Kidney International, Vol. 61 (2002), pp. 1794–1800

Increased genetic susceptibility to renal damage in thestroke-prone spontaneously hypertensive rat

PAUL C. CHURCHILL,† MONIQUE C. CHURCHILL, KAREN A. GRIFFIN, MARIA PICKEN,ROBERT CLINTON WEBB, THEODORE W. KURTZ, and ANIL K. BIDANI

Department of Physiology, Wayne State University, Detroit, Michigan; Departments of Internal Medicine and Pathology, LoyolaUniversity and Hines VA Hospital, Maywood, Illinois; Department of Physiology, Medical College of Georgia, Augusta, Georgia;and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA

Increased genetic susceptibility to renal damage in the stroke- the stroke-resistant and stroke-susceptible strains ofprone spontaneously hypertensive rat. spontaneously hypertensive rat (SHR and SHRsp, re-

Background. The spontaneously hypertensive rat (SHR) de- spectively) also exhibit differences in the severity of renalvelops much less renal damage than the stroke-prone straindamage [1–8], which are observed even after salt-supple-of SHR (SHRsp) after salt-supplementation, and it has beenmentation in the absence of a stroke prone diet [8–10].proposed that these strains differ in their genetic susceptibility

to renal damage. However, radiotelemetric BP measurements The reasons remain poorly defined, but intrinsic genetichave shown that salt-supplementation results in more severe differences in susceptibility to hypertensive renal dam-and accelerated hypertension in the SHRsp. Therefore, it is age have been postulated [1–3, 7–13]. However, differ-unclear whether the differences in renal damage are due to

ences in the severity of renal damage cannot be ascribeddifferences in BP exposure or true differences in intrinsic (ge-to differences in genetic susceptibility unless one cannetic) renal susceptibility to hypertensive damage.

Methods. Kidney cross transplantation was performed be- ensure equivalent control for the BP exposure of thetween the SHR and SHRsp strains in uninephrectomized recip- kidneys in the compared strains. Radiotelemetric BPients to allow an investigation of the susceptibility to renal

measurements have shown that the BP is more salt-damage in SHR and SHRsp kidneys maintained in the samesensitive in the SHRsp, that is, hypertension is morehost and exposed to the same BP profile and metabolic environ-

ment. Following transplantation, BP was radiotelemetrically severe and develops more rapidly after salt in the SHRspmonitored before and after an 8% NaCl diet given to accelerate than in the SHR [10]. Thus, differences in the severityhypertension and renal damage. Then the kidneys were re- of renal damage between the salt-supplemented SHRspmoved and renal damage was assessed histologically.

and SHR may reflect differences in BP exposure ratherResults. In the SHR recipients, the SHRsp donor kidneysthan genetic differences in renal damage susceptibility.exhibited more hypertensive damage than the contralateral

native SHR kidneys, but histologic evidence of mild cellular As the SHR and SHRsp share the same major histocom-immunologic rejection also was observed that could have facili- patibility complex (MHC) [14], we employed the tech-tated the increased renal damage. However, even in SHRsp nique of kidney cross transplantation to examine if thererecipients, the native SHRsp kidneys exhibited twice the dam-

are intrinsic differences in renal damage susceptibilityage seen in the contralateral transplanted SHR kidneys.after salt-supplementation between the kidneys of theseConclusion. These data unequivocally demonstrate that the

SHRsp kidneys are intrinsically more susceptible than the SHR two strains when exposed to an identical BP and meta-kidneys to renal damage when exposed to exactly the same bolic milieu [15]. Kidney cross transplantation in bothBP and metabolic environment. directions was performed between the SHRsp and SHR

strains using unilaterally nephrectomized recipients totest the hypothesis that the SHRsp kidney is genetically

In addition to a contrasting susceptibility to develop(intrinsically) more susceptible to renal damage than the

stroke when provided a Japanese style stroke-prone diet,SHR kidney.

† Deceased.METHODS

Key words: rats, genetic hypertension, salt-sensitivity, nephrosclerosis,Animals and animal carekidney cross transplantation.

