lisinopril and Nephrosis

Nephrin, podocin, CD2AP, and alpha-actinin-4 are important podocyte proteins that help maintain the integrity of the slit diaphragm and prevent proteinuria. Studies have shown that angiotensin-converting enzyme inhibitors, glucocorticoids, and all-trans retinoic acid (ATRA) have antiproteinuric effects. However, it is still unclear whether these drugs, with different pharmacological mechanisms, lead to a reduction in proteinuria by changing the expression and distribution of these important podocyte proteins. In this study, changes in the expression and distribution of nephrin, podocin, CD2AP, and alpha-actinin-4 were dynamically detected in Adriamycin-induced nephrotic (ADR) rats treated with three different drugs: lisinopril, prednisone, and ATRA. Nephropathy was induced by an intravenous injection of Adriamycin. After Adriamycin injection, rats received lisinopril, prednisone, and ATRA treatment, respectively. Renal tissues were collected at Days 3, 7, 14, and 28. The distribution and the expression of messenger RNA and protein of nephrin, podocin, CD2AP, and alpha-actinin-4 were detected by indirect immunofluorescence, real-time polymerase chain reaction, and Western blotting, respectively. With the intervention of lisinopril, prednisone, and ATRA, changes in the expression of nephrin, podocin, and CD2AP were diverse, which was different from that detected in ADR rats. After lisinopril and prednisone intervention, podocin exhibited prominent earlier changes compared with those of nephrin and CD2AP, whereas CD2AP showed more prominent changes after ATRA intervention. There was no change in the expression of alpha-actinin-4 molecule. In summary, we conclude that the antiproteinuric effects of lisinopril, prednisone, and ATRA were achieved by changes in the expression and distribution of the important podocyte molecules nephrin, podocin, CD2AP, and alpha-actinin-4. The pattern in the change of podocyte molecules after lisinopril and prednisone intervention was similar, but the pattern in the change of podocyte molecules after ATRA intervention was different from that of lisinopril or prednisone intervention.

Topics: Actinin; Adaptor Proteins, Vesicular Transport; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibiotics, Antineoplastic; Doxorubicin; Glucocorticoids; Intracellular Signaling Peptides and Proteins; Kidney Glomerulus; Lisinopril; Male; Membrane Proteins; Microfilament Proteins; Nephrosis; Podocytes; Prednisone; Proteinuria; Random Allocation; Rats; Rats, Sprague-Dawley; Tretinoin

Control of blood pressure (BP) and optimal reduction of proteinuria (Uprot) are necessary for long-term renoprotection. Unfortunately, angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II (Ang II) antagonists are not effective during sodium repletion. Vasopeptidase inhibitors (VPI) cause dual inhibition of ACE and neutral endopeptidase, the latter resulting in decreased atrial natriuretic peptide (ANP) breakdown and thus enhanced natriuresis. Therefore, in contrast with ACEI, VPI may be effective during high sodium intake.. To test this hypothesis, the renoprotective actions of the new VPI gemopatrilat (GEM) were studied during low (0.05% NaCl) and high (3.0% NaCl) sodium diets in normotensive Wistar rats with established adriamycin nephrosis. The ACEI lisinopril (LIS) was used as control. Rats received either GEM (0.3 mg/g chow), an equihypotensive dose of LIS (75 mg/L drinking water), or vehicle (VEH) from week 6 (that is, established Uprot) until sacrifice. The effect of therapy was monitored by measuring systolic BP and Uprot (weekly) and structural renal damage at the end of study (week 16).. During low sodium, GEM effectively reduced Uprot (-48 +/- 4%), but LIS was more effective (-80 +/- 2%), while Uprot slightly increased in VEH (+23 +/- 2%). The focal glomerulosclerosis (FGS) score after GEM (38 +/- 14) was lower than in the VEH group (79 +/- 27), although this was not significant. LIS (18 +/- 6) reduced FGS significantly. Remarkably, on high sodium, GEM was completely ineffective in reducing BP, Uprot and structural renal injury, just like LIS.. The renoprotective actions of VPI depend on dietary sodium intake in normotensive nephrotic rats: therapeutic efficacy is fully blunted by a high sodium diet. During a low sodium diet, gemopatrilat was renoprotective, but less effective than lisinopril. Whether higher doses of the VPI could improve its renoprotective efficacy remains to be elucidated.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Azepines; Blood Pressure; Creatinine; Enzyme Inhibitors; Lisinopril; Male; Nephrosis; Neprilysin; Proteinuria; Rats; Rats, Wistar; Sodium, Dietary

