AJP - Renal Fuel your research with LabChart
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Renal Physiol 293: F854-F859, 2007. First published June 20, 2007; doi:10.1152/ajprenal.00059.2007
0363-6127/07 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/3/F854    most recent
00059.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zafar, I.
Right arrow Articles by Edelstein, C. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zafar, I.
Right arrow Articles by Edelstein, C. L.

Effect of statin and angiotensin-converting enzyme inhibition on structural and hemodynamic alterations in autosomal dominant polycystic kidney disease model

Iram Zafar, Yunxia Tao, Sandor Falk, Kimberly McFann, Robert W. Schrier, and Charles L. Edelstein

University of Colorado School of Medicine, Denver, Colorado

Submitted 7 February 2007 ; accepted in final form 11 June 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening hereditary disease and is the fourth most common cause of end-stage kidney disease. Preclinical studies to identify effective interventions to prevent or slow progression of PKD nephropathy are therefore direly needed. Heterozygous Han:SPRD rats are an autosomal dominant PKD model with many of the characteristics of ADPKD in humans. In the present study, parameters known to antedate the decrease in renal function, namely, renal structure, renal blood flow (RBF), and mean arterial pressure (MAP), were evaluated with three different interventions, namely, HMG-CoA reductase inhibition with lovastatin, angiotensin-converting enzyme (ACE) inhibition with enalapril, and a combination of these two treatments. The statin therapy demonstrated structural and functional benefits, including increased RBF and decreased BUN, independently of a change in MAP, while the ACE inhibition therapy demonstrated structural benefit in association with a decrease in MAP. An enhancement of these protective interventions in this autosomal dominant PKD model was not demonstrated with the combined treatment.

renal blood flow; renal structure; blood pressure

A DECREASE IN RENAL BLOOD flow (RBF) by magnetic resonance imaging recently has been shown in patients with ADPKD to parallel the increase in total kidney volume and to precede the decline in glomerular filtration rate (GFR) (27). In a double-blind crossover study in 10 normocholesterolemic ADPKD patients, treatment for 4 wk with 40 mg simvastatin vs. placebo demonstrated an increase in RBF and GFR (30). Other HMG-CoA reductase inhibitors (i.e., statins) have been shown in animal models to ameliorate progression of nephropathy and to increase RBF (1, 12). The statin, cerivastatin, decreased blood pressure, serum creatinine, and albuminuria in rats transgenic for human renin and angiotensin with hypertension, cardiac hypertrophy, renal damage, and marked albuminuria (20).

There is considerable evidence that the renin-angiotensin system (RAS) is activated in ADPKD patients. The plasma renin and aldosterone responses to posture and angiotensin-converting enzyme (ACE) inhibition were greater in ADPKD patients than patients with essential hypertension of comparable age, gender, blood pressure, renal function, and urinary sodium excretion (3). Angiotensinogen, ACE, angiotensin II type I (AT1) receptor, and angiotensin II have been found within cysts and tubules of ADPKD kidneys, thus implicating intrarenal RAS (19). Immunoreactive renin also has been found in tubules and cyst fluid of ADPKD kidneys (26).

The effect of statin therapy with lovastatin to diminish the severity of renal disease in an autosomal dominant model of polycystic kidney disease, male Han:SPRD rats, has been reported (11). The effect of statin therapy on mean arterial pressure (MAP) and RBF in this model has, however, not been reported. It is also not known whether the effect of statin therapy occurs by modulation of the RAS or by an independent pathway. The present study, therefore, has focused on the effect of HMG-CoA reductase inhibition with lovastatin on MAP, RBF, GFR, kidney volume, and cyst density in the Han:SPRD rats compared with ACE inhibition with enalapril. The combination of statin and ACE inhibition on renal function and structure was also examined.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals. The study was conducted in heterozygous (Cy/+) and normal littermate control (+/+) Han:SPRD rats. All the normal rats and Cy/+ rats studied were males. The Cy/+ Han:SPRD rat develops clinically detectable polycystic kidney disease by 8 wk of age, as evidenced by a doubling of kidney size and kidney failure compared with +/+ control rats (4, 22). A colony of Han:SPRD rats was established in our animal care facility from a litter that was obtained from the Polycystic Kidney Program at the University of Kansas Medical Center. The study protocol was approved by the University of Colorado Health Sciences Center Animal Care and Use Committee. Rats had free access to tap water and standard rat chow.

