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• W1997592103 abstract "We have bred a Pkd1 floxed allele with a nestin-Cre expressing line to generate cystic mice with preserved glomerular filtration rate to address the pathogenesis of complex autosomal dominant polycystic kidney disease (ADPKD) phenotypes. Hypertension affects about 60% of these patients before loss of renal function, leading to significant morbimortality. Cystic mice were hypertensive at 5 and 13 weeks of age, a phenotype not seen in noncystic controls and Pkd1-haploinsufficient animals that do not develop renal cysts. Fractional sodium excretion was reduced in cystic mice at these ages. Angiotensinogen gene expression was higher in cystic than noncystic kidneys at 18 weeks, while ACE and the AT1 receptor were expressed in renal cyst epithelia. Cystic animals displayed increased renal cAMP, cell proliferation, and apoptosis. At 24 weeks, mean arterial pressure and fractional sodium excretion did not significantly differ between the cystic and noncystic groups, whereas cardiac mass increased in cystic mice. Renal concentrating deficit is also an early finding in ADPKD. Maximum urine osmolality and urine nitrite excretion were reduced in 10–13- and 24-week-old cystic mice, deficits not found in haploinsufficient and noncystic controls. A trend of higher plasma vasopressin was observed in cystic mice. Thus, cyst growth most probably plays a central role in early-stage ADPKD-associated hypertension, with activation of the intrarenal renin–angiotensin system as a key mechanism. Cyst expansion is also likely essential for the development of the concentrating deficit in this disease. Our findings are consistent with areas of reduced perfusion in the kidneys of patients with ADPKD. We have bred a Pkd1 floxed allele with a nestin-Cre expressing line to generate cystic mice with preserved glomerular filtration rate to address the pathogenesis of complex autosomal dominant polycystic kidney disease (ADPKD) phenotypes. Hypertension affects about 60% of these patients before loss of renal function, leading to significant morbimortality. Cystic mice were hypertensive at 5 and 13 weeks of age, a phenotype not seen in noncystic controls and Pkd1-haploinsufficient animals that do not develop renal cysts. Fractional sodium excretion was reduced in cystic mice at these ages. Angiotensinogen gene expression was higher in cystic than noncystic kidneys at 18 weeks, while ACE and the AT1 receptor were expressed in renal cyst epithelia. Cystic animals displayed increased renal cAMP, cell proliferation, and apoptosis. At 24 weeks, mean arterial pressure and fractional sodium excretion did not significantly differ between the cystic and noncystic groups, whereas cardiac mass increased in cystic mice. Renal concentrating deficit is also an early finding in ADPKD. Maximum urine osmolality and urine nitrite excretion were reduced in 10–13- and 24-week-old cystic mice, deficits not found in haploinsufficient and noncystic controls. A trend of higher plasma vasopressin was observed in cystic mice. Thus, cyst growth most probably plays a central role in early-stage ADPKD-associated hypertension, with activation of the intrarenal renin–angiotensin system as a key mechanism. Cyst expansion is also likely essential for the development of the concentrating deficit in this disease. Our findings are consistent with areas of reduced perfusion in the kidneys of patients with ADPKD. Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic life-threatening disease, with an estimated prevalence of 1:400–1000.1Torres V.E. Harris P.C. Autosomal dominant polycystic kidney disease: the last 3 years.Kidney Int. 2009; 76: 149-168Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar By the age of 60 years, more than half of the patients reach end-stage renal disease.2Reed B.Y. McFann K. Bekheirnia M.R. et al.Variation in age at ESRD in autosomal dominant polycystic kidney disease.Am J Kidney Dis. 2008; 51: 173-183Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Although mutations in one of two genes, PKD1 (polycystic kidney disease 1) or PKD2 (polycystic kidney disease 2), cause this disorder, ∼85% of the cases are linked to the PKD1 locus.3Rossetti S. Consugar M.B. Chapman A.B. et al.Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 2007; 18: 2143-2160Crossref PubMed Scopus (327) Google Scholar Mutations in PKD1, in turn, are usually associated with a more severe phenotype than PKD2.4Hateboer N. van Dijk M.A. Bogdanova N. et al.Comparison of phenotypes of polycystic kidney disease types 1 and 2.Lancet. 1999; 353: 103-107Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar,5Dicks E. Ravani P. Langman D. et al.Incident renal events and risk factors in autosomal dominant polycystic kidney disease: a population and family-based cohort followed for 22 years.Clin J Am Soc Nephrol. 2006; 1: 710-717Crossref PubMed Scopus (59) Google Scholar Although most patients seek medical attention because of kidney manifestations, ADPKD is a systemic illness and includes extrarenal phenotypes most often represented by liver cysts, intracranial aneurysms, and heart valve abnormalities.6Pirson Y. Extrarenal manifestations of autosomal dominant polycystic kidney disease.Adv Chronic Kidney Dis. 2010; 17: 173-180Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar The pathogenesis of critical and complex phenotypes is still unresolved in ADPKD. Systemic arterial hypertension (SAH) is one of the most common findings in this disorder, occurring in ∼60% of cases before a significant loss of renal function,7Ecder T. Schrier R.W. Cardiovascular abnormalities in autosomal dominant polycystic kidney disease.Nat Rev Nephrol. 2009; 5: 221-228Crossref PubMed Scopus (161) Google Scholar and 10 years earlier than in the general population.8Kelleher C.L. McFann K.K. Johnson A.M. et al.Characteristics of hypertension in young adults with autosomal dominant polycystic kidney disease compared with the general U.S. population.Am. J. Hypertens. 2004; 17: 1029-1034Crossref PubMed Scopus (88) Google Scholar SAH is a major risk factor for cardiovascular disease and accounts for significant morbidity and mortality in this patient population.9Oflaz H. Alisir S. Buyukaydin B. et al.Biventricular diastolic dysfunction in patients with autosomal-dominant polycystic kidney disease.Kidney Int. 2005; 68: 2244-2249Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar,10Johnson A.M. Gabow P.A. Identification of patients with autosomal dominant polycystic kidney disease at highest risk for end-stage renal disease.J Am Soc Nephrol. 1997; 8: 1560-1567PubMed Google Scholar The mechanisms involved in ADPKD-associated hypertension, however, are not completely understood, although renal abnormalities influence its genesis and maintenance.11Chapman A.B. Stepniakowski K. Rahbari-Oskoui F. Hypertension in autosomal dominant polycystic kidney disease.Adv Chronic Kidney Dis. 2010; 17: 153-163Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar It is currently thought that activation of the renin–angiotensin system (RAS), in response to cyst expansion and secondary vascular compression, plays a central role in the development of hypertension in this disease.7Ecder T. Schrier R.W. Cardiovascular abnormalities in autosomal dominant polycystic kidney disease.Nat Rev Nephrol. 