scholarly journals Enhancement of renin and prorenin receptor in collecting duct of Cyp1a1-Ren2 rats may contribute to development and progression of malignant hypertension

2011 ◽  
Vol 300 (2) ◽  
pp. F581-F588 ◽  
Author(s):  
Minolfa C. Prieto ◽  
Dustyn E. Williams ◽  
Liu Liu ◽  
Kimberly L. Kavanagh ◽  
John J. Mullins ◽  
...  
Keyword(s):  
Gene Expression ◽  
Collecting Duct ◽  
Normal Diet ◽  
Malignant Hypertension ◽  
Soluble Form ◽  
Transgenic Rat ◽  
Ang Ii ◽  
Transgenic Rats ◽  
Protein Levels ◽  
Prorenin Receptor

To determine whether in the transgenic rat model [TGR(Cyp1a1Ren2)] with inducible ANG II-dependent malignant hypertension changes in the activation of intrarenal renin-angiotensin system may contribute to the pathogenesis of hypertension, we examined the gene expression of angiotensinogen (AGT) in renal cortical tissues and renin and prorenin receptor [(P)RR] in the collecting duct (CD) of the kidneys from Cyp1a1Ren2 rats ( n = 6) fed a normal diet containing 0.3% indole-3-carbinol (I3C) for 10 days and noninduced rats maintained on a normal diet (0.6% NaCl diet; n = 6). Rats induced with I3C developed malignant hypertension and exhibited alterations in the expression of renin and (P)RR expressed by the CD cells. In the renal medullary tissues of the Cyp1a1Ren2 transgenic rats with malignant hypertension, renin protein levels in CD cells were associated with maintained renin content and lack of suppression of the endogenous Ren1c gene expression. Furthermore, these tissues exhibited increased levels of (P)RR transcript, as well as of the protein levels of the soluble form of this receptor, the s(P)RR. Intriguingly, although previous findings demonstrated that urinary AGT excretion is augmented in Cyp1a1Ren2 transgenic rats with malignant hypertension, in the present study we did not find changes in the gene expression of AGT in renal cortical tissues of these rats. The data suggest that upregulation of renin and the s(P)RR in the CD, especially in the renal medullary tissues of Cyp1a1Ren2 transgenic rats with malignant hypertension, along with the previously demonstrated increased availability of AGT in the urine of these rats, may constitute a leading mechanism to explain elevated formation of kidney ANG II levels in this model of ANG II-dependent hypertension.

Abstract 214: (pro) Renin Receptor Stimulates the Expression of Fibrotic Genes in Mouse Collecting Ducts Cells via Wnt/β-catenin Signaling, Independently of Angiotensin II

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Catherina A Cuevas ◽  
Alexis A Gonzalez ◽  
Nivaldo C Inestrosa ◽  
Carlos P Vio ◽  
Minolfa C Prieto
Keyword(s):  
Angiotensin Ii ◽  
Wnt Signaling ◽  
Cyclin D1 ◽  
Target Genes ◽  
Collecting Duct ◽  
Fold Change ◽  
Collagen I ◽  
Ang Ii ◽  
Protein Levels ◽  
Prorenin Receptor

The prorenin receptor (PRR) is upregulated in the kidney by high angiotensin II (Ang II) states such as those that occur with AngII-dependent hypertension and low salt diet. The PRR is an accessory protein of the vacuolar H-ATPase, which facilitates Wnt/β-catenin signaling. The Wnt/β-catenin pathway is involved in fibrosis processes. In the present study, we aimed to determine whether the stimulation of PRR in mouse collecting duct M-1 cells induces fibrotic genes independently of Ang II, and if this effect is mediated by activation of Wnt/β-catenin. Both Ang II (10 -7 M) and human recombinant prorenin (hRPr; 2,5 x 10 -8 M) treatments (8 and 16 hours) increased mRNA and protein levels of fibronectin and collagen I (1.5±0.08 and 1.5 ± 0.1 fold change, respectibely; p<0.05); however, the effects of hRPr were elicited earlier. Likewise, Ang II and hRPr stimulated the Wnt target genes, cyclin D1 and c-myc (cyclin D1: 2±0.2 for both; c-myc: 1.4 ± 0.03 and 1.2± 0.002 fold change for Ang II and hRPr, respectively; p<0.001). Ang II type 1 receptor (AT1R) blockade with candesartan (10 -7 M) completely prevented the Ang II-dependent stimulation but not the effects of hRPr on Wnt signaling genes. Upregulation of fibronectin and collagen I genes by Ang II or hRP at 16 h was prevented by Wnt signaling inhibition with Pyrvinium Pamoate (10 -7 M). The data indicate that in M-1 cells, activation of AT1R and PRR stimulate the synthesis of fibrotic genes via Wnt signaling by independent mechanisms.