Experimental protocol. Male Cy/+ and +/+ rats were weaned at 3 wk of age and then divided into three groups. Group 1 was treated with either lovastatin (4 mg·kg–1·day–1 sc) or vehicle (100% ethanol). Group 2 was treated with enalapril (50 mg/l) in the drinking water or drinking water that did not contain enalapril. Water intake was monitored. The mean water intake for each rat for the 5-wk duration of the study was 817 ± 19 ml. Thus the mean dose of enalapril per rat for the 5-wk period was 40.8 mg. Group 3 was treated with lovastatin (4 mg·kg–1·day–1 sc) and enalapril (50 mg/l) in the drinking water and the vehicle for both lovastatin and enalapril. Treatments were for 5 wk from 3 to 8 wk of age. In all the studies, littermates were used as controls. Lovastatin was obtained from Merck Sharp & Dohme Research Laboratories (Rahway, NJ). The dose of lovastatin was based on rat studies in ADPKD (11), experimental nephrotic syndrome (13), and tissue selectivity studies in rats in vivo. Enalapril was obtained from Sigma (St. Louis, MO). The dose of enalapril used has a significant antihypertensive effect in rats 3–12 wk of age (15, 18). At the end of the 8 wk of age, rats were anesthetized by an intraperitoneal injection of pentobarbital sodium (50 mg/kg body wt) and subjected to blood pressure and RBF studies before the kidneys were removed and weighed. The left kidney was fixed in 4% paraformaldehyde in PBS for 120 min and then put into 70% ethanol and embedded in paraffin for histological examinations.

Cyst volume density. Hematoxylin-eosin-stained sections were used to determine the cyst volume density. This was performed by a reviewer, blinded to the identity of the treatment modality, using point-counting stereology (5). Areas of the cortex at 90, 180, and 270° from the hilum of each section were selected to guard against field selection variation.

Chemistry. Blood urea nitrogen (BUN) levels were measured using a Beckman autoanalyzer (Beckman Instruments, Fullerton, CA).

Blood pressure and RBF. Blood pressure was measured by cannulation of the femoral artery (31). RBF was measured with a Transonic flow probe placed around the main renal artery (31). Briefly, the animals were anesthetized with pentobarbital sodium and placed on a thermostatically controlled surgical table. A tracheotomy was performed, at which time a steady steam of 100% oxygen was blown over the tracheal tube throughout the experiment. Catheters (custom pulled from PE-250) were placed in the jugular vein for maintenance infusion and the carotid artery for blood pressure determinations. The kidney was exposed by a left subcostal incision and was dissected free from perirenal tissue, and renal arteries were isolated for the determination of RBF using a blood flowmeter and probe (0.5v; Transonic Systems, Ithaca, NY) as described by Traynor and Schnermann (29). MAP was measured via a femoral artery catheter connected to a Transpac IV transducer and monitored continuously using Windaq Waveform recording software (Dataq Instruments).

Statistical analysis. Data were analyzed in two ways. 1) In three individual experiments a one-way ANOVA was used with a posttest according to Newman-Keuls (see Figs. 1–4): PKD plus vehicle for lovastatin, PKD plus lovastatin, and normal littermate controls; PKD plus vehicle for enalapril, PKD plus enalapril, and normal littermate controls; and PKD plus vehicles for both lovastatin and enalapril, PKD plus the combination of lovastatin and enalapril therapy, and normal littermate controls. 2) Experiments were combined to create a 2 x 2 factorial design. After the data from the three separate experiments from the PKD rats only (lovastatin vs. vehicle, enalapril vs. vehicle, and lovastatin+enalapril vs. vehicle) were combined, a two-way ANOVA was performed with lovastatin at two levels: "yes" or "no" and enalapril at two levels, yes or no. The Tukey-Kramer P value adjustment was used for post hoc multiple comparisons.


