PubMed Health⌕ Search

Biomedical subjects

Gopala K Rangan

Publications and source records attributed to Gopala K Rangan.

16 recordsLinked to original sources
PubMed2006

DNA vaccination with CCL2 DNA modified by the addition of an adjuvant epitope protects against "nonimmune" toxic renal injury.

CC-chemokine-encoding DNA vaccine has been reported to be capable of inducing immunologic memory to corresponding pathogenic self CC-chemokines in animal models of autoimmune disease. This study investigated whether introduction of a foreign T helper epitope into monocyte chemoattractant protein 1 (CCL2) DNA vaccine could boost its immunogenicity by inducing strong neutralizing autoantibody against the pathogenic chemokine CCL2 sufficiently to be protective in a classically nonimmune model of disease, Adriamycin nephropathy (AN). Modification of the CCL2 DNA vaccine by replacing a surface loop region of CCL2 sequence with tetanus toxoid T helper epitope P30 elicited a strong self-specific CCL2 autoantibody production, as well as an IFN-gamma-producing T cell cellular response. The increased immunogenicity of modified CCL2 DNA vaccination but not unmodified CCL2 DNA vaccination was protective against functional and structural renal injury in rat AN. The protective effect of the modified CCL2 DNA vaccine was associated with blockade of glomerular and interstitial macrophage recruitment by neutralizing autoantibody against CCL2, which plays a critical role in eliciting renal injury in AN. Therefore, modification with a foreign T helper epitope breaks self-tolerance by inducing a cellular and humoral response against self-protein and provides a strategy to increase the potency of DNA vaccination sufficiently to afford protection in toxin-induced chronic renal disease.

Animals↗
PubMed2006

Significance of CD25 positive cells and macrophages in noncrescentic IgA nephropathy.

The aim of this study was to determine whether infiltration by CD25 positive cells, macrophages, and activated macrophages in the kidney is predictive of chronic histological injury and renal prognosis in adults with noncrescentic IgA nephropathy. Renal biopsies of 36 patients with noncrescentic IgA nephropathy were examined by immunohistochemistry for glomerular and interstitial CD4, CD8, and CD25 positive cells, monocytes/macrophage (Mac387), and activated macrophages (27E10). Renal injury (glomerulosclerosis, mesangial cell hypercellularity, tubular atrophy, and interstitial fibrosis) at the time of biopsy and renal prognosis (follow-up creatinine and creatinine clearance) were assessed. The mean follow-up period was 22.5 +/- 16.5 months. The number of interstitial CD8 positive cells was the best predictor of renal injury at the time of biopsy, and was positively correlated with glomerulosclerosis (p = 0.04), tubular atrophy (p = 0.04), and interstitial fibrosis (p = 0.01) but not with mesangial cell hypercellularity. The number of interstitial Mac387 and 27E10 positive cells were the best predictors of renal prognosis (r2 = 0.33 and 0.34 respectively, both p < 0.01). These data suggest the presence of CD8 cells and macrophages in the kidney at the time of biopsy could potentially serve as pathological markers to identify patients with IgA nephropathy, which may warrant more aggressive medical therapy.

Adult↗
PubMed2006

Sirolimus-associated proteinuria and renal dysfunction.

Sirolimus is a novel immunosuppressant with potent antiproliferative actions through its ability to inhibit the raptor-containing mammalian target of rapamycin protein kinase. Sirolimus represents a major therapeutic advance in the prevention of acute renal allograft rejection and chronic allograft nephropathy. Its role in the therapy of glomerulonephritis, autoimmunity, cystic renal diseases and renal cancer is under investigation. Because sirolimus does not share the vasomotor renal adverse effects exhibited by calcineurin inhibitors, it has been designated a 'non-nephrotoxic drug'. However, clinical reports suggest that, under some circumstances, sirolimus is associated with proteinuria and acute renal dysfunction. A common risk factor appears to be presence of pre-existing chronic renal damage. The mechanisms of sirolimus-associated proteinuria are multifactorial and may be due to an increase in glomerular capillary pressure following calcineurin inhibitor withdrawal. It has also been suggested that sirolimus directly causes increased glomerular permeability/injury, but evidence for this mechanism is currently inconclusive. The acute renal dysfunction associated with sirolimus (such as in delayed graft function) may be due to suppression of compensatory renal cell proliferation and survival/repair processes. Although these adverse effects occur in some patients, their occurrence could be minimised by knowledge of the molecular effects of sirolimus on the kidney, the use of sirolimus in appropriate patient populations, close monitoring of proteinuria and renal function, use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers if proteinuria occurs and withdrawal if needed. Further long-term analysis of renal allograft studies using sirolimus as de novo immunosuppression along with clinical and laboratory studies will refine these issues in the future.