Spontaneously hypertensive rats (SHR) were obtainedReceived for publication August 22, 2001from a commercial source (Harlan Sprague-Dawley, In-and in revised form November 6, 2001

Accepted for publication December 17, 2001 dianapolis, IN, USA) and stroke-prone SHR (SHRsp)were obtained from a colony maintained since 1981 at 2002 by the International Society of Nephrology

1794

Churchill et al: Renal damage in SHRsp 1795

the University of Michigan in Ann Arbor. All rats were glands remained intact. The donor kidney was placedon an ice-cold coil during anastomosis of the vessels:cared for in accordance with the Principles of the Guide

for the Care and Use of Laboratory Animals (Depart- end-to-side of the donor kidney’s artery and the recipi-ent’s aorta, and end-to-end of the donor kidney’s andment of Health, Education, and Welfare). They were

housed in a constant temperature room with a 12-hour the recipient’s renal veins. The vessels were unclamped,and the cooling coil was removed. The donor’s kidneyslight and 12-hour dark cycle, and as described below,

free access to food and drinking water except that food and the recipient’s ureters were anastomosed end-to-end.The abdominal wall was closed with a continuous 6-0was restricted the night before transplantation surgery.prolene suture, the skin was closed with interrupted 6-0

Experimental protocol silk sutures, and the rat was put in a recovery cage withaccess to food and water.Unilaterally nephrectomized SHR and SHRsp recipi-

ents underwent renal cross transplantation and wereBP radiotelemetrymaintained on a standard (1.14% NaCl diet (Teklad,

Madison, WI, USA) and tap water. Six to ten days post- The rats were anesthetized with sodium pentobarbital(45 mg/kg via tail vein) six to ten days after transplanta-transplant, the recipients were instrumented for con-

tinuous BP monitoring by radiotelemetry (vide-infra). tion surgery and prepared for BP radiotelemetry [17].Each rat had a BP sensor inserted intraperitoneally. TheAfter an additional six to eight days, the rats were

weighed, a 24-hour urine collection was obtained for sensor’s catheter was inserted into the aorta below thelevel of the renal arteries, and the radiotransmitter wasbasal protein excretion and radiotelemetric BP monitor-

ing was begun. During the first week of monitoring, all fixed to the peritoneum. After allowing one week forrecovery, the rats were housed individually in polycarbo-rats were continued on the standard diet (1.05% NaCl

Lab Diet, catalog #5001) and tap water, following which nate cages placed on radio receivers connected to a mi-crocomputer running the Dataquest software packagethey were switched to an 8% NaCl diet (Lab Diet, Cata-

logue #5001 C-2) and tap water to accelerate the develop- (Data Sciences International, Minneapolis, MN, USA).Systolic BP was recorded for a 5-second interval everyment of hypertension and the associated renal damage.

The diets were isocaloric and otherwise identical in com- 10 minutes throughout the day and night.position. After three weeks (SHR recipients) or four

Histological analysisweeks (SHRsp recipients) of the 8% NaCl diet, a repeat24-hour urine collection was obtained for determination The kidneys were perfusion-fixed at the ambient pres-

sure before removal as previously described [18]. In brief,of proteinuria following which the rats were anesthetized(Na pentobarbital �45 mg/kg body wt) and the kidneys the kidneys were perfused with 150 mmol/L NaCl at 38�C

until the venous effluent cleared, followed by modifiedwere removed for histological analysis.Karnovsky’s fixative (2% wt/vol paraformaldehyde and