Figure 1
View larger version (10K):
[in this window]
[in a new window]

  		Fig. 1. Lovastatin therapy in polycystic kidney disease (PKD). Lovastatin significantly reduced percentage of kidney weight per body weight [2K/TBW(%)], cyst volume density, and blood urea nitrogen (BUN) and significantly increased renal blood flow (RBF) in PKD rats (n = 3–6/group). NS, not significant.

 

Figure 4
View larger version (10K):
[in this window]
[in a new window]

  		Fig. 4. Combination lovastatin and enalapril therapy in PKD. Combination therapy with the ACEI enalapril and lovastatin significantly reduced 2K/TBW(%), cyst volume density, and BUN in PKD rats. The combination therapy significantly increased RBF (n = 3–6/group).

 
In both analyses, a P value of <0.05 was considered statistically significant. Values are expressed as means ± SE.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Lovastatin therapy in PKD. Treatment of the PKD rats from 3 to 8 wk of age with lovastatin (4 mg·kg–1·day–1 sc) vs. vehicle was associated with significant differences (Fig. 1). The percent increase in weight of both kidneys corrected for body weight was significantly less in the lovastatin-treated animals compared with the vehicle-treated animals. Similarly, lovastatin treatment decreased the percentage of cyst volume density compared with the vehicle-treated PKD animals. This beneficial effect of lovastatin on cystic kidneys was only partial, since the kidney weights and cyst volume density percentages in the lovastatin-treated PKD animals were still greater than those same parameters in the littermate controls.

The effect of lovastatin on kidney structure was accompanied by a significant increase in RBF compared with vehicle-treated PKD rats. These hemodynamic and structural benefits were associated with a significant decrease in BUN in the lovastatin-treated PKD rats. The structural, functional, and RBF results occurred in the absence of differences in MAP (Fig. 2A) and body weight (data not shown).


Figure 2
View larger version (11K):
[in this window]
[in a new window]

  		Fig. 2. Mean arterial pressure (MAP; mmHg). Lovastain therapy did not have a significant effect on MAP (A). Angiotensin-converting enzyme inhibitor (ACEI; enalapril) therapy (B) and a combination of ACEI and lovastatin therapy (C) significantly reduced MAP in PKD rats.

 
Enalapril therapy in PKD. ACE inhibition in the PKD rats from 3 to 8 wk of age with enalapril was associated with a decrease in percentage of kidney weight per body weight and cyst volume density (Fig. 3). In contrast to lovastatin treatment, these differences in kidney structure with enalapril treatment were not associated with significant differences in BUN and RBF. There was, however, a significant decrease in MAP in the enalapril-treated PKD animals compared with the untreated PKD rats and littermates (Fig. 2B). There were no differences in body weight (data not shown).


Figure 3
View larger version (10K):
[in this window]
[in a new window]

  		Fig. 3. Enalapril therapy in PKD. The ACEI enalapril significantly reduced 2K/TBW(%) and cyst volume density in PKD rats. Enalapril did not have a significant effect on BUN and RBF (n = 4–8/group).

 
Lovastatin and enalapril therapy in PKD. Since the structural changes in PKD of lovastatin and enalapril were associated with different effects on RBF and MAP, the combination of these two therapeutic approaches was examined (Fig. 4). The combination therapy significantly decreased the percentage of kidney weight per body weight and cyst volume density. The significant decrease in BUN persisted with the combined therapy, but a significant increase in RBF was not observed. MAP was significantly decreased with the combined therapy (Fig. 2C). Body weight was significantly lower in the combined vs. vehicle treatment group (282 ± 12 vs. 223 ± 9 g, P < 0.01).

Two-way ANOVA. A two-way ANOVA was performed with lovastatin at two levels: yes or no and enalapril at two levels, yes or no. The following four groups were analyzed: 1) PKD rats (Cy/+), no treatment; 2) PKD rats, enalapril; 3) PKD rats, lovastatin; and 4) PKD rats, enalapril and lovastatin.