Animals↗
PubMed2005

Effect of nephrotoxins on tubulointerstitial injury and NF-kappaB activation in Adriamycin nephropathy.

In a previous study we found that an episode of acute subclinical nephrotoxicity with gentamicin (G) (but not that induced by another proximal tubular cell nephrotoxin: ferric nitrilotriacetate, FeNTA), paradoxically reduced the progression of renal function and injury in uninephrectomized rats with nephrotic glomerular disease due to Adriamycin nephropathy (AN). Here, we hypothesized that subclinical exposure to G reduces early renal cortical tubulointerstitial inflammation and NF-kappaB activation in AN. To test this hypothesis, male Wistar rats with established AN received either G (10, 40, or 80 mg/kg by daily s.c.i. for 3 days), FeNTA (1.25, 5, or 10 mg/kg by a single i.p.i.), or vehicle (n=8 per group), 13 to 15 days after disease induction. Although G and FeNTA caused acute tubular necrosis in a dose-dependant manner (day 17), only the highest doses (10 mg/kg and 80 mg/kg) produced an acute elevation in the serum creatinine. On day 33, chronic tubulointerstitial inflammation (tubular atrophy, interstitial ED-1+/CD8+ cell accumulation) and NF-kappaB activation were exacerbated only in the groups that caused functional nephrotoxicity. These data suggest that: 1) the protective effect of subclinical G nephrotoxicity in chronic AN does not involve early changes in interstitial inflammation or NF-kappaB activation; and 2) a single episode of G exposure must be accompanied by clinically apparent nephrotoxicity in order to accelerate progression in a nonuremic model of chronic glomerular disease.

Animals↗
PubMed2005

Partial depletion of macrophages by ED7 reduces renal injury in Adriamycin nephropathy.

BACKGROUND: Because macrophages are considered to be possible effectors of disease in Adriamycin (ADR) nephrosis, we hypothesized that depletion of macrophages might protect against the initiation of renal injury. In the present study, a monoclonal antibody (ED7) directed against CD11b/CD18 integrin, which is expressed by macrophages, was used to investigate the pathogenetic effects of macrophages in ADR nephropathy. METHODS: Male Wistar rats were treated with ED7 antibody, starting 1 day prior to ADR (7.5 mg/kg) treatment, or 7 days post-ADR when overt proteinuria was established. RESULTS: Circulating ED7-positive cells were reduced by approximately 30% in rats with ADR nephrosis by the ED7 antibody, while the number of macrophages in the renal cortex of ADR rats was reduced by nearly 50% with the ED7 treatment, whether administered before or after ADR. Creatinine clearance was significantly ameliorated by ED7 when commenced pre-ADR (P < 0.05), but not when commenced post-ADR (P = NS) in comparison to untreated ADR rats. However, proteinuria was not alleviated by either ED7 treatment. Morphometric analysis showed less glomerular sclerosis when ED7 was commenced pre-ADR compared with ADR alone (P < 0.01), but not when commenced post-ADR (P = NS). Tubular atrophy was reduced by ED7 when it was commenced pre-ADR (tubular cell height and tubular diameter: P < 0.01 and P < 0.001, respectively), as was interstitial expansion (P < 0.01) compared with ADR alone. Cortical macrophage infiltration was reduced by 50% compared with ADR alone by the ED7 commenced before or after ADR. The number of cortical CD4+ T cells fell with ED7 starting pre-ADR, but not with the ED7 treatment commencing after ADR. CONCLUSION: Partial macrophage depletion starting before but not after ADR protected both renal function and structure in this model of chronic proteinuric renal disease.