2009; 5: 221-228Crossref PubMed Scopus (161) Google Scholar,11Chapman A.B. Stepniakowski K. Rahbari-Oskoui F. Hypertension in autosomal dominant polycystic kidney disease.Adv Chronic Kidney Dis. 2010; 17: 153-163Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar This model, however, has not been proven yet. Additional data suggest that lower levels of nitric oxide (NO) as a result of ADPKD-associated endothelial dysfunction12Wang D. Iversen J. Wilcox C.S. et al.Endothelial dysfunction and reduced nitric oxide in resistance arteries in autosomal-dominant polycystic kidney disease.Kidney Int. 2003; 64: 1381-1388Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar contribute to increased angiotensin II generation through a local increase in oxidative stress. In addition, reduced cardiac relaxation that is typically associated with this disorder may lead to a reduction in renal blood flow and increase in angiotensin II formation.11Chapman A.B. Stepniakowski K. Rahbari-Oskoui F. Hypertension in autosomal dominant polycystic kidney disease.Adv Chronic Kidney Dis. 2010; 17: 153-163Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar The ADPKD renal phenotype is also classically associated with a concentrating deficit, one of the earliest manifestations of the disease.13Martinez-Maldonado M. Yium J.J. Eknoyan G. et al.Adult polycystic kidney disease: studies of the defect in urine concentration.Kidney Int. 1972; 2: 107-113Abstract Full Text PDF PubMed Scopus (55) Google Scholar This abnormality is usually mild and not associated with polyuria or polydipsia, but can be detected in childhood.14Fick G.M. Duley I.T. Johnson A.M. et al.The spectrum of autosomal dominant polycystic kidney disease in children.J Am Soc Nephrol. 1994; 4: 1654-1660PubMed Google Scholar The pathogenesis of this concentrating defect is not known, but disruption of the corticomedullary architecture because of cyst growth, a principal cell defect, and/or development of tubulointerstitial alterations have been proposed as possible causes. These first and third mechanisms, however, are not consistent with its early presentation.15Torres V.E. Vasopressin antagonists in polycystic kidney disease.Kidney Int. 2005; 68: 2405-2418Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Previous data exclude a central nervous cause, as vasopressin levels have been found to be high in ADPKD patients.15Torres V.E. Vasopressin antagonists in polycystic kidney disease.Kidney Int. 2005; 68: 2405-2418Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Increased plasma vasopressin in this illness16Danielsen H. Nielsen A.H. Pedersen E.B. et al.Exaggerated natriuresis in adult polycystic kidney disease.Acta Med Scand. 1986; 219: 59-66Crossref PubMed Scopus (15) Google Scholar,17Michalski A. Grzeszczak W. The effect of hypervolemia on electrolyte level and level of volume regulating hormones in patients with autosomal dominant polycystic kidney disease.Pol Arch Med Wewn. 1996; 96: 329-343PubMed Google Scholar has been postulated to contribute to the degree of hypertension. Notably, the observation that aquaporin-2 is upregulated in animal models of polycystic kidneys, as opposed to what is seen in the central and most nephrogenic forms of diabetes insipidus, suggests that the abnormality is positioned distally to the synthesis of this molecule.18Gattone 2nd, V.H. Wang X. Harris P.C. et al.Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist.Nat Med. 2003; 9: 1323-1326Crossref PubMed Scopus (522) Google Scholar,19Torres V.E. Wang X. Qian Q. et al.Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease.Nat Med. 2004; 10: 363-364Crossref PubMed Scopus (398) Google Scholar In order to test whether cystic disease is the principal determinant of hypertension and the concentrating defects, we have extensively evaluated and characterized these complex phenotypes in two independent PKD1 orthologous mouse models. We found that Pkd1-haploinsufficient animals were normotensive and had normal concentrating capacity, whereas cystic animals were hypertensive at the ages of 5 and 13 weeks, showed increased kidney expression of RAS components, and exhibited concentrating defects at 10–13 and 24 weeks of age. These findings suggest that cyst formation is critical for the pathogenesis of both these classic manifestations of ADPKD and that RAS activation plays a significant role in the pathogenesis of hypertension in this disorder. We have used two Pkd1-deficient mouse models in the current work. Using a Pkd1 floxed allele and a nestin-Cre transgene, we have generated homozygous animals for this conditional allele with a mosaic pattern of gene inactivation, via the excision of the exons 2–4 (Pkd1cond/cond:Nestincre (CY)).20Piontek K.B. Huso D.L. Grinberg A. et al.A functional floxed allele of Pkd1 that can be conditionally inactivated in vivo.J Am Soc Nephrol. 2004; 15: 3035-3043Crossref PubMed Scopus (114) Google Scholar This model, used in a previous study by Shillingford et al.,21Shillingford J.M. Piontek K.B. Germino G.G. et al.Rapamycin ameliorates PKD resulting from conditional inactivation of Pkd1.J Am Soc Nephrol. 2010; 21: 489-497Crossref PubMed Scopus (196) Google Scholar has developed a milder renal phenotype in our animal care facility than the one reported by these investigators. We have also worked with heterozygous mice for a Pkd1-null mutation (Pkd1+/- (HT)).20Piontek K.B. Huso D.L. Grinberg A. et al.A functional floxed allele of Pkd1 that can be conditionally inactivated in vivo.J Am Soc Nephrol. 2004; 15: 3035-3043Crossref PubMed Scopus (114) Google Scholar,22Bastos A.P. Piontek K. Silva A.M. et al.Pkd1 haploinsufficiency increases renal damage and induces microcyst formation following ischemia/reperfusion.J Am Soc Nephrol. 2009; 20: 2389-2402Crossref PubMed Scopus (73) Google Scholar Whereas the CY mice present cystic kidneys without a Pkd1-haploinsufficient cell background, the HT animals display noncystic kidneys in the setting of Pkd1-haploinsufficiency by 15 weeks of age.20Piontek K.B. Huso D.L. Grinberg A. et al.A functional floxed allele of Pkd1 that can be conditionally inactivated in vivo.J Am Soc Nephrol. 2004; 15: 3035-3043Crossref PubMed Scopus (114) Google Scholar,22Bastos A.P. Piontek K. Silva A.M. et al.Pkd1 haploinsufficiency increases renal damage and induces microcyst formation following ischemia/reperfusion.J Am Soc Nephrol. 2009; 20: 2389-2402Crossref PubMed Scopus (73) Google Scholar Serial sections of CY and noncystic (Pkd1cond/cond (NC)) left kidneys confirmed the presence of cysts and microcysts only in CY mice (data not shown). The average number of cysts present in 15-week CY left kidneys was 22±6; as expected, no cysts were observed in 15-week NC left kidneys. The total kidney weight/body weight (BW) ratios were significantly higher in CY than NC mice at the ages of 5, 15, and 24 weeks (Figure 1a and Table 1). Interestingly, heart weight/BW was also higher in CY animals at 24 weeks (Figure 1b and Table 1).Table 1BW, TKW/BW, HW/BW, renal cAMP, and cystic index in NC, CY, WT, and HT male miceParametersBW (g; mean±s.d.)TKW/BW (%; mean±s.d.)HW/BW (%; mean±s.d.)Renal cAMP (pmol/ml; mean±s.d.)Cystic index (%; median (lower quartile–upper quartile))NC, 5 weeks (n=5)15.8±2.3bP<0.05 versus 24 weeks.1.518±0.2030.641±0.033——CY, 