Degree Of Glomerular Injury Research Articles

Knockout of Dual-Specificity Protein Phosphatase 5 Protects Against Hypertension-Induced Renal Injury.

Dual-specificity protein phosphatase 5 (DUSP5) is a member of the tyrosine-threonine phosphatase family with the ability to dephosphorylate and inactivate extracellular signal-related kinase (ERK). The present study investigates whether knockout (KO) of Dusp5 improves renal hemodynamics and protects against hypertension-induced renal injury. The renal expression of DUSP5 was reduced, and the levels of phosphorylated (p) ERK1/2 and p-protein kinase C (PKC) α were elevated in the KO rats. KO of Dusp5 enhanced the myogenic tone of the renal afferent arteriole and interlobular artery in vitro with or without induction of deoxycorticosterone acetate-salt hypertension. Inhibition of ERK1/2 and PKC diminished the myogenic response to a greater extent in Dusp5 KO rats. Autoregulation of renal blood flow was significantly impaired in hypertensive wild-type (WT) rats but remained intact in Dusp5 KO animals. Proteinuria was markedly decreased in hypertensive KO versus WT rats. The degree of glomerular injury was reduced, and the expression of nephrin in the glomerulus was higher in hypertensive Dusp5 KO rats. Renal fibrosis and medullary protein cast formation were attenuated in hypertensive Dusp5 KO rats in association with decreased expression of monocyte chemoattractant protein 1, transforming growth factor-β1, matrix metalloproteinase (MMP) 2, and MMP9. These results indicate that KO of Dusp5 protects against hypertension-induced renal injury, at least in part, by maintaining the myogenic tone of the renal vasculature and extending the range of renal blood flow autoregulation to higher pressures, which diminish glomerular injury, protein cast formation, macrophage infiltration, and epithelial-mesenchymal transformation in the kidney. SIGNIFICANCE STATEMENT: Dual-specificity protein phosphatase 5 (DUSP5) is a tyrosine-threonine phosphatase that inactivates extracellular signal-related kinase (ERK). We previously reported that knockout (KO) of Dusp5 enhanced the myogenic response and autoregulation in the cerebral circulation. The present study investigates whether KO of DUSP5 improves renal hemodynamics and protects against hypertension-induced renal injury. Downregulation of DUSP5 enhanced the myogenic tone of renal arteriole and artery and autoregulation of renal blood flow in association with reduced proteinuria, glomerular injury, and interstitial fibrosis after the induction of hypertension. Inhibition of ERK1/2 and protein kinase C diminished the myogenic response to a greater extent in Dusp5 KO rats. These results suggest that DUSP5 might be a viable drug target for the treatment of hypertension nephropathy.

Abstract 056: Knockout of Dual-Specificity Protein Phosphatase 5 Protects Against Hypertension Induced Chronic Kidney Disease

Dual-specificity protein phosphatase 5 (Dusp5) is a member of serine-threonine phosphatase family that regulates intracellular signal transduction by dephosphorylating ERK1/2. We previously generated Dusp5 zinc-finger knockout (KO) rats and found that KO of Dusp5 enhances myogenic response of middle cerebral artery and autoregulation of cerebral blood flow. This study investigated whether Dusp5 KO also improves renal hemodynamics and protects against hypertension-induced chronic kidney disease (CKD). Renal tissue expression of Dusp5 was decreased and levels of phosphorylated ERK1/2 (p-ERK1/2) and p-PKC enhanced in KO rats. Blood pressure increased similarly to 180 mmHg in both WT and Dusp5 KO rats treated with DOCA/salt. KO of Dusp5 enhanced autoregulation of renal blood flow (RBF increased by 12.1 ± 4.1% vs. 32.7 ± 4.7% when MAP increased from 100 to 180 mmHg, p<0.05) and reduced renal vascular remodeling compared with WT rats (0.64±0.03 vs. 0.94±0.06 wall-to-lumen ratio, p<0.05). Improvement in renal hemodynamics in hypertensive Dusp5 KO vs. WT rats was associated with decreased proteinuria (226.71 ± 23.82 vs. 337.62 ± 30.41 mg/day, p<0.05) and protein cast formation in the renal corticomedullary region (1.01 ± 0.17% vs. 2.4 ± 0.51%, p<0.05). The degree of glomerular injury was reduced (2.22 ± 0.04 vs. 3.12 ± 0.04, p<0.05) and nephrin expression was greater in hypertensive Dusp5 KO rats vs. WT rats. Hypertension-induced renal fibrosis was attenuated in Dusp5 KO rats (5.32 ± 0.6% vs. 9.90 ± 0.7%, p<0.01) in association with decreased MCP-1 expression, reduced ED-1 + macrophage infiltration, down-regulated TGF-β1 expression, and attenuated fibrosis-related epithelial-mesenchymal transition (EMT) in the kidney (decreased expression of α-SMA and vimentin, and increased expression of E-cadherin). In conclusion, these results indicate that KO of Dusp5 protects against hypertension-induced proteinuria and renal fibrosis by enhancing renal hemodynamics and reducing vascular remodeling, glomerular injury, macrophage infiltration, TGF-β1 expression and EMT in the kidney. Thus, targeting Dusp5 may offer a novel approach for treating or preventing hypertension-induced CKD.