There was a significant main effect of lovastatin (P = 0.0334) and a main effect of enalapril (P = 0.0041) on the percentage of kidney weight per body weight, but no interaction effect (P = 0.1093). There was a near-significant main effect of lovastatin (P = 0.0611), but no main effect of enalapril (P = 0.2100) on body weight, and no interaction effect (P = 0.1571). There was no main effect of lovastatin (P = 0.0975), but a strong main effect of enalapril (P < 0.0001) on MAP, but no interaction effect (P = 0.2675). There was a main effect of lovastatin (P = 0.0158) and a main effect of enalapril (P = 0.0037) on BUN, but no interaction effect (P = 0.5278). There was a main effect of lovastatin (P = 0.0414), but no main effect of enalapril (P = 0.5773) on RBF, and no interaction effect (P = 0.9274). There was a near-significant main effect of lovastatin (P = 0.0614) and a near-significant main effect of enalapril (P = 0.0582) on cyst volume density, as well as an interaction effect (P = 0.0074) on cyst volume density. After an adjustment for multiple comparisons, treatment with lovastatin (18.7 ± 0.5, P = 0.0040), enalapril (18.7 ± 2.0, P = 0.0039), or lovastatin+enalapril (21.1 ± 5.5, P = 0.0220) lowered cyst volume density compared with no treatment (30.7 ± 1.1). Thus there was no synergistic effect of the combination of lovastatin and enalapril on cyst volume density.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
ADPKD is the most common life-threatening hereditary disease affecting from 1–400 in 1,000 Americans (8). ADPKD is more common than cystic fibrosis, sickle cell disease, Huntington's chorea, Down's syndrome, and myotonic dystrophy combined. Preclinical studies to detect potential interventions that will slow the progression of ADPKD to end-stage renal disease (ESRD) are, therefore, very important.

ADPKD is the fourth most common cause of ESRD in this country. There are no perfect animal models of ADPKD; however, the heterozygous Han:SPRD rat model is widely used and has several features which mimic ADPKD in humans (22). This animal model has autosomal dominant inheritance, progresses slowly to ESRD with hypertension and uremia, exhibits interstitial fibrosis and inflammation, and is more aggressive in male animals.

The progression of renal disease and hypertension in ADPKD in both children and adults is associated with increases in kidney volume and cystic volume density (10, 19, 25). These structural changes were, therefore, examined in the present study. The HMG-CoA reductase inhibitor lovastatin had been previously used in this autosomal dominant male PKD model because of its antiproliferative and anti-inflammatory effects which occur independently of effects on cholesterol. The current results confirm the effect of lovastatin to significantly decrease the kidney weight, cyst volume density, and BUN after early treatment from 3 to 8 wk after birth. Early treatment is relevant, since ADPKD is clinically apparent in children as evidenced by increased renal volume, blood pressure, and left ventricular mass index (8).

Since progression of ADPKD nephropathy correlates not only with renal structural and functional changes but also with blood pressure and RBF, the effects of these hemodynamic parameters were examined in the present study. There was no effect of lovastatin on MAP despite the above beneficial results. Of interest, however, was the effect of lovastatin to significantly increase RBF in this autosomal PKD model. As with most preventive interventions, intervention in ADPKD to slow or prevent progression of nephropathy may best occur before a decrease in GFR or rise in BUN. Increased kidney and cyst volumes by magnetic resonance imaging (2), an increase in RBF by magnetic resonance angiography (27), and hypertension (7, 17, 23) have emerged in ADPKD as early predictors of progression, before a decrease in GFR. Thus monitoring renal structure changes, MAP, and RBF in preclinical intervention trials is important. The current study is the first to report the effects of statin therapy on MAP and RBF on this model of ADPKD.

Since ADPKD is a variety of benign neoplasia, combination therapies may be necessary to aggressively thwart renal progression. In this regard, combination therapy with lisinopril and simvastatin was used in a rat model of passive Heymann nephritis (34). In this study, combination therapy significantly limited glomerulosclerosis, tubular damage, and interstitial inflammation compared with vehicle or the individual drugs alone. As noted below, the combination of enalapril and lovastatin therapy in the present study did not have an enhanced effect on PKD compared with the individual drugs alone.