scholarly journals Renal functional responses to selective intrarenal renin inhibition in Cyp1a1-Ren2 transgenic rats with ANG II-dependent malignant hypertension

2012 ◽  
Vol 302 (1) ◽  
pp. F52-F59 ◽  
Author(s):  
Catherine G. Howard ◽  
Kenneth D. Mitchell
Keyword(s):  
De Novo ◽  
Collecting Duct ◽  
Renal Plasma Flow ◽  
Renin Angiotensin System ◽  
Malignant Hypertension ◽  
Ang Ii ◽  
Functional Responses ◽  
Transgenic Rats ◽  
Excretory Function ◽  
Renin Inhibition

Angiotensin (ANG) II-dependent hypertension is characterized by increases in intrarenal ANG II levels, derangement in renal hemodynamics, and augmented tubular sodium reabsorptive capability. Increased nephron expression of renin-angiotensin system components, such as angiotensinogen by proximal tubule cells and renin by collecting duct principal cells, has been associated with an augmented ability of the kidney to form ANG II in hypertensive states. However, the contribution of de novo intrarenal ANG II production to the development and maintenance of ANG II-dependent hypertension remains unclear. The present study was performed to determine the effects of selective intrarenal renin inhibition on whole kidney hemodynamics and renal excretory function in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension in the absence of the confounding influence of associated reductions in mean arterial pressure (MAP). Male Cyp1a1-Ren2 transgenic rats were induced to develop malignant hypertension, anesthetized, and surgically prepared for intrarenal administration of the direct renin inhibitor aliskiren (0.01 mg/kg). Following acute aliskiren treatment, urine flow and sodium excretion increased (10.5 ± 1.1 to 15.9 ± 1.9 μl/min, P < 0.001; 550 ± 160 to 1,370 ± 320 neq/min, P < 0.001, respectively) and ANG II excretion decreased (120 ± 30 to 63 ± 17 fmol/h, P < 0.05). There were no significant changes in MAP, glomerular filtration rate, estimated renal plasma flow, plasma ANG II levels, or protein excretion. The present findings demonstrate that selective renal renin inhibition elicits diuretic and natriuretic responses in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension. Elevated intraluminal ANG II levels likely act to augment tubular reabsorptive function and, thereby, contribute to the elevated blood pressure in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension.

Enhanced tubuloglomerular feedback in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension

2005 ◽  
Vol 289 (6) ◽  
pp. F1210-F1216 ◽  
Author(s):  
Kenneth D. Mitchell ◽  
John J. Mullins
Keyword(s):  
Arterial Pressure ◽  
Receptor Activation ◽  
Normal Diet ◽  
Tubuloglomerular Feedback ◽  
Malignant Hypertension ◽  
Ang Ii ◽  
Transgenic Rats ◽  
Aryl Hydrocarbon ◽  
Flow Pressure ◽  
Feedback Responses