5 weeks (n=6)17.3±2.7bP<0.05 versus 24 weeks.2.198±0.612*0.693±0.110—8.63 (5.23–10.79)bP<0.05 versus 24 weeks.NC, 13 weeks (n=6)9.92±1.83—NC, 15 weeks (n=9)19.3±0.80bP<0.05 versus 24 weeks.1.629±0.1670.691±0.088—CY, 13 weeks (n=7)14.78±6.33*—CY, 15 weeks (n=9)19.8±2.1bP<0.05 versus 24 weeks.1.869±0.289*,aP<0.05 versus 24 weeks.0.718±0.05012.86 (5.67–17.83)NC, 24 weeks (n=6)28.0±1.81.636±0.1650.647±0.095——CY, 24 weeks (n=6)25.9±1.8*2.373±0.649*0.779±0.120*—17.31 (13.61–31.22)WT, 15 weeks (n=8)20.1±0.91.816±0.2170.841±0.135——HT, 15 weeks (n=8)19.6±0.81.964±0.1960.852±0.130——Abbreviations: BW, body weight; cAMP, cyclic adenosine monophosphate; CY, cystic; HT, Pkd1+/- heterozygous; HW, heart weight; NC, noncystic; TKW, total kidney weight; WT, wild-type.TKW/BW, HW/BW, and renal cAMP were compared using the nonpaired t-test.BW and cystic index were compared using the Mann–Whitney test.Group-time analyses were performed using analysis of variance (ANOVA) or Kruskal–Wallis.*P<0.05 versus NC.b P<0.05 versus 24 weeks. Open table in a new tab Abbreviations: BW, body weight; cAMP, cyclic adenosine monophosphate; CY, cystic; HT, Pkd1+/- heterozygous; HW, heart weight; NC, noncystic; TKW, total kidney weight; WT, wild-type. TKW/BW, HW/BW, and renal cAMP were compared using the nonpaired t-test. BW and cystic index were compared using the Mann–Whitney test. Group-time analyses were performed using analysis of variance (ANOVA) or Kruskal–Wallis. *P<0.05 versus NC. These models represent, therefore, the two cellular/genetic environments found in the human ADPKD kidneys: the HT mice show almost exclusively Pkd1+/- renal cells but do not display cysts, reproducing the background cell environment found in ADPKD1 patients; CY mice, on the other hand, have cysts presumably formed by Pkd1-/- cells, reproducing the ADPKD1 cystic phenotype and its expected consequences, but in a predominant wild-type cell (nonexpressing Cre) background. Illustrations of CY and NC kidneys are presented in Figure 1c. All experiments were performed in male mice to avoid potential gender-related experimental heterogeneity. We have also quantified cyclic adenosine monophosphate in kidney tissue at 13 weeks of age, having found higher levels in CY (14.78±6.33pmol/ml) than NC mice (9.92±1.83pmol/ml; P<0.05, Figure 1d and Table 1). Occasional compression exerted by renal cysts on blood vessels could be seen in CY kidneys, as shown in Figure 1e. A quantitative analysis of cystic involvement was carried out based on uniformly spaced CY kidney sections. This evaluation revealed significantly higher cystic indexes in CY mice at 24 weeks than in 5 weeks (17.31% (13.61–31.22) vs. 8.63% (5.23–10.79); P<0.05), a trend of lower indexes at 5 weeks compared with that in 15 weeks (8.63% (5.23–10.79) vs. 12.86% (5.67–17.83)), and a trend of higher values at 24 weeks than in 15 weeks (17.31% (13.61–31.22) vs. 12.86% (5.67–17.83); Figure 1f and Table 1). Invasive mean arterial pressure (MAP) measured at 13 weeks of age revealed higher levels in CY mice as compared with NC animals (149.79±4.66 vs. 132.86±4.21mmHg; P<0.001; Figure 2a and Table 2). We did not observe, however, a difference in MAP between HT and wild-type (Pkd1+/+ (WT)) mice (Figure 2b and Table 2). Following such findings, we extended this analysis to younger and older cystic animals, showing significantly higher MAP in CY as compared with NC mice at the age of 5 weeks (129.47±6.78 vs. 118.81±9.07mmHg; P<0.05; Figure 2a and Table 2). Cystic animals, however, did not present significantly higher MAP at 24 weeks, although a trend for more elevated MAP in CY than NC mice has been observed (Figure 2a and Table 2).Table 2MAP, SCr, SUN, and cystatin C in NC, CY, WT, and HT male miceParametersMAP (mmHg, mean±s.d.)SCr (mg/dl; median (lower quartile–upper quartile))SUN (mg/dl, mean±s.d.)Cystatin C (mg/l, mean±s.d.)NC, 5 weeks118.81±9.07 (n=6)0.46 (0.36–0.55) (n=6)27.88±1.33 (n=6)—CY, 5 weeks129.47±6.78*,aaaP<0.001 versus 13 weeks.,bP<0.05 versus 24 weeks. (n=6)0.44 (0.30–0.56)bP<0.05 versus 24 weeks.