A direct consequence of glomerular protein leakage is an increased exposure of proximal tubular cells to proteins. The aim of the present study was to examine whether chronic proteinuria affects the tubular handling of proteins and whether anti-proteinuric therapy by angiotensin-converting-enzyme (ACE) inhibition restores this tubular function. Renal uptake and catabolic rate of the low-molecular-weight protein (LMWP) myoglobin was determined in anaesthetized control and adriamycin-induced nephrotic rats by external counting after radiolabelling. Proteinuria correlated with the uptake as well as the catabolism of myoglobin. The higher the proteinuria, the lower was the renal uptake of myoglobin (r =0.72, P =0.002). Also, the catabolic rate of myoglobin (r =0.80, P =0.0002) was lower with increasing severity of proteinuria. During treatment with the ACE inhibitor lisinopril, proteinuria was lowered by 79+/-9% (mean+/-S.E.M.). Renal uptake and catabolic rate of the LMWP were not restored by ACE inhibition. The catabolic rate of myoglobin was even decreased further with 48+/-5% compared with pretreatment levels. In summary, adriamycin-induced proteinuria is associated with a lower uptake and a lower catabolic rate of LMWP in the proximal tubule. ACE inhibition lowers proteinuria, but does not restore the affected LMWP uptake and rate of catabolism. The rate of LMWP catabolism is even decreased further. In contrast, the urinary excretion of N -acetyl glucosaminidase, the tubular marker of toxicity, was effectively returned to normal levels during ACE inhibition. Taken together, the data suggest that proteinuria is toxic for the proximal tubular cells and that ACE inhibition protects the remaining functional tubular cells directly against destruction through decreasing hypercatabolism.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antibiotics, Antineoplastic; Doxorubicin; Iodine Radioisotopes; Kidney Tubules; Lisinopril; Male; Models, Animal; Myoglobin; Nephrosis; Proteinuria; Rats; Rats, Wistar

Angiotensin-converting enzyme (ACE) inhibitors provide renoprotection, but there is considerable interindividual variability in therapeutic efficacy, with residual proteinuria and progressive renal function loss in many individuals. This requires additional strategies to optimize therapy response, particularly for individuals with a poor response to ACE inhibition. We studied whether co-treatment with an angiotensin II subtype 1 (AT1) receptor antagonist (AII-A) improves the individual antiproteinuric response of maximal ACE inhibition in established adriamycin nephrosis.. Rats were instituted on lisinopril (75 mg/L) six weeks after disease induction. After two weeks rats were re-stratified for residual proteinuria to continue this regimen, to a higher dose of lisinopril (150 mg/L) or to co-treatment with the AII-A L 158,809 for another four weeks. Groups on monotherapy AII-A and vehicle served as controls (all groups N=15).. Lisinopril lowered proteinuria by 63% from 741 to 246 g/day (range of percentage change -90 to +2%). Neither increasing the dose of the ACE inhibitor nor addition of AII-A to ACE inhibition improved the antiproteinuric efficacy on a group or individual level: non-responders remained non-responders. All drug categories reduced hard end-points of focal glomerulosclerosis to a similar degree.. ACE inhibition has variable renal protective efficacy in the adriamycin model. Neither increasing the dose of the ACE inhibitor beyond the optimal level nor co-treatment with AII-A overcome the individual therapy resistance. Thus, in established adriamycin nephrosis, blockade of the renin-angiotensin system at two different levels offers no additional benefit over ACE inhibition alone, either on the group or individual level.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Antineoplastic Agents; Blood Pressure; Body Weight; Disease Models, Animal; Doxorubicin; Drug Resistance; Drug Therapy, Combination; Glomerulosclerosis, Focal Segmental; Imidazoles; Lisinopril; Male; Nephrosis; Proteinuria; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Tetrazoles