Kidney transplantation 2.5% glutaraldehyde in 0.1 mol/L cacodylate buffer, pH7.4) for 10 minutes. Two transverse sections of the kidneyOnly males were used, and the donors and recipients

were age-matched (6 to 8 weeks old) at the time of through the papilla were post-fixed in buffered formalinand embedded in paraffin. Sections (3 to 4 �m) weretransplantation. At this age, no evidence of renal damage

is present in either strain [9, 10]. The techniques for stained with hematoxylin and eosin (H&E) and periodicacid-Schiff (PAS). Glomerular and vascular injuries wereharvesting and transplanting kidneys were described in

detail previously [15, 16]. Briefly, donors and recipients quantitated separately in both of the sections from eachkidney as previously described [15, 18]. All of the glomer-were anesthetized and maintained on a surgical plane of

anesthesia with Na pentobarbital (initial dose �45 mg/kg uli in each section were counted and classified as normalor abnormal. Abnormal glomeruli were separated intobody wt given via a tail vein). The donor rat was heparin-

ized (100 milliunits in 0.1 mL, IV) and the left kidney three categories, those exhibiting (a) acute hypertensiveinjury (necrosis, thrombosis, microaneurysms and capil-was removed after it was flushed via the aorta with 5

mL of an ice-cold solution (150 mmol/L NaCl and 200 lary wall disruption), (b) segmental glomerular sclerosis(collapsed capillary loops with mesangial matrix expan-mmol/L mannitol, pH 6.4). The donor kidney was kept

in ice-cold flush solution while preparing the recipient. sion), or (c) ischemic injury (globally shrunk glomeruliwith collapsed capillary loops). The percentages of glo-A midline incision was made, and the left kidney was

removed after transecting the ureter near the hilum, the meruli exhibiting each of these three lesions were re-corded, and the sum of the three percentages was takenrenal artery near its origin (or distal to the inferior adre-

nal artery if it arose from the renal artery rather than as the % glomerular damage score. The total number ofvascular profiles exhibiting evidence of acute hypertensivefrom the aorta), and the renal vein near the kidney,

leaving the adrenal and spermatic veins patent. With this injury (fibrinoid necrosis, myointimal proliferation, frag-mentation of internal elastic lamellae, and aneurysmalmethod, the circulation of both of the recipient’s adrenal

Churchill et al: Renal damage in SHRsp1796

Fig. 2. Renal damage scores in the native SHR (�) and the trans-planted SHRsp (�) kidneys in SHR recipients at sacrifice after 3 weeksof an 8% NaCl diet (N � 4). Details about BP monitoring are in thelegend to Figure 1; the renal damage score is the sum of the vascularand % glomerular histological damage scores as found in the Methods

Fig. 1. Weekly averages of systolic blood pressure in spontaneous hy- section.pertensive rats (SHR; N � 4) and stroke-prone SHR (SHRsp; N � 8)given standard rat chow (1.05% NaCl) and tap water to drink for thefirst week, followed by an 8% NaCl and tap water for 3 weeks (SHRrecipients; �) or 4 weeks (SHRsp recipients; �). Because of a radio- of the BP radiotelemetry when the rats were receivingtransmitter malfunction, the data for one SHRsp recipient are not

a standard diet (1.05% NaCl) for body weight (253 � 6included. In each rat, average systolic blood pressure was determinedby radiotelemetry during a 5-second interval every 10 minutes. The vs. 233 � 9 g) or proteinuria (8.9 � 0.9 and 7.8 � 0.6weekly average for each rat was calculated as the average of �1000 mg/24 h), respectively. Similarly, these parameters weresuch systolic BP measurements at 10 minute intervals. The group aver-

not significantly different at the conclusion of the studyages were calculated by averaging the weekly averages of individualrats. Also shown is the difference in the increase in BP by week 4 in after three to four weeks of 8% NaCl diet (body weightthe SHR and SHRsp recipients, *P � 0.05. 316 � 9 vs. 303 � 7 g; proteinuria 113 � 18 vs. 75 � 12

mg/24 h). The weekly averages of systolic BP in the twogroups of rats are shown in Figure 1. There were no

dilation) was counted in each section. The number of significant differences in the average systolic BP duringsuch vascular profiles with damage was expressed per the initial week of BP radiotelemetry on the standard100 glomeruli as a vascular damage score to correct for 1.05% NaCl diet (189 � 10 vs. 175 � 5 mm Hg). Bothany differences in the amount of renal parenchymal pres- groups exhibited increases in systolic BP after beingent in sections from individual kidneys. Finally, a com- switched to the 8% NaCl diet, but the rate of increaseposite score for total renal damage was calculated as the was significantly greater in the SHRsp recipients as dem-sum of the vascular damage score and the % glomerular onstrated by a comparison of the BP increases by thedamage score. fourth week between the two groups (4th week BP �

Additionally, sections from each kidney (native or 1st week BP).transplanted) were carefully evaluated for evidence of Figure 2 shows the results obtained in four unilaterallyimmunologic rejection in the form of tubulointerstitial nephrectomized SHR recipients of SHRsp kidneys. Al-mononuclear cellular infiltrates away from the sites of though the transplanted SHRsp kidneys showed greaterhypertensive glomerular and vascular damage [19]. renal damage as compared to the native SHR kidneys,

they also exhibited focal cellular infiltrates away fromStatistical analysisthe sites of hypertensive vascular and glomerular damage

All data, including the renal damage scores, are ex- indicating immunologic rejection, probably due to thepressed as means � SEMs. Paired t test was used to

differences in minor histocompatibility antigens (Fig. 3statistically compare the differences in histologic damageA, B). Because of the small numbers, the differences inobserved between the two kidneys in the same recipientrenal damage scores did not reach statistical significanceand thus exposed to the same BP hormonal and meta-(P � 0.06). Moreover, such results could not have ex-bolic milieu. The unpaired Student t test was used tocluded the possibility that immunologic rejection wasdetermine the statistical significance of other differencescontributing to the more severe renal damage seen inbetween the two groups. A two-tailed P of �0.05 wasthe transplanted SHRsp kidneys. Therefore, this proto-considered significant [20].col was abandoned in favor of the converse protocol inwhich uninephrectomized SHRsp served as the recipi-

RESULTS ents of transplanted kidneys from age-matched SHR do-nors (N � 9).Significant differences were not present between the

two recipient groups (SHR and SHRsp) at the initiation Figure 4 shows the results of these studies. An identical

Churchill et al: Renal damage in SHRsp 1797

Fig. 3. Histologic findings in (A) native SHR kidney, (B) transplanted SHRsp kidney in the same SHR recipient, (C ) transplanted SHR kidney,and (D) native SHRsp kidney in the same SHRsp recipient. A greater severity of vascular (arrows) and glomerular (asterisk) damage is seen inthe native and transplanted SHRsp kidneys. However, the transplanted kidneys also exhibit significant cellular infiltrate (arrowheads) indicativeof rejection (B and C). Periodic acid-Schiff (PAS) stain, �160.

Churchill et al: Renal damage in SHRsp1798

avoided. In previous intrastrain transplantation studies,we have extensively validated our transplantation tech-niques and shown essentially identical structure andfunction of transplanted and native kidneys [15, 28–30].Moreover, given that the results were qualitatively simi-lar in both sets of cross transplantation studies, it isunlikely that technical vascular problems played a rolein the observed differences in renal damage betweenSHR and SHRsp kidneys. The SHRsp kidneys, nativeor transplanted, exhibit nearly twice the severity of renaldamage as compared to the SHR kidneys, whether native

Fig. 4. Renal damage scores in the transplanted SHR (�) and native or transplanted, when exposed to an identical milieu ofSHRsp (�) in SHRsp recipients at sacrifice after 4 weeks of an 8%

systemic BP and metabolic environment of either theNaCl diet (N � 9). As noted in the legend to Figure 1, the BP data forone SHRsp recipient are not included because of a radiotransmitter salt supplemented SHR or the SHRsp recipient. Themalfunction and thus, are for 8 rats only. *P � 0.0005. relative resistance of SHR kidneys to hypertensive renal

damage in the present study is consistent with a similarresistance to DOCA-salt induced hypertensive damageof the SHR kidneys noted in our previous transplanta-protocol was followed as for the previous experimenttion study between Brown-Norway and a congenic histo-except that the 8% NaCl diet was continued for fourcompatible SHR strain [15]. The present results thusweeks in order to achieve a greater separation in histo-clearly demonstrate that the SHRsp kidneys are signifi-logic damage between the two kidneys. The rats werecantly more susceptible to hypertensive renal damagethen sacrificed and perfusion fixed kidneys harvested forthan the SHR kidneys, independent of the differenceshistologic quantitation of renal damage. As expected,between the two strains in the rate and severity of BPfocal cellular infiltrates indicative of immunologic rejec-increases after salt-supplementation [10].tion in this instance were observed in the transplanted