Animals↗
PubMed2005

Can murine diabetic nephropathy be separated from superimposed acute renal failure?

BACKGROUND: Streptozotocin (STZ) is commonly used to induce diabetes in experimental animal models, but not without accompanying cytotoxic effects. This study was undertaken to (1) determine an optimal dose and administration route of STZ to induce diabetic nephropathy in wild-type mice but without the concurrent acute renal injury resulting from cytotoxic effects of STZ and (2) evaluate the pattern of tubular injury and interstitial inflammation in this model. METHODS: Male Balb/c mice received either (1) STZ (225 mg/kg by intraperitoneal injection.); or (2) two doses of STZ 5 days apart (150 mg/150 mg/kg; 75 mg/150 mg/kg; 75 mg/75 mg/kg; and 100 mg/100 mg/kg by intravenous injection). Another strain of mice, C57BL/6J, also received STZ (200 mg/kg intravenously or intraperitoneally). Renal function and histology were examined at weeks 1, 2, 4, and 8 after induction of diabetes. In initial optimization studies, animals were sacrificed at week 1 or week 2 and histology examined for acute renal injury. RESULTS: Following a single intraperitoneal injection of 225 mg/kg of STZ, only two thirds of animals developed hyperglycemia, yet the model was associated with focal areas of acute tubular necrosis (ATN) at week 2. ATN was also observed in C57BL/6J mice given a single intravenous or intraperitoneal dose of STZ (200 mg/kg), at week 2 post-diabetes. At an optimal diabetogenic dose and route (75 mg/150 mg/kg by intravenous injection 5 days apart), all mice developed diabetes and no ATN was observed histologically. However, even with this regimen, glomerular filtration rate (GFR) was significantly impaired from week 2. This regimen was accompanied by progressive histologic changes, including tubular and glomerular hypertrophy, mesangial area expansion, as well as interstitial macrophage, CD4+ and CD8+ T-cell accumulation. CONCLUSION: By careful optimization of STZ dose, a stable and reproducible diabetic murine model was established. However, even in this optimized model, renal functional impairment was observed. The frequency of ATN and functional impairment casts doubt on conclusions about experimental diabetic nephropathy drawn from reports in which ATN has not been excluded rigorously.

Acute Kidney Injury↗
PubMed2005

Rapamycin worsens renal function and intratubular cast formation in protein overload nephropathy.

BACKGROUND: Rapamycin (sirolimus) is associated with functional nephrotoxicity in some patients with nephrotic glomerular diseases but the pathophysiologic mechanisms are not known. This study investigated the effects of rapamycin on renal function and structure in protein overload nephropathy. METHODS: Rats with protein overload nephropathy [induced by bovine serum albumin (BSA), 2.1 g by daily intraperitoneal injection, day 0 to day 3] received daily intraperitoneal injections of either vehicle [dimethyl sulfoxide (DMSO)], rapamycin (0.2 mg/kg, an inhibitor of mammalian target of rapamycin), or roscovitine (3.5 mg/kg, a small molecule cyclin-dependent kinase inhibitor) (N= 9 each) from day -3 to day 3. RESULTS: In protein overload nephropathy, rapamycin caused severe acute renal failure and mild hypercholesterolemia (both P < 0.05). Rapamycin dramatically increased intratubular cast formation, and proximal tubular epithelial cells were swollen and engorged with increased cytoplasmic protein droplets. The number of 5-bromo-2'-deoxyuridine (BrdU)-positive tubular epithelial cells increased by more than 20-fold on day 3 in protein overload nephropathy, and this was attenuated by 65% with rapamycin (P < 0.05), whereas roscovitine was ineffective. Rapamycin increased the protein expression of p27(kip1) in tubular epithelial cells, but did not alter D-type cyclin expression or apoptosis. CONCLUSION: Rapamycin caused a specific pattern of acute renal injury characterized by increased intratubular cast formation in protein overload nephropathy. This could be due to disruption of a potentially important compensatory mechanism in nephrotic glomerular diseases involving tubular epithelial cell protein endocytosis and proliferation.