The present study was performed to evaluate tubuloglomerular feedback responses in transgenic rats [TGR(Cypa1a1Ren2)] with inducible malignant hypertension and to determine the degree to which feedback responsiveness is modulated by ANG II in these rats. Male Cyp1a1-Ren2 rats were fed a normal diet containing the aryl hydrocarbon indole-3-carbinol (I3C; 0.3%), for 5–6 days to stimulate expression of the Cyp1a1-Ren2 transgene and, thereby, to induce malignant hypertension. Stop-flow pressure (SFP) feedback responses to a late proximal perfusion rate of 40 nl/min were assessed in pentobarbital sodium-anesthetized rats during control conditions and after administration of the AT1 receptor antagonist candesartan (0.1 mg/kg iv). Rats induced with I3C ( n = 6) exhibited elevated mean arterial pressure and increased maximal SFP feedback responses compared with noninduced rats ( n = 4; 163 ± 4 vs. 130 ± 2 mmHg, P < 0.01 and 16.3 ± 1.4 vs. 11.7 ± 0.5 mmHg, P < 0.05, respectively). Systemic candesartan decreased arterial pressure (to 98 ± 7 and to 101 ± 5 mmHg, respectively, P < 0.001) and attenuated SFP feedback responses (to 2.0 ± 0.4 and to 3.3 ± 0.9 mmHg, respectively, P < 0.01) in both hypertensive and normotensive rats. In additional experiments, peritubular capillary infusion of 10−3 M candesartan did not alter arterial pressure but attenuated feedback responses in both hypertensive (19.3 ± 1.4 to 8.8 ± 0.9 mmHg, P < 0.01, n = 9) and normotensive Cyp1a1-Ren2 rats (9.0 ± 0.8 to 4.7 ± 0.6 mmHg, P < 0.01, n = 7). The present findings indicate that Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension exhibit augmented tubuloglomerular feedback responses. The data also show that AT1 receptor activation by ANG II contributes to the enhanced feedback responsiveness in Cyp1a1-Ren2 rats with malignant hypertension.

Abstract P264: Interaction of Collecting Duct-Derived Prorenin and Soluble Prorenin Receptor Increases Intraluminal Renin Activity and Augments Intratubular Angiotensin II Formation in Ang II-Dependent Hypertensive Rats

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Minolfa C Prieto ◽  
Liu Liu ◽  
Alexis A Gonzalez ◽  
Dale M Seth ◽  
L Gabriel Navar
Keyword(s):  
Angiotensin Ii ◽  
De Novo ◽  
Collecting Duct ◽  
Renin Activity ◽  
Soluble Form ◽  
Sodium Reabsorption ◽  
Ang Ii ◽  
Distal Nephron ◽  
Nephron Segments ◽  
Prorenin Receptor

Upregulation of collecting duct (CD)-derived renin (CD renin) in angiotensin II (Ang II)-dependent hypertension may provide a pathway for intratubular Ang II formation by acting on angiotensinogen (AGT) delivered from proximal tubule segments. Recently, a prorenin/renin receptor (PRR) has been cloned and shown to enhance renin and prorenin activation. The soluble form of the PRR (sPRR) is augmented in the renal inner medulla of chronic Ang II-infused rats. The present study was performed to determine if renin is secreted into the lumen by the CD cells in chronic Ang II-infused rats and to establish the functional contribution of sPRR to the enhanced renin activity in distal nephron segments. Accordingly, urinary levels of renin ( uRen ) and Ang II ( uAngII ) were measured by RIA in chronic Ang II-infused male Sprague-Dawley rats [80 ng/min, SC minipumps for 14 d, n=10] and sham-operated rats [n=10]. Systolic blood pressure increased in the Ang II rats by Day 5 and continued to increase throughout the study (Day 13; Ang II: 175±10 vs. sham: 116±2 mmHg; p <0.05). Although plasma renin activity (PRA) was suppressed in the Ang II-infused rats, renal medullary renin content was significantly augmented (12,605±1,343 vs. 7,956±765 ng Ang I/h/mg; p <0.05). The excretion of uAngII was also increased (3,813±431 vs. 2,080±361 fmol/day; p <0.05). In addition, renin and prorenin excretion rates increased progressively and were markedly augmented by Day 13 of Ang II infusion [renin (8.6±1.5 vs. 2.8±0.5x10 -6 Enzyme Units Excreted (EUE) /day; prorenin: 15.8 ± 2.8 vs. 2.6 ± 0.7x10 -3 EUE /day, p <0.05). Renin and prorenin protein levels examined by Western Blot in the urine were similarly increased. Importantly, the incubation of urine samples of Ang II-infused rats with recombinant human prorenin showed increased Ang I formation compared to sham-operated rats. In conclusion, in chronic Ang II-infused rats, the presence of sPRR in the urine reflects augmented enzymatic activity of prorenin secreted by the principal cells of the CD, which increase intratubular Ang II de novo formation in the distal nephron segments thus contributing to enhanced sodium reabsorption during Ang II-dependent hypertension.