The present data also illustrate a potential limitationSHR kidneys (Fig. 3C). Nevertheless, greater renal dam-of the cross transplantation strategy. Despite the SHRage was seen in the native SHRsp kidneys (Fig. 3D).and SHRsp strains possessing the same MHC [14], histo-logic evidence of some rejection was observed in the

DISCUSSION cross-transplanted SHR and SHRsp kidneys, probablydue to differences in the minor histocompatibility anti-Genetic factors are widely believed to contribute to

the considerable variability observed in the incidence gens. However, the histologic changes were relativelymild and consisted of focal tubulointerstitial cellular in-and severity of renal damage in hypertensive humans

and experimental animals [1–13, 21–25]. However, little filtrates. Nevertheless, it is possible that such cellularrejection may alter local tissue susceptibility and magnifyprogress has been made in identifying the responsible

genes and/or intermediate mechanisms, despite the avail- the degree of hypertensive renal damage sustained inthe transplanted kidneys. Therefore, the results obtainedability of various rat strains that appear to exhibit such

differences in susceptibility to renal damage. This is in in the SHRsp recipients with the native SHRsp kidneyshowing significantly greater renal damage than thepart due to the fact that it has been difficult to unequivo-

cally demonstrate that the observed differences in the transplanted SHR kidneys provide the more definitiveevidence of the genetically greater susceptibility of theseverity of renal damage are due to intrinsic genetic

differences in susceptibility rather than due to differ- SHRsp kidneys. However, it is of note that proportion-ately similar differences were observed in the SHR recip-ences in BP exposure. Given the natural lability of BP

that is further exaggerated in hypertensive states, it is ients between the transplanted SHRsp kidneys (with re-jection) and the native SHR kidneys (without rejection),almost impossible to ensure equivalent BP exposure of

genetically different kidneys with conventional BP mea- suggesting that it is unlikely that such cellular rejectioncontributed significantly to the quantitated renal damagesurement techniques [13, 15, 17, 26, 27]. The difficulty

is further compounded by the additional potential differ- in either the transplanted SHR or the SHRsp kidneys.For the same reasons, these data also suggest that trans-ences between the compared strains in metabolic and

hormonal factors that can interact with hypertension to plantation associated denervation per se does not sig-nificantly alter the genetic susceptibility to renal damage,promote renal damage. Our experimental design—cross

transplantation using unilaterally nephrectomized recipi- consistent with our previous transplantation studies inthe SHR and Brown Norway rat strains [15]. Theoreti-ents—circumvents these limitations, provided technical

problems related to the transplantation procedure such cally, the alternative strategy of using unilaterally ne-phrectomized F1 hybrids as recipients for both SHR andas stenosis of the vascular anostomotic site can be

Churchill et al: Renal damage in SHRsp 1799

SHRsp kidneys would have avoided the potential prob- involved in the differential susceptibility to hypertensivelem of rejection. However, such a strategy would not renal damage of the SHR and SHRsp kidneys whenhave ensured the simultaneous response to an identical exposed to an identical BP and metabolic milieu. Theo-BP milieu. Conceivably, the BP profiles of F1 recipients retically, such differences may result if systemic pressuresof SHR kidneys could differ from that of F1 recipients of are transmitted to the renal microvasculature to a greaterSHRsp kidneys complicating interpretations of differ- extent in the salt supplemented SHRsp as compared toences in renal damage between SHR and SHRsp kidneys. the SHR (less efficient autoregulatory capacity in the