(n=6)29.23±3.21 (n=6)—NC, 10–13 weeks0.37 (0.35–0.38) (n=9)25.23±1.22 (n=9)NC, 13 weeks132.86±4.21 (n=6)3.21±0.50 (n=6)CY, 10–13 weeks0.32 (0.30–0.35)** (n=9)26.70±1.43* (n=9)CY, 13 weeks149.79±4.66***P<0.05 versus 24 weeks. (n=6)3.61±0.53 (n=7)NC, 24 weeks131.64±13.08 (n=6)0.23 (0.21–0.34) (n=6)27.80±4.62 (n=6)—CY, 24 weeks139.95±7.20 (n=6)0.33 (0.22–0.37) (n=7)30.14±5.10 (n=7)—WT, 10–13 weeks0.38 (0.36–0.39) (n=8)26.27±1.16 (n=8)—WT, 13 weeks127.54±2.99 (n=8)HT, 10–13 weeks0.36 (0.34 to 0.36) (n=8)25.34±1.18 (n=8)—HT, 13 weeks131.03±4.36 (n=6)Abbreviations: CY, cystic; HT, Pkd1+/- heterozygous; MAP, mean arterial pressure; NC, noncystic; SCr, serum creatinine; SUN, serum urea nitrogen; WT, wild-type.MAP, SUN, and cystatin C were compared using the nonpaired t-test.SCr was compared using the Mann–Whitney test.Group-time analyses were performed using analysis of variance (ANOVA) or Kruskal–Wallis.*P<0.05 versus NC.**P<0.01 versus NC.***P<0.001 versus NC.aaa P<0.001 versus 13 weeks.b P<0.05 versus 24 weeks. Open table in a new tab Abbreviations: CY, cystic; HT, Pkd1+/- heterozygous; MAP, mean arterial pressure; NC, noncystic; SCr, serum creatinine; SUN, serum urea nitrogen; WT, wild-type. MAP, SUN, and cystatin C were compared using the nonpaired t-test. SCr was compared using the Mann–Whitney test. Group-time analyses were performed using analysis of variance (ANOVA) or Kruskal–Wallis. *P<0.05 versus NC. **P<0.01 versus NC. ***P<0.001 versus NC. We found no serum creatinine (SCr) difference between CY and NC mice at the ages of 5 and 24 weeks, although slightly lower levels have been found in CY animals at 10–13 weeks (Figure 3a and Table 2). Serum urea nitrogen (SUN) also did not differ between these groups at 5 and 24 weeks, but mildly higher values were detected in the cystic versus noncystic mice at 10–13 weeks (26.70±1.43 vs. 25.23±1.22mg/dl; P<0.05, Figure 3b and Table 2). No significant SCr and SUN differences, however, were verified between HT and WT animals at 10–13 weeks of age (Figure 3a and b and Table 2). As an additional method to indirectly assess glomerular filtration in CY and NC mice, we evaluated their serum cystatin C levels at 13 weeks. No significant difference, however, was observed between the two groups (Figure 3c and Table 2). Next, we studied the renal handling of Na+ and K+. We found that CY mice had a significantly lower fractional excretion of Na+ (FENa) compared with NC animals at 10–13 weeks (0.60±0.06% vs. 0.74±0.09%; P<0.001), a finding that was reproduced at 5 weeks (0.57±0.22% vs. 0.88±0.15%; P<0.01) but not at 24 weeks (Figure 4a and Table 3). Serum Na+ (SNa) analysis revealed lower values in CY than in NC mice at 10–13 weeks (137 (136–139) vs. 143mEq/l (142–144); P<0.01), but this difference was not found at 5 and 24 weeks (Figure 4b and Table 3). No serum K+ (SK) difference was detected between these groups at the three analyzed ages (Table 3). Transtubular K+ gradient (TTKG), in turn, did not differ between CY and NC mice at all evaluated ages (Table 3 and Supplementary Figure S1 online).Table 3FENa, TTKG, SNa, SK, and UosmMax in NC, CY, WT, and HT male miceParametersFENa (%, mean±s.d.)TTKG (mean±s.d.)SNa(mEq/l; median (lower quartile–upper quartile))SK (mEq/l; median (lower quartile–upper