Abstract 559: Augmented Renal Levels of PDGFß And PDGFß Receptors in Cyp1a1-Ren2 Transgenic Rats With Angiotensin II-Dependent Malignant Hypertension

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Kenneth D Mitchell ◽  
Minolfa C Prieto ◽  
Dale M Seth ◽  
Porcha D Davis ◽  
Camille Bourgeois ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Renal Injury ◽  
Renal Cortex ◽  
Renal Medulla ◽  
Receptor Activation ◽  
Malignant Hypertension ◽  
Pdgf Receptor ◽  
Ang Ii ◽  
Transgenic Rats ◽  
Protein Levels

PDGF receptor antagonism with imatinib mesylate prevents the renal injury, proteinuria and augmented urinary ANG II excretion independent of changes in blood pressure that occur in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension. These findings suggest that arterial pressure-dependent increases in PDGFβ protein levels and PDGFβ receptor activation contribute importantly to the marked renal functional and morphological derangements that occur in ANG II-dependent malignant hypertension. To address this issue, the present study was performed to determine the protein levels of PDGFβ and PDGFβ receptors in renal cortical and medullary tissue from kidneys of hypertensive Cyp1a1-Ren2 transgenic rats. Male Cyp1a1-Ren2 rats were fed a diet containing indole-3-carbinol (I3C; 0.3%) for 10 days to induce malignant hypertension (n=5) or a non-I3C containing diet (controls, n=6). Rats induced with I3C developed malignant hypertension and exhibited increases in PDGFβ protein levels in both the renal cortex (0.046±0.002 vs.0.026±0.003 AU, P<0.05) and renal medulla (0.054±0.007 vs.0.026±0.003 AU, P<0.05), and elevated PDGFβ receptor levels in both renal cortex (0.26±0.03 vs.0.12±0.02 AU, P<0.05) and renal medulla (0.60±0.06 vs.0.21±0.02 AU, P<0.05). In a separate group (n=5), rats were chronically treated with the PDGF receptor antagonist, imatinib mesylate, by oral gavage (60 mg/kg/d) starting 3 days before initiating I3C induction and maintained on imatinib for the 10 day duration of I3C administration. Chronic PDGF receptor blockade prevented the increase in PDGFβ protein levels in both renal cortical and medullary tissues (0.027±0.004 vs. 0.026±0.003 and 0.029±0.005 vs. 0.026±0.003 AU, respectively) but did not influence the elevated PDGFβ receptor levels in either renal cortex (0.23±0.02 vs. 0.26±0.02 AU) or renal medulla (0.46±0.03 vs.0.60±0.06 AU). These data demonstrate that both PDGFβ protein and PDGFβ receptor levels are elevated in both renal cortex and medulla in ANG II-dependent malignant hypertension. Such elevated levels may contribute to the renal injury and the increased urinary ANG II excretion in ANG II-dependent malignant hypertension.

scholarly journals Increased Collecting Duct Renin Protein Expression in Cyp1a1‐Ren2 Transgenic Rats with Inducible Ang II‐dependent Malignant Hypertension.

2009 ◽  
Vol 23 (S1) ◽  
Author(s):  
Minolfa C. Prieto ◽  
Fady T. Botros ◽  
Victoria L Martin ◽  
Porcha D Davis ◽  
Kenneth D Mitchell
Keyword(s):  
Protein Expression ◽  
Collecting Duct ◽  
Malignant Hypertension ◽  
Ang Ii ◽  
Transgenic Rats

scholarly journals Vasopressin/V2 receptor stimulates renin synthesis in the collecting duct

2016 ◽  
Vol 310 (4) ◽  
pp. F284-F293 ◽  
Author(s):  
Alexis A. Gonzalez ◽  
Flavia Cifuentes-Araneda ◽  
Cristobal Ibaceta-Gonzalez ◽  
Alex Gonzalez-Vergara ◽  
Leonardo Zamora ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Critical Role ◽  
Combined Treatment ◽  
Receptor Activation ◽  
Ang Ii ◽  
Principal Cells ◽  
Protein Levels ◽  
Renin Synthesis ◽  
Renin Mrna ◽  
Creb Pathway