A greater severity of renal damage to both SHR and SHRsp) [35–38]. Alternatively, there might be geneticSHRsp kidneys was observed in the SHRsp recipients differences in the structural and/or functional character-as compared to that in the SHR recipients. This most istics of the renal vasculature in the SHRsp that renders itlikely is a consequence of the additional exposure to more susceptible to the development of renal damage atmore severe hypertension during the fourth week after any given level of intrarenal pressures, for instance throughthe 8% NaCl diet in the SHRsp recipients. It is of inter- differences in the activity and/or expression of local tissueest, however, that the greater overall renal damage in (cellular) mediators of renal damage [34, 39].the SHRsp as compared to SHR recipients was not paral- Our conclusion that the SHRsp is genetically moreleled by similar differences in proteinuria. In fact, less

susceptible than the SHR to renal damage is intriguingproteinuria was observed in the SHRsp recipients, al-

in the context of several publications. In a segregatingthough the difference was not significant. Such a resultpopulation derived from SHRsp and SHR, Rubattu etis probably not entirely unexpected given the nature ofal, mapped a quantitative trait locus (QTL) for suscepti-renal damage that involves significant injury to preglo-bility to stroke to a region of rat chromosome 1 in themerular vessels resulting in poorly perfused ischemicvicinity of D1Mit3 [8]. We reported increased suscepti-glomeruli distal to the sites of vascular injury. Consistentbility to hypertension induced renal damage in a con-with such an interpretation, the greater renal damagegenic strain of SHR (SHR.BN-D1Mit3/Igf2) versus thein the SHRsp recipients was accompanied by a greaterSHR [40]. This congenic strain is genetically identical tonumber of histologically ischemic glomeruli. The greaterthe SHR except for a 22 cM segment of rat chromosomeincrease in BP by the third week after salt supplementa-1 introgressed from the Brown Norway rat, a strain thattion in the SHRsp recipients as compared to the SHRis genetically more susceptible to hypertensive renalrecipients, despite a similar complement of kidneys, isdamage than the progenitor SHR strains [15]. The seg-more difficult to interpret. It may reflect the greaterment of chromosome 1 trapped in our congenic strainsalt sensitivity of the SHRsp strain [10], and data fromoverlaps with the region that contains the stroke suscep-previous transplantation studies have suggested that the

BP phenotype is influenced by both the kidney and the tibility QTL mapped by Rubattu et al [8]. Both of theserecipient genotype [31, 32]. However, other factors such regions also appear to be in proximity to a segment ofas differential renal damage and/or differential effects chromosome 1 that contains a QTL for renal failureof denervation on SHR and SHRsp kidneys also may mapped by Brown et al in a linkage study of the Fawnhave played a role. Hooded Hypertensive rat [24]. Collectively, these obser-

In our current studies, accelerated renal damage was vations suggest that rat chromosome 1 contains QTLinvestigated in hypertensive rats in which hypertension that increase the risk for vascular damage in a varietywas additionally and rapidly exacerbated by administra- of organs, including the brain and the kidney, and maytion of a high (8%) NaCl diet. We have previously shown play a role in the increased genetic susceptibility ofthat such salt supplementation in the absence of a Japa- SHRsp to renal injury.nese style stroke-prone diet minimizes strokes, but thedifferences in the severity of renal damage between ACKNOWLEDGMENTSSHRsp and SHR are still noted [10]. Although it is possi-

This research was supported by grants from the National Institutesble that the potential BP-independent deleterious effectsof Health (HL64807, HL56608, DK40426, HL18575 and the Office of

of a high NaCl diet [33, 34] may have contributed to the Research and Development, Medical Research Service of the Depart-observed renal damage, the acute disruptive histologic ment of Veterans Affairs. The authors thank Ms. Jennifer Orr Quinn

and Ms. Shilpa Gude for technical assistance and Ms. Martha Pradolesions observed and quantitated were those of malig-for secretarial assistance.nant nephrosclerosis, typical of hypertensive injury [35,

This work is dedicated to the memory of Dr. Paul Churchill, whose36]. These data suggest that at least in the present study, scientific creativity was the driving force behind these experiments andsuch BP independent adverse effects of supplemental whose dedication to research remains a source of inspiration to us all.

salt, if present, are primarily mediated through an en-Reprint requests to Anil K. Bidani, M.D., Department of Internalhancement of the phenotypic expression of hypertensive

Medicine, Loyola/Hines VA Hospital, Mail Slot 151, Hines, Illinoisrenal damage. The present data also do not allow any 60141, USA.

