r rats was
122.8 ± 2.77 mm Hg at a median of 17 weeks after
surgery. This pressure level contrasted with that of
the uninephrectomized sibling S controls who averaged 186.0 ± 13.61 mm Hg at the same times (P <
0.01) (Fig. 1).
The 12 R, rats were derived from recipient R rats
with an average blood pressure of 115.5 ± 2.55 mm
Hg and S donor rats with an average blood pressure
of 146.8 ± 7.15 mm Hg prior to surgery. Postoperatively, at a median of 24 weeks, the Rg rats
averaged 155.0 ± 4.80 mm Hg, and their uninephrectomized sibling R controls averaged 128.1 ±
3.88 mm Hg (P < 0.01) (Fig. 2).
The ten S s rats originated from S donors with an
average blood pressure of 142.4 ± 6.47 mm Hg and
S recipients with an average blood pressure of 159.4
± 1.88 mm Hg. The average pressure of the S8 rats
Circulation Research, Vol. 36, June 1975
FIGURE 1
Effect of the genotype of the renal homograft on chronic blood
pressure levels at a median time of 17 weeks after surgery. Data
are for S rats with R renal homografts (Sr). The mean blood
pressure ± SE is indicated for each group.
at a median of 10 weeks after surgery was 166.8 ±
11.31 mm Hg compared with an average blood
pressure of 167.4 ± 11.06 mm Hg for their uninephrectomized S controls (P > 0.05).
The 12 Rr rats came from R donors with an
average blood pressure of 111.2 ± 2.55 mm Hg and
R recipients with an average blood pressure of 107.5
± 4.32 mm Hg. At a median of 30 weeks after
surgery, the Rr homograft rats averaged 132.1 ±
3.92 mm Hg at a time when their uninephrectomized R controls averaged 132.4 ± 3.61 mm Hg (P
> 0.05).
Among the rats with homografts, azotemia, defined as a blood urea nitrogen level of more than 50
mg/100 ml blood, occurred in five rats in the R.,
group (53, 90, 78, 54, and 59 mg/100 ml blood), but
DAHL. HEINE
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pressure levels at a median time of 24 weeks after surgery. Data
are for R rats with S renal homografts (R,). The mean blood
pressure ± SE is indicated for each group.
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azotemia did not occur in the S r , S s , and Rr
groups. There were four cases of azotemia in the
uninephrectomized controls, all in S rats (53, 77,
74, and 51 mg/100 ml blood). This incidence is
similar to the pattern we observed previously (2),
i.e., the rats with homografts do approximately as
well as their controls in this respect. Rats with a
single R kidney (S r , R r , and Runi) had generally
lower blood urea nitrogen levels than did those with
a single S kidney (R,, S s , and Suni) (Table 1). As
seen previously (2) there was no correlation between nitrogen retention and blood pressure levels.
Weights of rats with a homograft and their
respective controls were similar (P > 0.05) and
therefore are not discussed further.
Discussion
This study extends and strengthens the conclusions derived from our earlier work (1, 2) with renal
homografts in these two unique strains of rats with
Circulation Research. Vol. 36, June 1975
695
RENAL HOMOGRAFTS AND CHRONIC BLOOD PRESSURE
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opposite predispositions for developing hypertension. Depending on the genotype of the renal
homograft, blood pressure can be chronically raised
or lowered. Although it might be unwarranted to
discount entirely the role of the host genotype, the
kidney genotype appears to play the dominant role
in setting chronic blood pressure levels. When for
instance, rats from the hypertension-prone (S)
strain are allowed to develop moderate hypertension from salt, replacement of both host kidneys by
a single R homograft results in a significant chronic
lowering of blood pressure: at similar times after
surgery the average systolic blood pressure of S
homograft rats is ~60 mm Hg less than that of
their sibling S controls. By contrast, if an S donor is
used, the resulting Ss rat shows no fall in blood
pressure but instead a slight rise; in fact, such Ss
rats and their uninephrectomized S controls have
almost identical blood pressures of approximately
167 mm Hg. The homograft per se, therefore, does
not induce a fall in blood pressure, a conceivable
possibility from the results with the S r homografts.
The R, combination results in opposite findings:
R rats that are normotensive before surgery have
average blood pressures after implantation of a
single S hypertensive homograft kidney that are
chronically 27 mm Hg higher than those in appropriate R controls at similar times after surgery. But
if instead of an S donor, an R donor is used, the
resulting Rr combinations have identical blood
pressures with their R uninephrectomized controls.