Acute kidney injury aggravated by treatment initiation with apixaban: Another twist of anticoagulant-related nephropathy.

Anticoagulant-related nephropathy (ARN) was initially described in patients on warfarin (as warfarin-related nephropathy) and recently in those using dabigatran. Herein, we report clinical history and kidney biopsy findings in a patient on apixaban (Eliquis). Initiation of treatment with apixaban resulted in aggravation of preexisting mild acute kidney injury (AKI). A few days after apixaban therapy, the patient became oligoanuric, and kidney biopsy showed severe acute tubular necrosis with numerous occlusive red blood cell casts. Only one out of 68 glomeruli with open capillary loops had small segmental cellular crescent. Therefore, there was major discrepancy between the degree of glomerular injury and the glomerular hematuria. Considering that the onset of this AKI was associated with apixaban treatment initiation, we propose that this patient had ARN associated with factor Xa inhibitor (apixaban), which has not previously been described. Monitoring of kidney function is recommended after initiation of anticoagulant therapy.

Abstract 097: Knockout of Matrix Metalloproteinase 9 Protects Against Hypertension-induced Renal Disease in Hypertensive Dahl S Rats

Matrix metalloproteinase 9 (MMP9) is a member of gelatinase family of enzymes with potentially opposing actions on tissue fibrosis (i.e. the degradation of extracellular matrix). Our previous study showed that two nonselective MMP inhibitors, XL081 and XL784, which inhibit MMP2, 9, 13 and Adam10 could delay and even reverse the development of renal fibrosis in hypertensive Dahl Salt sensitive (SS) rats. However, the specific role of MMP9 to the development of hypertensive nephropathy in MMP9 knockout (KO) rat models is unknown. In the present study, MMP9 KO rats were created on the SS genetic background using a CRISPR/Cas 9 system and the effect of KO was verified in this model. The systolic pressure, diastolic pressure and mean blood pressure (MAP) were similar in 12 weeks old MMP9 KO (n=6) and SS rats (n=9) fed a low salt diet (145 ± 3 vs. 148 ± 2mmHg; 111 ± 2 vs. 107 ± 2mmHg; 128 ± 2 vs. 126 ± 2mmHg). MAP increased to 180 ± 4 vs. 154 ± 3mmHg in SS rats versus MMP9 KO rats fed 8% high salt (HS) diet for 3 weeks. Proteinuria increased from 196 ± 18 mg/day to 718 ± 61mg/day in HS treated SS rats (n=9). It was significantly reduced in HS treated MMP9 KO rats (211 ± 30mg/day, n=6). The degree of glomerular injury (2.88 ± 0.08 vs. 3.52 ± 0.02), interstitial fibrosis (4.57 ± 0.35% vs. 10.45 ± 0.55%), vascular wall-to-lumen ratio (0.63 ± 0.04 vs. 1.22 ± 0.08) and protein cast area (6.40 ± 0.07% vs. 20.27 ± 2.65%) were all significantly reduced in MMP9 KO rats (n=6) versus the corresponding values in SS rats (n=6) fed 8% HS diet for 3 weeks. Autoregulation of renal blood flow (RBF) to elevations in perfusion was impaired in SS rats prior to the development of hypertension, for RBF rose by 20.6 ± 3.6% (n=8) when MAP was increased from 110 to 150 mmHg. Autoregulation of RBF was restored in MMP9 KO rats and only increased by 7% when pressure was increased over the same range. In contrast, there was no difference in the fall in RBF in SS versus MMP9 KO rats when pressure was reduced from 110 to 50 mmHg. These findings suggest that knockout of MMP9 in SS rats restores autoregulation of RBF and opposes the development of hypertension, proteinuria, glomerular injury and renal interstitial fibrosis.