ACE inhibition exerts an antiproteinuric and renoprotective effect. However, residual proteinuria is often present. As residual proteinuria is associated with a poor renal outcome, identification of its determinants is important. We found previously that the systemic sequelae of proteinuria enhance renal damage in untreated nephrotic rats. The impact of systemic nephrosis on renal therapy response, however, is unclear. In the present study we therefore investigated whether the severity of systemic nephrosis, estimated from plasma cholesterol, predicts residual proteinuria during ACE inhibition.. Sixty male Wistar rats with established adriamycin nephrosis were studied. Six weeks after the induction of nephrosis, rats were stratified for proteinuria and treated for 2 weeks with lisinopril (75 mg/l) or vehicle.. At the start of treatment, median proteinuria was 744 mg/day (95% confidence interval (CI) 609-860) and plasma cholesterol was 10.4 mmol/l (95% CI 8.0-12.6), reflecting the state of systemic nephrosis. Lisinopril, but not vehicle, reduced blood pressure and proteinuria (-62%; range -70 to -48; P<0.001). Residual proteinuria was 275 mg/day, with a wide range (47-1119 mg/day). Pre-treatment proteinuria and pre-treatment cholesterol correlated positively with residual proteinuria. By multivariate analysis (r(2) of model =0.92), both pre-treatment cholesterol and pre-treatment proteinuria were independent predictors of residual proteinuria. The quantitative impact of this multivariate analysis is illustrated by the difference in residual proteinuria between rats with a cholesterol:proteinuria ratio less than, compared with greater than, the median (residual proteinuria 298 mg/day (CI 129-496) vs 439 mg/day (CI 158-670), respectively). Blood pressure response was not predicted by the tested predictor variables.. In this model of proteinuria-induced renal damage, not only proteinuria as such, but also the concomitant nephrotic alterations predict residual proteinuria. Further studies, applying specific interventions, are needed to determine which components of the systemic derangements could play a causal role in the modulation of therapy response.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cholesterol; Doxorubicin; Drug Administration Schedule; Lisinopril; Male; Nephrosis; Prognosis; Proteinuria; Rats; Rats, Wistar; Severity of Illness Index

The gradual onset of the antiproteinuric effects of ACE inhibition suggests that structural effects on the glomerular basement membrane (GBM) may be involved in their renoprotective action. To test this hypothesis, we studied the effects of lisinopril (5 mg/kg/24 h) on proteinuria, focal glomerulosclerosis (FGS) and glomerular heparan sulfate (HS) proteoglycan (HSPG) GBM staining in rats with established Adriamycin nephrosis. Treatment was started 6 weeks after disease induction. As expected, lisinopril reduced blood pressure, proteinuria and the FGS score. In control rats, Adriamycin nephrosis was associated with significantly impaired GBM staining for both HSPG core protein (assessed from BL-31 staining) and HS staining (assessed from JM-403 staining) 12 weeks after disease induction. In rats treated with lisinopril (5 mg/kg/24 h) GBM staining was significantly better preserved for HS as well as for HSPG core protein. These data suggest that structural effects on the GBM, improving glomerular permselectivity, may be involved in the renoprotective effects of ACE inhibition in proteinuria-induced renal damage.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Basement Membrane; Doxorubicin; Glomerulosclerosis, Focal Segmental; Heparan Sulfate Proteoglycans; Kidney Glomerulus; Lisinopril; Male; Nephrosis; Proteinuria; Rats; Rats, Wistar

Angiotensin-converting enzyme (ACE) inhibition reduces proteinuria in established adriamycin nephrosis. To investigate whether the reduction in proteinuria is due to decreased generation of angiotensin II (AngII) or to decreased degradation of bradykinin, four series of experiments in established adriamycin nephrosis were performed. In the first series, 2 mg/kg lisinopril reduced BP from 117 +/- 4 to 67 +/- 2 mmHg and proteinuria from 335 +/- 66 to 57 +/- 10 mg/24 h after 2 wk of treatment. Subsequent continuous intraperitoneal infusion of AngII (250 ng/kg per min) for 2 wk partially restored proteinuria to 180 +/- 42 mg/24 h, whereas BP increased to 97 +/- 3 mmHg. Subsequent withdrawal of AngII restored the antiproteinuric effects of lisinopril, whereas subsequent withdrawal of lisinopril restored proteinuria to pretreatment values. In the second series, AT1 receptor blockade induced a fall in BP and proteinuria similar to that by lisinopril. In the third series, lisinopril reduced BP from 121 +/- 5 to 68 +/- 2 mmHg and proteinuria from 355 +/- 90 to 101 +/- 10 mg/24 h. Subsequent intraperitoneal infusion of bradykinin antagonist (HOE 140; 1 mg/kg per 24 h) for 2 wk did not affect BP (72 +/- 2 mmHg) or proteinuria (92 +/- 15 mg/24 h). In the fourth series, bradykinin (3 mg/kg per 24 h) was infused for 2 wk to mimic decreased bradykinin breakdown. This did not affect proteinuria, but induced a fall in BP from 114 +/- 3 to 93 +/- 4 mmHg. The BP-lowering effect of exogenous bradykinin was completely reversed by 1 wk infusion of HOE 140 (93 +/- 4 to 113 +/- 4 mmHg), while proteinuria remained unchanged. In conclusion, the antiproteinuric effect of ACE inhibition appears to be independent of bradykinin in this model, supporting a main role for reduction of AngII in the antiproteinuric action of ACE inhibition.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Doxorubicin; Injections, Intraperitoneal; Lisinopril; Male; Nephrosis; Proteinuria; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Time Factors