quartile))UosmMax (mOsm/kg H2O, mean±s.d.)NC, 5 weeks (n=6)0.88±0.15bbbP<0.001 versus 24 weeks.3.00±0.85140 (139–142)aP<0.05 versus 10–13 weeks.4.0 (3.5–4.5)aP<0.05 versus 10–13 weeks.3045±694CY, 5 weeks (n=6)0.57±0.22**3.61±1.09139 (139–141)aP<0.05 versus 10–13 weeks.4.0 (3.9–4.1)aP<0.05 versus 10–13 weeks.2705±543NC, 10–13 weeks (n=9)0.74±0.09bbbP<0.001 versus 24 weeks.2.51±0.49143 (142–144)bP<0.05 versus 24 weeks.4.9 (4.8–4.9)bP<0.05 versus 24 weeks.3199±288CY, 10–13 weeks (n=9)0.60±0.06***2.71±0.57137 (136–139)**, b4.8 (4.7–5.0)bP<0.05 versus 24 weeks.2734±195***NC, 24 weeks (n=6)0.38±0.223.45±0.47141 (139–142)4.6 (4.3–4.7)3127±303CY, 24 weeks (n=7)0.54±0.254.31±1.65140 (139–142)4.6 (4.2–4.9)2518±582*WT, 10–13 weeks (n=8)0.81±0.06—143 (142–144)4.8 (4.7–4.9)3067±176HT, 10–13 weeks (n=8)0.73±0.07#—142 (140–144)4.8 (4.6–4.9)3158±123Abbreviations: CY, cystic; FENa, fractional excretion of Na+; HT, Pkd1+/- heterozygous; NC, noncystic; SK, serum K+; SNa, serum Na+; TTKG, transtubular K+ gradient; UosmMax, maximum urine osmolality; WT, wild-type.FENa, TTKG, and UosmMax were compared using the nonpaired t-test.SNa and SK were compared using the Mann–Whitney test.Group-time analyses were performed using analysis of variance (ANOVA) or Kruskal–Wallis.*P<0.05 versus NC.**P<0.01 versus NC.***P<0.001 versus NC.#P<0.05 versus WT.a P<0.05 versus 10–13 weeks.b P<0.05 versus 24 weeks.bbb P<0.001 versus 24 weeks. Open table in a new tab Download .jpg (.06 MB) Help with files Supplementary Figure S1 Abbreviations: CY, cystic; FENa, fractional excretion of Na+; HT, Pkd1+/- heterozygous; NC, noncystic; SK, serum K+; SNa, serum Na+; TTKG, transtubular K+ gradient; UosmMax, maximum urine osmolality; WT, wild-type. FENa, TTKG, and UosmMax were compared using the nonpaired t-test. SNa and SK were compared using the Mann–Whitney test. Group-time analyses were performed using analysis of variance (ANOVA) or Kruskal–Wallis. *P<0.05 versus NC. **P<0.01 versus NC. ***P<0.001 versus NC. #P<0.05 versus WT. Interestingly, HT mice exhibited a lower FENa than WT animals at 10–13 weeks of age, although the difference was less striking than that observed between CY and NC mice (Figure 4a and Table 3). There was no significant difference in SNa or SK between the HT and WT groups at this age (Figure 4b and Table 3). As the renin–angiotensin–aldosterone system has been implicated in ADPKD-associated hypertension, we evaluated this system in our animal models. We did not detect a significant difference in plasma renin (evaluated at 13 weeks), plasma vasopressin (14 weeks), and serum aldosterone (15 weeks) between CY and NC mice (Figure 5a and Table 4). Despite considerable variability, there was a trend toward higher plasma vasopressin in CY animals (515.0pg/ml (187.6–1265.0) vs. 71.3pg/ml (54.3–472.8); P=0.13; Figure 5a and Table 4)). The plasma renin, plasma vasopressin, and serum aldosterone levels did not differ between HT and WT mice (Figure 5b and Table 4).Table 4Plasma renin, plasma vasopressin, and serum aldosterone in NC, CY, WT, and HT male miceParametersPlasma renin (pg/ml; median (lower quartile–upper quartile))Plasma vasopressin (pg/ml; median (lower quartile–upper quartile))Serum aldosterone (ng/dl; median (lower quartile–upper quartile))NC (n=8)2.45 (1.42–4.19)71.3 (54.3–472.8)26.9 (15.7–37.7)CY (n=9)2.71 (0.79–2.98)515.0 (187.6–1265.0)30.4 (26.5–53.0)WT (n=8)2.31 (1.15–12.63)57.7 (52.8–109.6)26.3 (18.4–33.7)HT (n=8)2.46 (2.18–3.29)54.6 (48.0–72.5)27.6 (22.0–32.6)Abbreviations: CY, cystic; NC, noncystic; HT, Pkd1+/- heterozygous, WT, wild-type. Plasma renin, plasma vasopressin, and serum aldosterone were compared using the Mann–Whitney