Abstract P610: Alterations in 20-HETE Production Contribute to End Organ Damage in Dahl S Rats

It is well documented that a sexual dimorphism exists in the regulation of blood pressure in both the human population as well as experimental animal models, such that males have higher blood pressures than females of the same age. While there is a clear disparity in the development of hypertension and progression of renal injury in many rodent models, evidence of a sex difference is lacking in the Dahl S rat. While the current reports present conflicting data, we hypothesize that alterations in CYP450 expression and 20-HETE production contributes to the relative resistance of female Dahl S rats to target organ damage compared to males. Consistent to what we have previously reported, the time course for the development of proteinuria and renal injury were significantly reduced in female Dahl SSJr rats challenged with a high salt diet relative to male rats. In addition, renal cortical 20-HETE production was elevated in female (120.8±4.2 pmol/min/mg) versus male rats (45.1±11.78 pmol/min/mg), while no difference was noted in the outer medulla (19.6±1.8 vs 17.15± 3.9 pmol/min/mg). Introgression of the CYP4A1 gene into the Dahl S genetic background, resulted in significant elevations in 20-HETE production both on low salt and high salt diets. Furthermore the rise in mean arterial pressure was attenuated in CYP4A1 overexpressing rats in both sexes (Δ19mmHg in CYP females vs 61mmg in Dahl S females; 20mmHg in CYP males vs 50mmHg in Dahl S males). Moreover, the degree of glomerular injury was reduced in CYP rats, both male and female, compared to Dahl S rats in response to a high salt diet. Therefore, increases in the CYP gene expression and 20-HETE production prevent the rise in mean arterial pressure and kidney injury in male Dahl S rats. AHA 14SDG20160020

Heterozygous knockout of transforming growth factor-β1 protects Dahl S rats against high salt-induced renal injury

The present study employed a zinc-finger nuclease strategy to create heterozygous knockout (KO) rats for the transforming growth factor-β1 (Tgfb1) gene on the Dahl SS/Jr genetic background (TGF-β1(+/-) Dahl S). Intercrossing TGF-β1(+/-) rats did not produce any homozygous KO rats (66.4% +/-, 33.6% +/+), indicating that the mutation is embryonic lethal. Six-week-old wild-type (WT) littermates and TGF-β1(+/-) Dahl S rats were fed a 0.4% (low salt, LS) or 8% NaCl (high salt, HS) diet for 5 wk. Renal cortical expression of TGF-β1, urinary TGF-β1 excretion, proteinuria, glomerular injury and tubulointerstitial fibrosis, and systolic blood pressure were similar in WT and TGF-β1(+/-) Dahl S rats maintained on the LS diet. The expression and urinary excretion of TGF-β1 increased to a greater extent in WT than in TGF-β1(+/-)Dahl S rats fed an HS diet for 1 wk. Systolic blood pressure rose by the same extent to 235 ± 2 mmHg in WT and 239 ± 4 mmHg in TGF-β1(+/-) Dahl S rats fed a HS diet for 5 wk. However, urinary protein excretion was significantly lower in TGF-β1(+/-) Dahl S than in the WT animals. The degree of glomerular injury and renal cortical and outer medullary fibrosis was markedly less in TGF-β1(+/-) than in WT rats. These findings suggest that the loss of one copy of the TGF-β1 gene blunts the increase in renal TGF-β1 protein expression and slows the progression of proteinuria, glomerulosclerosis, and renal interstitial fibrosis in Dahl S rats fed an HS diet independently of changes in blood pressure.