The homograft operation per se does not lead to a
rise in blood pressure just as it does not lead to a
fall in blood pressure. Any change in blood pressure
induced in these homograft rats appears to be tied
directly to the genotype of the renal transplant.
It seems reasonable to conclude that genetically
controlled factors acting through the kidney can
chronically modify the blood pressure up or down.
Our studies with parabiosis between the two
strains (15-17) have suggested indirectly that a
humoral factor from the S kidney (or requiring the
presence of the S kidney) can elevate blood pressure in a parabiont partner. Two later studies with
renal homografts (1, 2) have led more directly to
the conclusion that among normotensive rats from
these strains the blood pressure can be directed to
hypertensive levels or maintained at normotensive
levels, depending on whether an S or an R genotype
renal homograft is the sole source of renal function.
The present study indicates that elevated blood
pressures can be reduced to normal levels by a
normotensive R kidney in a hypertensive S rat and
that a hypertensive S homograft can raise the blood
pressure of a normotensive R host.
Circulation Research, Vol. 36, June 1975
In related studies with these two strains of rats,
Tobian et al. (18) and Tobian (19) followed for 5
days the effect of renal homografts from the two
strains on the blood pressure of rats with renal
hypertension: kidneys from the S rats had less
antihypertensive capacity than did kidneys from
the R rats. This observation is compatible with our
observations, but we now think that S kidneys have
a greater capacity for raising blood pressure as well
as a lesser capacity for lowering it compared with R
kidneys.
The role of the kidneys in hypertension has been
a subject of discussion since the time of Richard
Bright and the subject of experiments for much of
the twentieth century. The importance of the
kidneys in controlling blood pressure has been
reemphasized in a series of papers utilizing systems
analysis by Guyton and his collaborators (20). It
would not be helpful to the present thesis to detail
the numerous factors outlined by these workers
which modify chronic arterial blood pressure levels.
The important point is that the central role of the
kidneys in hypertension is documented in a series
of elegant mathematical analyses combined with
appropriate deductions based on experiments.
It perhaps is not surprising, therefore, that our
work should point to the primary role of the
kidneys in determining chronic blood pressure
levels. The unique aspect of our studies is the
finding that genetic determinants are involved in
setting these blood pressure levels, i.e., in determining whether hypertension will develop; these
genetic determinants clearly involve renal function. Nothing in this work suggests what aspect of
renal function(s) is under genetic control. As we
have pointed out earlier (2), the work of Muirhead
et al. (21), Muehrcke et al. (22), and Tobian et al.
(23) suggests the possibility that the antihypertensive capacity of the renal medulla differs in the two
strains. We have no evidence at present either to
support or refute involvement of the medulla in
these rats, however.
References
1. DAHL LK, HEINE M, THOMPSON K: Genetic influence of renal
homografts on blood pressure of rats from different
strains. Proc Soc Exp Biol Med 140:852-856, 1972
2. DAHL LK, HEINE M, THOMPSON K: Genetic influence of the
kidneys on blood pressure: Evidence from chronic renal
homografts in rats with opposite predispositions to hypertension. Circ Res 34:94-101, 1974
3. DAHL LK, HEINE M, TASSINARI L: Role of genetic factors in
susceptibility to experimental hypertension due to
chronic excess salt ingestion. Nature (Lond) 194:480-482,
1962
4. DAHL LK, HEINE M, TASSINARI L: Effects of chronic excess
salt ingestion: Evidence that genetic factors play an
696
DAHL. HEINE
important role in susceptibility to experimental hypertension. J Exp Med 115:1173-1190. 1962
5. DAHL LK, HEINE M, TASSINARI L: Effects of chronic excess
salt ingestion: Role of genetic factors in both DOCA-salt
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7. DAHL LK: Effects of chronic excess salt feeding: Elevation of
plasma cholesterol in rats and dogs. J Exp Med
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8. DAHL LK, HEINE M: Effects of chronic excess salt feeding:
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Circulation Research, Vol. 36, June 1975
Primary role of renal homografts in setting chronic blood pressure levels in rats.
L K Dahl and M Heine
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Circ Res. 1975;36:692-696
doi: 10.1161/01.RES.36.6.692
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