The RAS, along with sodium retention, has been shown to be involved in the early hypertension in ADPKD (3, 28, 32). Moreover, inhibition of the RAS with ACE inhibition has been shown in prospective, randomized studies to better reverse left ventricular hypertrophy (24) and decreased urinary albumin excretion (6) in ADPKD patients than calcium channel blockers at comparable effects on blood pressure. A meta-analysis has shown to have a beneficial effect of ACE inhibition on renal progression in patients with baseline protein excretion rates of 1 g/day or greater (14). Studies of RAS inhibition on renal progression in the Han:SPRD rat, however, are conflicting. The ACE inhibitor enalapril and angiotensin receptor blocker losartan were shown to decrease kidney weight, histology score, and serum creatinine compared with hydralazine treatment in Han:SPRD rats (15). However, the MAP values were much lower in the enalapril and losartan than hydralazine treatment groups. Another study using early treatment with the ACE inhibitor cilazapril demonstrated a significant decrease in blood pressure, serum creatinine, and renal cyst volume in this autosomal model of PKD (21). In contrast, however, another study was unable to observe an effect on renal progression, as assessed by serum urea concentration, in Han:SPRD rats with enalapril treatment (33). The ACE inhibition treatment was, however, started later in these studies, and surprisingly no effect of enalapril on blood pressure was observed. In the current study, the same dose of enalapril (50 mg/l drinking water) was shown to significantly decrease MAP whether administered alone or with lovastatin. In the present study, MAP was measured by direct arterial cannulation vs. tail plethysmography in the previous study (33). ACE inhibition in the current study demonstrated a significantly decreased kidney weight and cyst volume density but not BUN. RBF was not increased with enalapril treatment. Thus, in the ADPKD model the functional benefit, as assessed by BUN, was better with statin than ACE inhibition treatment.

The effects of the two agents on PKD structure were comparable. The effects of lovastatin to decrease kidney weight, cyst volume density, BUN, and to increase RRF were sustained when combined with enalapril. The effect of enalapril to decrease MAP was sustained when combined with lovastatin, but combined therapy did not enhance the effect on renal structure. Currently, an National Institutes of Health-funded, prospective, randomized study comparing ACE inhibition vs. ACE inhibition plus statin therapy in ADPKD children on renal function, albuminuria, endothelial function, and left ventricular mass index has been initiated.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
The study was funded by a grant from the Polycystic Kidney Disease Foundation and National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-34039.


   ACKNOWLEDGMENTS
 
The excellent editorial assistance of Jan Darling is acknowledged.