Role of 20-HETE in the antihypertensive effect of transfer of chromosome 5 from Brown Norway to Dahl salt-sensitive rats

This study examined whether substitution of chromosome 5 containing the CYP4A genes from Brown Norway rat onto the Dahl S salt-sensitive (SS) genetic background upregulates the renal production of 20-HETE and attenuates the development of hypertension. The expression of CYP4A protein and the production of 20-HETE were significantly higher in the renal cortex and outer medulla of SS.5(BN) (chromosome 5-substituted Brown Norway rat) consomic rats fed either a low-salt (LS) or high-salt (HS) diet than that seen in SS rats. The increase in the renal production of 20-HETE in SS.5(BN) rats was associated with elevated expression of CYP4A2 mRNA. MAP measured by telemetry rose from 117 ± 1 to 183 ± 5 mmHg in SS rats fed a HS diet for 21 days, but only increased to 151 ± 5 mmHg in SS.5(BN) rats. The pressure-natriuretic and diuretic responses were twofold higher in SS.5(BN) rats compared with SS rats. Protein excretion rose to 354 ± 17 mg/day in SS rats fed a HS diet for 21 days compared with 205 ± 13 mg/day in the SS.5(BN) rats, and the degree of glomerular injury was reduced. Baseline glomerular capillary pressure (Pgc) was similar in SS.5(BN) rats (43 ± 1 mmHg) and Dahl S (44 ± 2 mmHg) rats. However, Pgc increased to 59 ± 3 mmHg in SS rats fed a HS diet for 7 days, while it remained unaltered in SS.5(BN) rats (43 ± 2 mmHg). Chronic administration of an inhibitor of the synthesis of 20-HETE (HET0016, 10 mg·kg(-1)·day(-1) iv) reversed the antihypertensive phenotype seen in the SS.5(BN) rats. These findings indicate that the transfer of chromosome 5 from the BN rat onto the SS genetic background increases the renal expression of CYP4A protein and the production of 20-HETE and that 20-HETE contributes to the antihypertensive and renoprotective effects seen in the SS.5(BN) consomic strain.

Mechanisms of Everolimus‐Induced Glomerulosclerosis After Glomerular Injury in the Rat

Despite the lack of nephrotoxicity, adverse effects of the new antiproliferative immunosuppressant everolimus have been reported. By varying time point and dose of everolimus treatment as well as the degree of glomerular injury, the specific conditions and potential mechanisms leading to adverse actions in the anti-Thy1 model have been determined. Only the combination of early and high-dose everolimus treatment (1-3 mg/kg bw) with a severe glomerular lesion ('full-dose' anti-Thy1 model) caused adverse effects with a high mortality rate, progressive apoptosis, crescent formation and glomerulosclerosis. In contrast, either later start or low-dose (0.3 mg/kg bw) therapy or treatment of a less severe lesion ('reduced dose' anti-Thy1 model) appeared to be relatively safe for the glomerular architecture. The adverse effects of everolimus were linked to its marked inhibition of endothelial cell, but not necessarily mesangial cell proliferation. In addition, everolimus markedly inhibited the angiogenic cytokine vascular endothelial growth factor in nephritic glomeruli in vivo. These experimental results suggest special caution regarding the use of everolimus in all situations of severe glomerular cell injury requiring extensive capillary repair, where at least adaption to a low dose needs to be considered.