Renin is synthesized in the principal cells of the collecting duct (CD), and its production is increased via cAMP in angiotensin (ANG) II-dependent hypertension, despite suppression of juxtaglomerular (JG) renin. Vasopressin, one of the effector hormones of the renin-angiotensin system (RAS) via the type 2-receptor (V2R), activates the cAMP/PKA/cAMP response element-binding protein (CREB) pathway and aquaporin-2 expression in principal cells of the CD. Accordingly, we hypothesized that activation of V2R increases renin synthesis via PKA/CREB, independently of ANG II type 1 (AT1) receptor activation in CD cells. Desmopressin (DDAVP; 10−6 M), a selective V2R agonist, increased renin mRNA (∼3-fold), prorenin (∼1.5-fold), and renin (∼2-fold) in cell lysates and cell culture media in the M-1 CD cell line. Cotreatment with DDAVP+H89 (PKA inhibitor) or CREB short hairpin (sh) RNA prevented this response. H89 also blunted DDAVP-induced CREB phosphorylation and nuclear localization. In 48-h water-deprived (WD) mice, prorenin-renin protein levels were increased in the renal inner medulla (∼1.4- and 1.8-fold). In WD mice treated with an ACE inhibitor plus AT1 receptor blockade, renin mRNA and prorenin protein levels were still higher than controls, while renin protein content was not changed. In M-1 cells, ANG II or DDAVP increased prorenin-renin protein levels; however, there were no further increases by combined treatment. These results indicate that in the CD the activation of the V2R stimulates renin synthesis via the PKA/CREB pathway independently of RAS, suggesting a critical role for vasopressin in the regulation of renin in the CD.

Abstract 021: Nephron Specific Deletion of the Prorenin Receptor Modulates Blood Pressure and Urinary Na+ Excretion

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Nirupama Ramkumar ◽  
Deborah Stuart ◽  
Elena V Mironova ◽  
Vladislav Bugay ◽  
Mykola Mamenko ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Structural Defects ◽  
Ang Ii ◽  
Open Probability ◽  
Protein Levels ◽  
Prorenin Receptor ◽  
Collecting Ducts ◽  
Dependent Pathway ◽  
Early Lethality ◽  
Specific Deletion

The nephron prorenin receptor (PRR) may modulate blood pressure (BP) and Na+ balance. Since previous models of PRR knockout (KO) mice had early lethality and/or structural defects, we developed an inducible nephron-wide PRR KO using the Pax8/LC1 transgenes. Disruption of nephron PRR at 1 month of age caused no renal histological abnormalities. On a normal Na+ diet, wild-type (WT) and PRR KO mice had similar BP and Na+ excretion. However, PRR KO mice had elevated PRC (KO- 377 ± 77 vs WT- 127 ± 19 ng Ang-I/ml/hr) and a 50% decrease in renal ENaC-α protein. Protein levels of NHE3, NKCC2, NCC and ENaC-β/γ were similar between the two groups. Treatment with mouse prorenin (10 nM for 30 min) increased ENaC channel number by 2-fold, but not open probability, in isolated split-open cortical collecting ducts (CCD) from WT mice; this was prevented by Akt inhibition (A6730) but unaffected by blockade of AT-1 (losartan), ERK1/2 (U0126) or p38 MAPK (SB203580). Addition of prorenin (10 nM) did not change isolated CCD [Ca2+]i as assessed by Fura-2 loading (10 min exposure with readings every 3 sec). On a low Na+ diet, PRR KO mice had increased Na+ excretion (Day 2: KO - 66 ± 11 vs WT- 42 ± 6 μmol/day; Day 6: KO - 39 ± 4 vs ET- 23 ± 4 μmol/day) however, no differences in BP were observed. PRC was elevated in PRR KO mice on a low Na+ diet (KO- 384 ± 40 vs WT-174 ± 12 ng/ Ang-I/ml/hr). PRR KO mice had an attenuated hypertensive response to Angiotensin-II (Ang-II) infusion at 600 ng/Kg/min for 2 weeks (MAP: KO - 117 ± 4 vs WT - 133 ± 4 mm Hg over the course of Ang-II infusion). Urinary Na+ excretion was elevated in Ang-II treated PRR KO mice as compared to WT mice (KO-344 ± 14 vs WT-268 ±30 μmol/day). Taken together, these data indicate that nephron PRR, likely via direct prorenin/renin stimulation of an Akt-dependent pathway, stimulates CCD ENaC activity. Absence of nephron PRR promotes Na+ wasting and reduces the hypertensive response to Ang-II.

scholarly journals Collecting duct prorenin receptor knockout reduces renal function, increases sodium excretion, and mitigates renal responses in ANG II-induced hypertensive mice