   FOOTNOTES
 

Address for reprint requests and other correspondence: R. W. Schrier, Univ. of Colorado School of Medicine, 4200 East Ninth Ave., B173, Denver, CO 80262 (e-mail: robert.schrier{at}uchsc.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Buemi M, Senatore M, Corica F, Aloisi C, Romeo A, Cavallaro E, Floccari F, Tramontana D, Frisina N. Statins and progressive renal disease. Med Res Rev 22: 76–84, 2002.[CrossRef][ISI][Medline]
  2. Chapman AB, Guay-Woodford LM, Grantham JJ, Torres VE, Bae KT, Baumgarter DA, Kenney PJ, King BF Jr, Glockner JF, Wetzel LH, Brummer ME, O'Neill WC, Robbin ML, Bennett WM, Klahr S, Hirschman GH, Kimmel PL, Thompson PA, Miller JP. Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort. Kidney Int 64: 1035–1045, 2003.[CrossRef][ISI][Medline]
  3. Chapman A, Johnson A, Gabow P, Schrier RW. The renin-angiotensin-aldosterone system and autosomal dominant polycystic kidney disease. N Engl J Med 323: 1091–1096, 1990.[Abstract]
  4. Cowley BD Jr, Gudapaty S, Kraybill AL, Barash BD, Harding MA, Calvet JP, Gattone VH. Autosomal-dominant polycystic kidney disease in the rat. Kidney Int 43: 522–534, 1993.[ISI][Medline]
  5. Cowley BD Jr, Rupp JC, Muessel MJ, Gattone VH 2nd. Gender and the effect of gonadal hormones on the progression of inherited polycystic kidney disease in rats. Am J Kidney Dis 29: 265–272, 1997.[ISI][Medline]
  6. Ecder T, Chapman AB, Brosnahan GM, Edelstein CL, Johnson AM, Schrier RW. Effect of antihypertensive therapy on renal function and urinary albumin excretion in hypertensive patients with autosomal dominant polycystic kidney disease. Am J Kidney Dis 35: 427–432, 2000.[ISI][Medline]
  7. Ecder T, Schrier RW. Hypertension in autosomal-dominant polycystic kidney disease: early occurrence and unique aspects. J Am Soc Nephrol 12: 194–200, 2001.[Free Full Text]
  8. Ecder T, Fick-Brosnahan G, Schrier RW.Polycystic kidney disease. In: Diseases of the Kidney and Urinary Tract, edited by Schrier RW. Philadelphia, PA: Lippincott Williams and Wilkins, 2006.
  9. Fick-Brosnahan G, Belz M, McFann K, Johnson A, Schrier RW. Relationship between renal volume growth and renal function in autosomal dominant polycystic kidney disease: a longitudinal study. Am J Kidney Dis 39: 1127–1134, 2002.[CrossRef][ISI][Medline]
  10. Gabow PA, Johnson AM, Kaehny WD, Kimberling WJ, Lezotte DC, Duley IT, Jones RH. Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease. Kidney Int 41: 1311–1319, 1992.[ISI][Medline]
  11. Gile RD, Cowley BD, Gattone VH, O'Donnell MP, Swan SK, Grantham JJ. Effect of lovastatin on the development of polycystic kidney disease in the Han:SPRD rat. Am J Kidney Dis 26: 501–507, 1995.[ISI][Medline]
  12. Glazer AA, Inman SR, Stowe NT, Novick AC. Renal microcirculatory effects of lovastatin in a rat model of reduced renal mass. Urology 50: 812–817, 1997.[CrossRef][ISI][Medline]
  13. Harris KP, Purkerson ML, Yates J, Klahr S. Lovastatin ameliorates the development of glomerulosclerosis and uremia in experimental nephrotic syndrome. Am J Kidney Dis 15: 16–23, 1990.[ISI][Medline]
  14. Jafar T, Stark P, Schmid C, Strandgaard S, Kamper AL, Maschio G, Backer G, Perrone R, Levey A, for the ACE Inhibition in Progressive Renal Disease (AIPRD) Study Group. The effect of angiotensin-converting-enzyme inhibitors on progression of advanced polycystic kidney disease. Kidney Int 67: 265–271, 2005.[CrossRef][ISI][Medline]
  15. Keith DS, Torres VE, Johnson CM, Holley KE. Effect of sodium chloride, enalapril, and losartan on the development of polycystic kidney diseases in Han: SPRD rats. Am J Kidney Dis 24: 491–498, 1994.[ISI][Medline]
  16. Kelleher CL, McFann KK, Johnson AM, Schrier RW. Characteristics of hypertension in young adults with autosomal dominant polycystic kidney disease compared with the US population. Am J Hypertens 17: 1029–1034, 2004.[CrossRef][ISI][Medline]
  17. Kennefick TM, Al-Nimri MA, Oyama TT, Thompson MM, Kelly FJ, Chapman JG, Anderson S. Hypertension and renal injury in experimental polycystic kidney disease. Kidney Int 56: 2181–2190, 1999.[CrossRef][ISI][Medline]