Expression of decay accelerating factor mRNA and complement C3 mRNA in human diseased kidney

Decay accelerating factor (DAF), a product of mesangial cells in vitro, is expressed on the surface of cells and is a candidate for the focal suppression of complement activation. It is not clear at present whether the levels of expression of DAF and intrarenal C3 synthesis correlate with the level of tissue injury. Immunohistochemistry for DAF and C3 and nonradioactive in situ hybridization with digoxigenin-labeled oligonucleotide probe for DAF and C3 mRNA were performed in 22 tissue samples of kidneys from patients with IgA nephropathy (IgAN), 6 with membranous nephropathy (MN), 6 with lupus nephritis (LN), and five normal kidneys. In the normal kidney, DAF was confined to the juxtaglomerular apparatus and little or no C3 was detected; however, a few glomerular cells were positive for DAF mRNA but no C3 mRNA positive cells were detected. In diseased kidneys, DAF and C3 as well as their mRNAs were detected in mesangial cells, tubular cells and infiltrating cells. Glomerular epithelial cells and Bowman's capsule cells contained little or no DAF and C3 but were positive for their mRNAs. The mean percentages of mesangial cells positive for DAF and C3 mRNAs were 49.3 +/- 11.5% and 50.7 +/- 10.3% in IgAN, and 17.0 +/- 6.3% and 19.4 +/- 9.0% in MN, respectively. The percentage of mesangial cells positive for DAF and C3 mRNAs among intraglomerular cells correlated positively with the degree of mesangial proliferation and glomerular sclerosis in IgAN. In contrast, in LN the percentage of glomerular cells positive for DAF mRNA correlated negatively with the degree of glomerular injury, while the percentage of cells positive for C3 mRNA did not change with the progression of the disease. The ratio of C3 mRNA/DAF mRNA of glomerular cells correlated with the degree of glomerular injury in both IgAN and LN. In the tubulointerstitium, the percentage of cells expressing mRNA, and C3 mRNA/DAF mRNA radio correlated with the degree of tubular atrophy and interstitial broadening in both IgAN and LN. We conclude that DAF and C3 mRNAs are synthesized in human diseased kidneys, and that a balance between locally synthesized DAF and C3 may be important in the progression of glomerulonephritis.

Expression of endothelial and inducible nitric oxide synthase in human glomerulonephritis

The presence of nitric oxide (NO) in the kidney has been implicated in the pathogenesis of human glomerulonephritis. However, the exact type of glomerular cells that express NO synthase (NOS) and the NOS isoform involved in the local production of NO has not been identified in the human diseased kidney. We examined the expression of three isoforms of NOS, inducible NOS (iNOS), endothelial NOS (eNOS) and brain NOS (bNOS) in the renal tissue of patients with IgA nephropathy (IgAN, N = 10), lupus nephritis (LN, N = 5), membranous nephropathy (MN, N = 5) and minimal change nephrotic syndrome (MCNS, N = 5). Sections were immunostained and the correlation between the expression of each NOS and the degree of glomerular injury in that section was also examined. Normal portions of surgically resected kidneys served as controls. eNOS was present in glomerular endothelial cells and endothelium of cortical vessels in the control and diseased kidneys. iNOS was localized in mesangial cells, glomerular epithelial cells and infiltrating cells in the diseased glomeruli, whereas immunostaining for iNOS was hardly detected in control kidneys. In addition, the expression pattern of eNOS in each glomerulus was the reverse of that of iNOS. In IgAN and LN, the extent of staining for eNOS correlated negatively with the degree of glomerular injury, while the extent of staining for iNOS correlated positively with the degree of glomerular injury in the same tissues. bNOS was not detected in normal or nephritic glomeruli. Our results indicate the presence of a NO pathway in human diseased kidney, and suggest that NO derived from eNOS and iNOS may be involved in the progression of renal diseases and that NO derived from each NOS may play an important role in different way in human inflamed glomeruli.

Abrogation of glomerular injury in nephrotoxic nephritis by continuous infusion of interleukin-6