Acute Kidney Injury↗
PubMed2005

C5b-9 does not mediate chronic tubulointerstitial disease in the absence of proteinuria.

BACKGROUND: In nephrotic glomerular diseases, the intratubular assembly of the membrane attack complex (C5b-9) is one of the principal mediators of chronic tubulointerstitial damage. Here, we examined whether C5b-9 has a pathogenic role in tubulointerstitial disease in the absence of proteinuria. METHODS: Three pathophysiologically distinct models of nonproteinuric chronic tubulointerstitial disease were induced in Piebald-Viral-Glaxo (PVG) rats, with or without C6 deficiency (C6+ and C6): (1) unilateral ureteric obstruction (UUO, days 1, 3, 6, 14, and 21; N= 5-6/group); (2) cyclosporine (CsA) nephropathy (15 mg/kg SC daily with 0.05% sodium diet; day 14, 35 N= 9/group); and (3) streptozotocin (STZ)-induced diabetes (day 90, N= 8/group). RESULTS: The peritubular deposition of C5b-9 increased in all three models. In UUO, the number of vimentin-positive tubules, interstitial volume expansion, and monocyte accumulation were similar in both the C6+ and C6- groups at all time points. There was a trend toward an earlier peak in myofibroblast accumulation in C6- rats with UUO (d3 vs. d6; P= 0.05), but this did not prevent fibrosis at later time points. In CsA nephropathy, cortical tubulointerstitial damage was also similar in both C6+ and C6- groups on day 14, despite equivalent CsA trough levels. Finally, in STZ-induced diabetes, rats did not develop proteinuria, and tubulointerstitial disease (distal tubule glycogen nephrosis, interstitial volume expansion, and tubular dilatation) was not altered by C6 deficiency. CONCLUSION: These data suggest that, in contrast to proteinuric states, C5b-9 does not have a significant impact on the progression of tubulointerstitial damage in nonproteinuric chronic renal disease.

Animals↗
PubMed2004

C5b-9 regulates peritubular myofibroblast accumulation in experimental focal segmental glomerulosclerosis.

BACKGROUND: In human focal segmental glomerulosclerosis (FSGS), the tubulointerstitial deposition of the complement (C5b-9) membrane attack complex is correlated with interstitial myofibroblast accumulation and proteinuria. Here, we hypothesized that C5b-9 formation regulates renal myofibroblast accumulation in Adriamycin nephropathy. METHODS: Adriamycin nephropathy was induced in complement C6-sufficient (C6+) and C6-deficient (C6-) piebold viral glaxo (PVG) rats. Groups of animals (N= 7 to 8 each) were examined on days 21 and 42. A group of C6+ animals, injected with vehicle, served as the control group. RESULTS: C6+ and C6- rats with Adriamycin nephropathy had equivalent proteinuria. C5b-9 deposition was increased and present on the apical surface of proximal tubular epithelial cells (day 21 and 42) and peritubular region (day 42 only) in C6+ rats with Adriamycin nephropathy, and absent in C6- rats. Peritubular myofibroblast accumulation increased in a time-dependent manner in C6+ proteinuric rats (control 1.2 +/- 0.4; Adriamycin nephropathy day 21 11.0 +/- 0.7; Adriamycin nephropathy day 42 19.8 +/- 1.7 cells per high power field). In C6- rats this increase was blunted by 87% and 56% on days 21 and 42, respectively (P < 0.01), and was associated with reduced interstitial extracellular matrix (ECM) deposition. Tubulointerstitial injury, tubular vimentin and interstitial monocyte accumulation were also reduced in C6- rats with Adriamycin nephropathy on day 21, but not at day 42. In contrast, the increase in periglomerular myofibroblast accumulation and glomerulosclerosis in Adriamycin nephropathy were not altered by C6 deficiency. CONCLUSION: These data suggest that glomerular ultrafiltration of complement components and the intratubular formation of C5b-9 is a specific promotor of peritubular myofibroblast accumulation in FSGS.