  18. Loghman-Adham M, Soto CE, Inagami T, Cassis L. The intrarenal renin-angiotensin system in autosomal dominant polycystic kidney disease. Am J Physiol Renal Physiol 287: F775–F788, 2004.[Abstract/Free Full Text]
  19. Park JK, Muller DN, Mervaala EM, Dechend R, Fiebeler A, Schmidt F, Bieringer M, Schafer O, Lindschau C, Schneider W, Ganten D, Luft FC, Haller H. Cerivastatin prevents angiotensin II-induced renal injury independent of blood pressure- and cholesterol lowering effects. Kidney Int 58: 1420–1430, 2000.[CrossRef][ISI][Medline]
  20. Ogborn M, Sareen S, Pinette Gilles. Cilazapril delays progression of hypertension and uremia in rat polycystic kidney disease. Am J Kidney Dis 26: 942–946, 1995.[ISI][Medline]
  21. Schafer K, Gretz N, Bader M, Oberbaumer I, Eckardt KU, Kriz W, Bachmann S. Characterization of the Han:SPRD rat model for hereditary polycystic kidney disease. Kidney Int 46: 134–152, 1994.[ISI][Medline]
  22. Schrier RW. Optimal care of autosomal dominant polycystic kidney disease patients. Nephrology 11: 124–130, 2006.[CrossRef][Medline]
  23. Schrier RW, McFann K, Johnson A, Chapman A, Edelstein CL, Brosnahan G, Ecder T, Tison L. Cardiac and renal effects of standard versus rigorous blood pressure control in autosomal-dominant polycystic kidney disease: results of a seven-year prospective randomized study. J Am Soc Nephrol 13: 1733–1739, 2002.[Abstract/Free Full Text]
  24. Shamshirsaz AA, Bekheirnia MR, Kamgar M, Johnson AM, McFann K, Cadnapaphornchai MA, Nobakthaghighi N, Schrier RW. Autosomal dominant polycystic kidney disease in infancy and childhood: progression and outcome. Kidney Int 68: 2218–2224, 2005.[CrossRef][ISI][Medline]
  25. Torres VE, Donovan KA, Scicli G, Holley KE, Thibodeau SN, Carretero OA, Inagami T, McAteer JA, Johnson CM. Synthesis of renin by tubulocystic epithelium in autosomal dominant polycystic kidney disease. Kidney Int 42: 364–373, 1992.[ISI][Medline]
  26. Torres V, King B, Chapman A, Brummer M, Bae Glockner J, Arya K, Risk D, Felmlee J, Grantham J, Guay-Woodford L, Bennett W, Klahr Meyers C S, Zhang X, Thompson P, Miler J, and the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP). Magnetic resonance measurements of renal blood flow and disease progression in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2: 112–120, 2007.[Abstract/Free Full Text]
  27. Torres VE, Wilson DM, Burnett JC Jr, Johnson CM, Offord KP. Effect of inhibition of converting enzyme on renal hemodynamics and sodium management in polycystic kidney disease. Mayo Clin Proc 66: 1010–1017, 1991.[ISI][Medline]
  28. Traynor TR, Schnermann J. Renin-angiotensin system dependence of renal hemodynamics in mice. J Am Soc Nephrol 10, Suppl 11: S184–S188, 1999.[ISI][Medline]
  29. Van Dijk M, Kamper A, van Veen S, Souverign J, Blauw G. Effect of simvastatin on renal function in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 16: 2152–2157, 2001.[Abstract/Free Full Text]
  30. Wang W, Falk Jittikanont S, Gengaro P, Edelstein CL, Schrier RW. Protective effect of renal denervation on normotensive endotoxemia-induced acute renal failure (ARF) in mice. Am J Physiol Renal Physiol 283: F583–F587, 2002.[Abstract/Free Full Text]
  31. Watson ML, Macnicol AM, Allan PL, Wright AF. Effects of angiotensin converting enzyme inhibition in adult polycystic kidney disease. Kidney Int 41: 206–210, 1992.[ISI][Medline]
  32. Zeier M, Pohlmeyer G, Deeerberg F, Schönherr R, Ritz E. Progression of renal failure in the Han:SPRD polycystic kidney rat. Nephrol Dial Transplant 9: 1734–1739, 1994.[Abstract/Free Full Text]
  33. Zoja C, Corna D, Rottoli D, Cattaneo D, Zanchi C, Tomasoni S, Abbate M, Remuzzi G. Effect of combining ACE inhibitor and statin in severe experimental nephropathy. Kidney Int 61: 1635–1645, 2002.[CrossRef][ISI][Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/3/F854    most recent
00059.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zafar, I.
Right arrow Articles by Edelstein, C. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zafar, I.
Right arrow Articles by Edelstein, C. L.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2007 by the American Physiological Society.