Interleukin-6 (IL-6) has been reported to have pro- and anti-inflammatory effects. It has also been shown to cause mesangial cell proliferation in vitro and has been suggested as a mediator of injury in proliferative nephritis. We have assessed the effects of continuous infusion of human recombinant (hr) IL-6, by osmotic minipump, on the degree of glomerular injury, and on glomerular and interstitial cell proliferation, in the accelerated autologous phase of nephrotoxic nephritis. Two groups of rats were pre-immunized with 1 mg of normal rabbit IgG in Freund's complete adjuvant. One week later, nephritis was induced by an intravenous injection of 1 ml of rabbit nephrotoxic serum. One day before the induction of nephritis, group 1 (N = 9) was subcutaneously implanted with osmotic minipumps filled with 50 micrograms (200 microliters) of IL-6 (equivalent to a dose of 6 micrograms/day), while in group 2 (N = 11) the minipumps were filled with 200 microliters of normal saline. In group 3 (N = 6) normal rats were infused with 50 micrograms of IL-6 alone. The rats were killed seven days after implantation of minipumps. The administered hrIL-6 was detectable in the circulation within the pathophysiological range, and induced a hepatic acute phase response, as assessed by alpha 2-macroglobulin levels. Continuous treatment with IL-6 resulted in a significant reduction in albuminuria (from 195 +/- 37 mg/20 hr to 60 +/- 15 mg/20 hr on day 1, and from 494 +/- 52 mg/20 hr to 238 +/- 30 mg/20 hr on day 7, P < 0.002) and in the prevalence of glomerular capillary thrombosis (from 19 +/- 3% to 5 +/- 1%, P < 0.002). There was also a reduction in macrophage infiltration (ED1 + ve cells from 524 +/- 34 to 466 +/- 14 per 50 glomeruli, P < 0.02) and activation (ED3 + ve cells from 106 +/- 13 to 42 +/- 5 per 50 glomeruli, P < 0.002). Immunohistology showed fewer interstitial Ia + ve cells (OX3 and OX4) in the IL-6 treated group. Similar results were obtained in a second set of experiments in which the IL-6 treatment was extended until day 14. Kidney sections taken from nephritic rats infused with IL-6 showed no increase in glomerular or interstitial cell proliferation when stained with antibodies to proliferating cell nuclear antigen. There was no difference in the deposition of rabbit IgG or rat IgG along the glomerular basement membrane (GBM), and the titer of rat anti-rabbit IgG was similar in the IL-6 and control treated rats. Infusion of IL-6 alone in normal rats had no functional or pathological effects. In conclusion, these results show that IL-6 has powerful anti-inflammatory effects in a rat model of anti-GBM nephritis, and does not induce mesangial cell proliferation in vivo.

Involvement of IL-4 in human glomerulonephritis: an in situ hybridization study of IL-4 mRNA and IL-4 receptor mRNA.

Interleukin-4 (IL-4) has been recently implicated in the pathogenesis of glomerulonephritis. However, the expression of IL-4 and IL-4 receptor (IL-4R) in human kidney has not been fully determined. Nonradioactive in situ hybridization was used to examine the expression of IL-4 mRNA and IL-4R mRNA in tissues from normal kidneys and specimens from a variety of human kidney diseases. In normal glomeruli, a few mesangial cells and cells of the Bowman's capsule weakly expressed IL-4 and IL-4R mRNA, whereas in diseased glomeruli both mRNA types were strongly expressed in resident glomerular cells, including mesangial cells, glomerular epithelial cells, and cells of the Bowman's capsule. The relationship between the expression of these mRNA and the degree of glomerular injury was different in different types of glomerulonephritis. In IgA nephropathy and non-IgA mesangial proliferative glomerulonephritis, IL-4 expression correlated positively with the degree of mesangial hypercellularity and extracellular matrix expansion. However, IL-4R expression was relatively constant. In contrast, the expression of IL-4 and IL-4R mRNA correlated negatively with the degree of glomerular injury in lupus nephritis. Coexpression and discordant expression of these mRNA forms were observed in individual cells. In tubulointerstitium with severe lesions, IL-4 mRNA and IL-4R mRNA were observed in atrophic tubules and some of the infiltrating cells and fibroblasts. The interstitial expression of these mRNA forms was similar in IgA nephropathy, non-IGA mesangial proliferative glomerulonephritis, and lupus nephritis and correlated positively with the degree of tubulo-interstitial changes. These results suggest that an autocrine and/or paracrine pathway of IL-4 is present in human diseased kidneys and that IL-4 may be involved in tissue injury in glomerulonephritis.

Gene expression of PDGF and PDGF receptor in various forms of glomerulonephritis.