E-mail: Martha.Prado@med.va.govinferences as to the potential intermediate mechanisms

Churchill et al: Renal damage in SHRsp1800

20. Wallenstein S, Zucker CL, Fleiss JJ: Some statistical methodsREFERENCESuseful in circulation research. Circ Res 47:1–9, 1980

21. Rostand SG, Brown G, Kirk KA, et al: Racial differences in the1. Okamoto K, Yamori Y, Nagaoka A: Establishment of the stroke-incidence for end-stage renal disease. N Engl J Med 306:1276–prone spontaneously hypertensive rat (SHR). Circ Res 34/35(Suppl1279, 19821):143–153, 1974

22. Jones CA, Agodoa L: Kidney disease and hypertension in blacks:2. Yamori Y, Nagaoka A, Okamoto K: Importance of genetic factorsScope of the problem. Am J Kidney Dis 21(Suppl 1):6–9, 1993in hypertensive cerebrovascular lesions; an evidence obtained by

23. Freedman BI, Spray BJ, Tubble AB, Buckaley VM: The familialsuccessive selective breeding of stroke-prone and resistant SHR.risk of end-stage renal disease in African-Americans. Am J KidneyJpn Circ J 38:1095–1100, 1974Dis 21:378–393, 19933. Nagaoka A, Iwatsuka H, Suzuoki Z, Okamoto K: Genetic predis-

24. Brown DM, Provoost AP, Daly MJ, et al: Renal disease suscepti-position to stroke in spontaneously hypertensive rats. Am J Physiolbility and hypertension are under independent genetic control in230:1354–1359, 1976the fawn-hooded rat. Nat Genet 12:44–51, 19964. Ogata J, Fujishima M, Tamaki K, et al: Stroke-prone spontane-

25. Freedman BI, Satko SG: Genes and renal disease. Curr Opinously hypertensive rats as an experimental model of malignantNephrol Hypertens 9:273–277, 2000hypertension. A pathological study. Virchows Arch A 394:185–

26. Calhoun DA, Sutao Z, Wyss MJ, Oparil S: Diurnal blood pres-194, 1982sure variation and dietary salt in spontaneously hypertensive rats.5. Yamori Y, Horie R, Tanase H, et al: Possible role of nutritionalHypertens 24:1–7, 1994factors in the incidence of cerebral lesions in stroke-prone sponta-

27. Tanaka M, Schmidlin O, Olson JL, et al: Chloride-sensitive renalneously hypertensive rats. Hypertens 6:49–53, 1984microangiopathy in the stroke-prone spontaneously hypertensive6. Feld LG, VanLiew JB, Galaske RG, Boyland JW: Selectivityrat. Kidney Int 59:1066–1076, 2001of renal injury and proteinuria in the spontaneously hypertensive

28. Churchill M, Churchill PC, Schwartz M, et al: Reversible com-rat. Kidney Int 12:332–343, 1977pensatory hypertrophy in transplanted Brown-Norway rat kidneys.7. Smeda JS: Hemorrhagic stroke development in spontaneously hy- Kidney Int 40:13–20, 1991pertensive rats fed a North-American, Japanese-style diet. Stroke 29. Schwartz MM, Churchill M, Bidani A, Churchill PC: Revers-20:1212–1218, 1989 ible compensatory hypertrophy in rat kidneys: Morphometric char-

8. Rubattu S, Volpe M, Kreutz R, et al: Chromosomal mapping of acterization. Kidney Int 43:610–614, 1993quantitative trait loci contributing to stroke in a rat model of 30. Churchill P, Churchill M, Bidani A, Dunbar J Jr: Streptozo-complex human disease. Nat Genet 13:429–434, 1996 tocin-induced renal hemodynamic changes in isogeneic Lewis rats:

9. Shimamura T, Nakajima M, Iwasaki T, et al: Analysis of circadian A kidney transplant study. Am J Physiol 264:F100–F105, 1993blood pressure rhythm and target-organ damage in stroke-prone 31. Morgan DA, DiBona GF, Mark AL: Effects of interstrain renalspontaneously hypertensive rats. J Hypertens 17:211–220, 1999 transplantation on NaCl-induced hypertension in Dahl rats. Hyper-

10. Griffin KA, Churchill PC, Picken M, et al: Differential salt- tens 15:436–442, 1990sensitivity in the pathogenesis of renal damage in SHR and stroke 32. Churchill PC, Churchill M, Bidani A, Kurtz TW: Kidney spe-prone SHR. Am J Hypertens 14:311–320, 2001 cific chromosome transfer in hypertension: The Dahl hypothesis

11. Weening JJ, Beukers JJB, Grond JD, Elema JD: Genetic factors revisited. Kidney Int 60:705–714, 2001in focal segmental glomerulosclerosis. Kidney Int 29:789–798, 1986 33. Tobian L, Hanlon S: High sodium chloride diets injure arteries

12. Cusi D, Tripodi G, Casari G, et al: Genetics of renal damage in and raise mortality without changing blood pressure. Hypertens15:900–903, 1990primary hypertension. Am J Kidney Disease 21(Suppl 2):2–9, 1993

34. Sanders PW, Gibbs CL, Akhi KM, et al: Increased dietary salt13. Dominiczak AF, Clark JS, Jeffs B, et al: Genetics of experimentalaccelerates chronic allograft nephropathy in rats. Kidney Int 39:hypertension. J Hypertens 16:1859–1869, 19981149–1157, 200114. Matsumoto K, Sakai T, Yamada T, et al: Genetic analysis for

35. Olson JL: Hypertension: Essential and secondary forms, in Heptin-major histocompatibility complex in spontaneously hypertensivestall’s Pathology of the Kidney (5th ed), edited by JC Jennette, JLrat and its control strains. Genet Hypertens 218:329–331, 1992Olson, MM Schwartz, FG Silva, Philadelphia, Lippincott-Raven15. Churchill PC, Churchill MC, Bidani AK, et al: Genetic suscepti-Publishers, 1998, pp 943–1001bility to hypertension-induced renal damage in the rat: Evidence

36. Byrom FB: The Hypertensive Vascular Crisis: An Experimentalbased on kidney-specific genome transfer. J Clin Invest 100:1373–Study. Heinemann Monograph, London, Pittman Press, 19691382, 1997

37. Bidani AK, Schwartz MM, Lewis EJ: Renal autoregulation and16. Churchill M, Kline R, Schwartz M, et al: Kidney transplants vulnerability to hypertensive injury in remnant kidney. Am J Phys-in cyclosporine-treated Sprague Dawley rats. Transplantation 49:8– iol 252:F1003–F1010, 198713, 1990 38. Griffin KA, Picken MM, Bidani AK: Deleterious effects of cal-

17. Bidani AK, Griffin KA, Picken M, Lansky DM: Continuous cium channel blockade on pressure transmission and glomerulartelemetric BP monitoring and glomerular injury in the rat remnant injury in rat remnant kidneys. J Clin Invest 96:798–800, 1995kidney model. Am J Physiol 265:F391–F398, 1993 39. Stier CT Jr, Adler LA, Levine S, Chander PN: Stroke prevention

18. Bidani AK, Griffin KA, Plott W, Schwartz MM: Renal ablation by losartan in stroke-prone spontaneously hypertensive rats. J Hy-acutely transforms ‘benign’ hypertension to ‘malignant’ nephro- pertens 11(Suppl 3):S37–S42, 1993sclerosis in hypertensive rats. Hypertens 24:309–316, 1994 40. St. Lezin E, Griffin KA, Picken M, et al: Genetic isolation of

19. Paul LC, Grothman GT, Benediktsson H, et al: Macrophage a chromosome 1 region affecting susceptibility to hypertension-subpopulations in normal and transplanted heart and kidney tissues induced renal damage in the spontaneously hypertensive rat. Hy-in the rat. Transplantation 53:157–162, 1992 pertens 34:187–191, 1999