2017 ◽  
Vol 313 (6) ◽  
pp. F1243-F1253 ◽  
Author(s):  
Minolfa C. Prieto ◽  
Virginia Reverte ◽  
Mykola Mamenko ◽  
Marta Kuczeriszka ◽  
Luciana C. Veiras ◽  
...  
Keyword(s):  
Renal Function ◽  
Collecting Duct ◽  
Ang Ii ◽  
Open Probability ◽  
Sodium Transporters ◽  
Prorenin Receptor ◽  
Active Channels ◽  
The Impact ◽  
Renal Responses ◽  
Stimulation Of

Augmented intratubular angiotensin (ANG) II is a key determinant of enhanced distal Na+ reabsorption via activation of epithelial Na+ channels (ENaC) and other transporters, which leads to the development of high blood pressure (BP). In ANG II-induced hypertension, there is increased expression of the prorenin receptor (PRR) in the collecting duct (CD), which has been implicated in the stimulation of the sodium transporters and resultant hypertension. The impact of PRR deletion along the nephron on BP regulation and Na+ handling remains controversial. In the present study, we investigate the role of PRR in the regulation of renal function and BP by using a mouse model with specific deletion of PRR in the CD (CDPRR-KO). At basal conditions, CDPRR-KO mice had decreased renal function and lower systolic BP associated with higher fractional Na+ excretion and lower ANG II levels in urine. After 14 days of ANG II infusion (400 ng·kg−1·min−1), the increases in systolic BP and diastolic BP were mitigated in CDPRR-KO mice. CDPRR-KO mice had lower abundance of cleaved αENaC and γENaC, as well as lower ANG II and renin content in urine compared with wild-type mice. In isolated CD from CDPRR-KO mice, patch-clamp studies demonstrated that ANG II-dependent stimulation of ENaC activity was reduced because of fewer active channels and lower open probability. These data indicate that CD PRR contributes to renal function and BP responses during chronic ANG II infusion by enhancing renin activity, increasing ANG II, and activating ENaC in the distal nephron segments.

Renal vascular and tubulointerstitial inflammation and proliferation in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension

2007 ◽  
Vol 292 (6) ◽  
pp. F1858-F1866 ◽  
Author(s):  
Miguel L. Graciano ◽  
Cynthia R. Mouton ◽  
Matthew E. Patterson ◽  
Dale M. Seth ◽  
John J. Mullins ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Morphological Changes ◽  
Periodic Acid ◽  
Cell Number ◽  
Malignant Hypertension ◽  
Nuclear Antigen ◽  
Ang Ii ◽  
Transgenic Rats ◽  
Periodic Acid Schiff ◽  
Proliferating Cell

Transgenic rats with inducible ANG II-dependent malignant hypertension [TGR(Cyp1a1Ren2)] were generated by inserting the mouse Ren2 renin gene into the genome of the rat. The present study was performed to assess renal morphological changes occurring during the development of ANG II-dependent malignant hypertension in these rats. Male Cyp1a1-Ren2 rats ( n = 10) were fed normal rat food containing indole-3-carbinol (I3C; 0.3%) for 10 days to induce malignant hypertension. Rats induced with I3C had higher mean arterial pressures (173 ± 9 vs. 112 ± 11 mmHg, P < 0.01) than noninduced normotensive rats ( n = 9). Glomerular damage was evaluated by determination of the glomerulosclerosis index (GSI) in tissue sections stained with periodic acid-Schiff. Kidneys of hypertensive rats had a higher GSI than normotensive rats (21.3 ± 5.6 vs. 3.5 ± 1.31 units). Quantitative analysis of macrophage ED-1-positive cells and proliferating cell nuclear antigen using immunohistochemistry demonstrated increased macrophage numbers in the renal interstitium (106.4 ± 11.4 vs. 58.7 ± 5.0 cells/mm2) and increased proliferating cell number in cortical tubules (37.8 ± 5.7 vs. 24.2 ± 2.1 cells/mm2), renal cortical vessels (2.2 ± 0.5 vs. 0.13 ± 0.07 cells/vessel), and the cortical interstitium (33.6 ± 5.7 vs. 4.2 ± 1.4 cells/mm2) of hypertensive rat kidneys. These findings demonstrate that the renal pathological changes that occur during the development of malignant hypertension in Cyp1a1-Ren2 rats are characterized by inflammation and cellular proliferation in cortical vessels and tubulointerstitium.

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