Platelet-derived growth factor (PDGF) is an important mitogenic factor for various cells. In order to elucidate the role of PDGF in the development of human glomerulonephritis, we examined the gene and protein expression of the PDGF-B chain (PDGF-B) and PDGF-beta receptor (PDGFR-beta) in renal biopsy specimens from patients with various forms of glomerulonephritis using a nonradioactive in situ hybridization and an immunohistochemical technique. The mRNA expression of PDGF-B and PDGFR-beta was significantly increased in the glomeruli of patients with mesangial proliferative glomerulonephritis (IgA nephropathy, Henoch-Schönlein purpura nephritis, and lupus nephritis) compared with those in normal glomeruli. In cases with increased protein expression of PDGF-B and PDGFR-beta, each mRNA expression was also increased. The degree of glomerular injury was positively correlated with the number of mRNA-positive cells for both PDGF and PDGF receptor. There was also a positive correlation between the number of mRNA-positive cells for PDGF-B and PDGFR-beta. PDGF-B and PDGFR-beta were also expressed on cells of the capillary wall, cellular crescents and infiltrated cells in the interstitium. The results suggest that PDGF acts as an important and common mediator for the development of various forms of human mesangial proliferative glomerulonephritis. Furthermore, PDGF may participate in crescent formation and tubulo-interstitial injury.

Preglomerular sudanophilia in L-NAME hypertensive rats: involvement of endothelin.

To characterize alterations of renal vessels occurring during systemic hypertension elicited in rats by 5, 10, and 25 days of treatment by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME)(20 mg/kg daily), preglomerular vasculatures, consisting of arcuate arteries and their branches, interlobular arteries, and afferent arterioles, were isolated by HCl maceration. Blockade of nitric oxide synthase significantly increased tail-cuff systolic blood pressure by 21 +/- 2% and 42 +/- 3% after 5 and 25 days, respectively. Medias of hypertensive arcuate arterial branches and interlobular arteries but not of afferent arterioles had focal deposits of Sudan black-positive lipid droplets. At 25 days, vessel wall thickness increased by 72 +/- 6% along the sudanophilic areas. Immunostaining of sudanophilic lesions with a panel of antibodies unveiled medial cell proliferation, macrophage invasion, immunoreactive vascular cell adhesion molecule-1, and low-density lipoprotein. The frequency of sudanophilic lesions increased with time to affect 26 +/- 2% and 36 +/- 3% of arcuate arterial branches and interlobular arteries, respectively, at 25 days. Hypertensive L-NAME-treated rats developed glomerular injury probed by albuminuria and glomerular immunostaining for alpha-smooth muscle actin. Administration of the nonselective endothelin antagonist bosentan (30 mg/kg daily) blunted the development of sudanophilic lesions during L-NAME treatment without affecting arterial hypertension or degree of glomerular injury. Therefore, L-NAME hypertension leads to rapid development of focal, inflammatory, proliferative, and sudanophilic lesions along preglomerular vessels, suggesting atherosclerosis-like processes. Furthermore, endothelin is a likely mediator in the development of these lesions.

Influence of long-term treatment with the dihydropyridine-type calcium antagonist nicardipine on renal microanatomical changes in spontaneously hypertensive rats.

1. The influence of hypertension and treatment with the dihydropyridine-type Ca2+ antagonist, nicardipine, on the structure of the kidney was assessed in spontaneously hypertensive rats (SHR) of 12 weeks of age. Treatment went for 8 weeks with a daily oral dose of 1 mg/kg of nicardipine. 2. Control SHR exhibited hypertension and microanatomical vascular and glomerular changes. Vascular changes consisted of a thickening of the tunica media and decreased luminal area of medium- and small-sized intrarenal artery branches. Glomerular changes included glomerulosclerosis and atrophy of varying degrees. 3. Administration of nicardipine significantly reduced blood pressure. The drug also decreased the thickening of tunica media and luminal narrowing of renal artery branches as well as the degree of glomerular injury in SHR. 4. These data indicate that nicardipine treatment is able to control elevated blood pressure in SHR, and to counter hypertension-dependent microanatomical impairment of the kidney. This suggests that the compound exerts a protective effect on hypertensive kidney.