Animals↗
PubMed2002

Dietary quercetin augments activator protein-1 and does not reduce nuclear factor-kappa B in the renal cortex of rats with established chronic glomerular disease.

BACKGROUND/AIMS: Quercetin, a naturally occurring dietary flavonoid, is a potent in vitro inhibitor of the transcription factors, nuclear factor (NF)-kappa B and activator protein (AP)-1. Here we investigated the efficacy of quercetin to suppress renal cortical NF-kappa B/AP-1 activation and tubulointerstitial injury, in vivo, in a nephrotic rat model of chronic glomerular disease. METHODS: Adult male Wistar rats with (n = 27) or without (n = 15) Adriamycin nephropathy (AN) were stratified into six groups (according to proteinuria and endogenous creatinine clearance, measured on day 10) and pair-fed a semipurified diet supplemented with or without quercetin (0.5, 2%) from day 14 to 36. RESULTS: Quercetin-fed rats had minimal weight gain during the study (p < 0.05). In AN, proteinuria, the decline in endogenous creatinine clearance, hypercholesterolaemia and cortical tubulointerstitial injury were not reduced by quercetin. Quercetin had no effect on renal cortical NF-kappa B activation, but unexpectedly exacerbated the induction of AP-1 in AN (by 67%, p < 0.05). In normal rats, quercetin increased proteinuria (by 75%, p < 0.05), renal cortical AP-1 activation (by 198%, p = 0.06), and malondialdehyde production (by 110%, p < 0.05). CONCLUSION: These data suggest that supplementation of the diet with quercetin is not an effective therapeutic strategy alone to reduce NF-kappa B/ AP-1 activation in chronic glomerular diseases, and paradoxically could be associated with adverse renal effects.

Animals↗
PubMed2001

Pharmacologic modulators of nitric oxide exacerbate tubulointerstitial inflammation in proteinuric rats.

Nitric oxide (NO) regulates inflammatory responses partly by cell-specific inhibition of the transcription factor nuclear factor kappaB (NF-kappaB). This study investigated the effect of continuous oral administration of an NO donor (molsidomine [Mol]), NO precursor (L-arginine [L-arg]), or selective inhibitors of inducible NO synthase (iNOS; aminoguanidine [AG], L-N(6)-(1-iminoethyl)lysine [L-NIL]) on the progression of tubulointerstitial inflammation and NF-kappaB activation in a non-immune model of chronic glomerular disease (Adriamycin nephropathy [AN]), from day 8 until day 30 after disease induction. On day 30, rats with AN had heavy proteinuria, reduced creatinine clearance, and tubulointerstitial disease. Treatment with both AG and L-NIL exacerbated the progression of AN as evidenced by (1) increased renal cortical malondialdehyde; (2) reduced creatinine clearance; and (3) increased tubular atrophy, interstitial volume, and monocyte infiltration. Unexpectedly, Mol also increased renal malondialdehyde and worsened tubular injury, whereas L-arg had no effect. The increase in renal cortical NF-kappaB activation in AN was not altered by AG, L-NIL, or Mol, but the mRNA expression of monocyte chemoattractant protein-1, interleukin-10, and osteopontin were elevated in these groups. Nitrite release from kidney slices reduced in AN. Treatment with Mol restored renal nitrite release to normal, whereas neither L-arg nor the NOS inhibitors had an effect. It is concluded that endogenous iNOS-derived NO has a protective role against tubulointerstitial injury and cytokine production in AN. However, the pro-oxidant activity of NO donors may limit their potential benefit in proteinuric renal disease.

Animals↗