The therapeutic effects of angiotensin converting enzyme inhibitor, lisinopril, on puromycin aminonucleoside (PAN)-induced nephrosis were investigated using unilaterally nephrectomized rats. Lisinopril showed potent dual effects on PAN nephrosis. Lisinopril treatment (50 mg/l in drinking water) from day 5 or day 9 reduced urinary protein excretion and suppressed the development of glomerular sclerosis at 8 weeks after PAN injection (150 mg/kg, i.p.), indicating a therapeutic effect on the nephrosis. Recovery of decreased anionic charge sites on the glomerular basement membrane was involved, at least in part, in the therapeutic action of lisinopril against proteinuria. On the other hand, oliguria and progressive azotemia derived from continuous deterioration of the renal function was induced if the treatment of lisinopril was started on the same day as PAN injection. The renal dysfunction induced by simultaneous administration of lisinopril with PAN could be abolished by combination dosing with sarcosine, an angiotensin II (AII)-receptor agonist. These results indicate that lisinopril treatment attenuates proteinuria by ameliorating the anionic charge barrier on the glomerular basement membrane and that it also protects against the development of chronic renal disease with segmental glomerular sclerosis, although AII depletion during the acute nephrotic stage exacerbates the renal damage in PAN nephrosis of unilaterally nephrectomized rats.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Bacterial Agents; Basement Membrane; Body Weight; Drug Interactions; Injections, Intraperitoneal; Kidney Glomerulus; Lisinopril; Male; Microscopy, Electron; Nephrectomy; Nephrosis; Oliguria; Proteinuria; Puromycin; Rats; Rats, Wistar; Receptors, Angiotensin; Sarcosine; Uremia

1. The mechanism of renal protection by angiotensin-converting enzyme inhibition is still the subject of debate. Inhibition of proteinuria might play a role. If so, a good antiproteinuric response to angiotensin-converting enzyme inhibition should predict subsequent protection against renal structural damage. This hypothesis has not been tested in models where treatment is started after the renal disease is well established, i.e. models that mimic the clinical situation. 2. We therefore investigated this hypothesis in 96 male Wistar rats with established adriamycin nephrosis. Reduction of proteinuria was achieved by lisinopril (0, 2, 5 and 10 mg day-1 kg-1) on two different sodium diets (0.3% and 0.05% NaCl). Therapy started 6 weeks after adriamycin (at stable proteinuria) and was continued for 6 weeks. 3. Lisinopril reduced blood pressure by 32 +/- 4% and proteinuria by an average of 72 +/- 7%, with stabilization after 2 weeks. Considerable interindividual differences in antiproteinuric response was found. Glomerulosclerosis score was reduced by 15 +/- 5%. All the effects of angiotensin-converting enzyme inhibitors were enhanced by sodium depletion, but sodium depletion in itself did not affect blood pressure (124 +/- 4 mmHg), proteinuria (664 +/- 68 mg/day) or glomerulosclerosis score (30 +/- 5%). Interestingly, the more proteinuria was reduced initially in an individual rat, the less sclerosis was found in the long term in that rat. 4. In conclusion, angiotensin-converting enzyme inhibition lowers proteinuria and prevents glomerulosclerosis in established adriamycin nephrosis. These effects are enhanced by sodium depletion. The individual short-term antiproteinuric effect predicts the protection against ultimate glomerular damage. This is consistent with the hypothesis that reduction of proteinuria is a mechanism by which angiotensin-converting enzyme inhibitors exert renoprotection.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antibiotics, Antineoplastic; Blood Pressure; Doxorubicin; Glomerulosclerosis, Focal Segmental; Lisinopril; Male; Nephrosis; Proteinuria; Rats; Rats, Wistar; Sodium