test. Open table in a new tab Abbreviations: CY, cystic; NC, noncystic; HT, Pkd1+/- heterozygous, WT, wild-type. Plasma renin, plasma vasopressin, and serum aldosterone were compared using the Mann–Whitney test. In addition to its primary synthesis and secretion by hepatic cells, angiotensinogen can also be produced locally in the kidneys and constitutes a component of the intrarenal RAS.23Kobori H. Nangaku M. Navar L.G. et al.The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease.Pharmacol Rev. 2007; 59: 251-287Crossref PubMed Scopus (933) Google Scholar The angiotensinogen mRNA expression level was elevated in CY mouse kidneys at 18 weeks of age (1.76±0.65 arbitrary units) as compared with NC organs (1.06±0.39 arbitrary unit; P<0.05; Figure 6a); however, no significant difference was observed at 5 and 24 weeks (Figure 6a). There was no difference in renin and angiotensin-converting enzyme (ACE) gene expression levels between CY and NC kidneys at 18 weeks (Figure 6b and c). Next we studied expression of ACE and AT1 receptor (AT1R) in 15-week-old mice. At this time point, CY kidneys showed nonuniform immunohistochemical ACE staining in renal cyst epithelia, as well as occasional positive signal in tubular segments (Figure 6d). We did not observe ACE staining in the vasculature of CY kidneys. In contrast, NC mouse kidneys showed no ACE staining in either tissue compartment. Blood vessels from both CY and NC mouse kidneys exhibited positive AT1R staining (Figure 6e). In addition, cystic epithelia in the CY kidneys stained for AT1R at 15 weeks. There was no AT1R signal in glomeruli or in normal-appearing tubules in both CY and NC kidneys (Figure 6e). The urinary excretion of nitrite (UENO2) was lower in CY than NC mice at 10–13 weeks (8.5μmol/g of creatinine (3.2–10.1) vs. 13.9μmol/g of creatinine (9.9–18.1); P<0.01) and at 24 weeks of age (4.3μmol/g of creatinine (3.9–5.2) vs. 5.5μmol/g of creatinine (4.8–7.8); P<0.05) but no significant difference was detected at 5 weeks (Figure 7a and Table 5). In contrast, the urinary excretion of nitrate (UENO3) did not differ between the two sets of animals at the three evaluated ages (Table 5 and Supplementary Figure S2A online). There was no difference in urinary excretion of these NO metabolites between the HT and WT groups at 10–13 weeks of age (Table 5, Figure 7b, and Supplementary Figure S2B online).Table 5UENO2 and UENO3 in NC, CY, WT, and HT male miceParametersUENO2(μmol/g creat; median (lower quartile–upper quartile))UENO3 (mmol/g creat, mean±s.d.)NC, 5 weeks (n=6)7.4 (6.1–10.4)13.1±3.4bbCY, 5 weeks (n=6)9.0 (5.0–16.9)12.4±6.3NC, 10–13 weeks (n=8)13.9 (9.9–18.1)b12.3±3.1 bbCY, 10–13 weeks (n=9)8.5 (3.2–10.1)**8.2±5.6NC, 24 weeks (n=6)5.5 (4.8–7.8)4.6±4.8CY, 24 weeks (n=7)4.3 (3.9–5.2)*5.7±3.2UENO2(μmol/g creat, mean±s.d.)UENO3(mmol/g creat, mean±s.d.)WT, 10–13 weeks (n=8)14.0±13.05.7±3.8HT, 10–13 weeks (n=8)16.0±11.07.9±3.8Abbreviations: creat, creatinine; CY, cystic; HT, Pkd1+/- heterozygous; NC, noncystic; UENO2, urinary excretion of NO2; UENO3, urinary excretion of NO3; WT, wild-type.UENO3 was compared using the nonpaired t-test. UENO2 was compared using the Mann–Whitney or nonpaired t-test.Group-time analyses were performed using analysis of variance (ANOVA) or Kruskal–Wallis.*P<0.05 versus NC.**P<0.01 versus NC.bP<0.05 versus 24 weeks.bbP<0.01 versus 24 weeks. Open table in a new tab Download .jpg (.1" @default.
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• W1997592103 title "Renal cyst growth is the main determinant for hypertension and concentrating deficit in Pkd1 -deficient mice" @default.
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