Nephropathy in patients with type 2 diabetes mellitus.
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Angiotensin-Converting Enzyme Inhibitors↗
Biomedical subjects
S R Orth
Publications and source records attributed to S R Orth.
The ET(A) receptor blocker LU 135252 prevents chronic transplant nephropathy in the "Fisher to Lewis" model.
The effect of the orally highly bioavailable and specific endothelin A (ET(A)) receptor antagonist LU 135252 was assessed in a model of chronic renal allograft nephropathy. Kidneys of Fisher rats were orthotopically grafted to Lewis rats. Fisher autografts and kidneys after uninephrectomy served as controls. All animals received low-dose cyclosporin A (CsA; 1.5 mg/kg body wt) for 10 d after surgery. Allotransplanted animals were then randomized to receive standard diet or a diet designed to deliver 30 mg of LU 135252/kg body wt per d for 35 wk. BP was monitored telemetrically. Treatment with LU 135252 did not affect systolic or diastolic pressure. Indices of glomerulosclerosis (GSI), and tubulointerstitial and vascular damage were measured. Chronic transplant nephropathy was almost completely prevented by LU 135252 compared with untreated allografts or kidneys of uninephrectomized controls, i.e., GSI 0.7 +/- 0.12 versus 1.6 +/- 0.25 (P < 0.001) versus 0.7 +/- 0.06 (P < 0.001). Allograft weight and serum creatinine were significantly lower in treated versus untreated animals. The results are consistent with the notion that ET(A) receptor-mediated events play a role in the genesis of chronic transplant nephropathy.
Animals↗
Smoking as a risk factor for end-stage renal failure in men with primary renal disease.
BACKGROUND: It is not known whether smoking increases the risk of end-stage renal failure (ESRF) in patients with primary renal disease. METHODS: We performed a retrospective multicenter case-control study including 582 patients from nine centers in Germany, Italy and Austria. The diseases investigated were IgA glomerulonephritis (IgA-GN) as a model of inflammatory renal disease and autosomal dominant polycystic kidney disease (ADPKD) as a model of non-inflammatory renal disease. Cases were patients who had progressed to ESRF and controls were patients who were not in ESRF, that is, whose serum-creatinine failed to progress to >3 mg/dl during the observation period and who did not require renal replacement therapy. Matching for renal disease (IgA-GN, ADPKD), gender, age at renal death and region of residence resulted in 102 individually matched pairs (IgA-GN N = 54, ADPKD N = 48). Multiple conditional logistic regression was used to estimate adjusted odds ratios for independent tobacco effects. RESULTS: In men (matched pairs: IgA-GN N = 44, ADPKD N = 28), a significant dose-dependent increase of the risk to progress to ESRF was found (non-adjusted). The baseline risk was defined as <5 pack-years (PY): (i) 5 to 15 PY, odds ratio 3.5 (95% CI 1.3 to 9.6), P = 0.017; (ii) >15 PY = 5.8 (2.0 to 17), P = 0.001. Systolic blood pressure, ACE inhibitor treatment and age at diagnosis emerged as potential confounders. After adjustment, the risk for ESRF in men with >5 PY was highly increased for patients without ACE inhibitor treatment [10.1 (2.3 to 45), P = 0.002] but not with ACE inhibitor treatment [1.4 (0.3 to 7.1), P = 0.65]. CONCLUSION: Smoking increases the risk of ESRF in men with inflammatory and non-inflammatory renal disease.
Adult↗
Effect of 1,25 (OH)2 vitamin D3 on glomerulosclerosis in subtotally nephrectomized rats.
In the past, there has been considerable concern that treatment with active vitamin D might accelerate progression independent of hypercalcemia and hypercalcuria. Nevertheless, 1,25(OH)2D3 has known antiproliferative properties and has also been shown to inhibit renal growth. Since glomerular growth is a permissive factor for the development of glomerulosclerosis, we reasoned that 1,25(OH)2D3 might even attenuate progression. To test this working hypothesis we performed two experiments of 8 and 16 weeks duration, respectively, to compare subtotally nephrectomized (SNX) rats treated with ethanol and SNX treated with 1,25(OH)2D3. Control animals were sham operated and pair-fed with SNX animals. 1,25(OH)2D3 (3 ng/100 g body wt/day) was administered by osmotic minipump. 1,25(OH)2D3 had no significant effect on systolic blood pressure and only a transient effect on weight gain. SNX reduced the number of glomeruli (left kidney) from an average of 3.3 x 10(4) to 1.2 x 10(4) per kidney. Mean glomerular volume was 3.87 +/- 0.71 x 10(6) microns 3 in sham operated animals and significantly (P < 0.05) higher (10.1 +/- 1.75 x 10(6) microns 3) in untreated animals 16 weeks after SNX. Glomerular volume was significantly (P < 0.05) less in 1,25(OH)2D3 treated SNX [10.1 +/- 1.75 in ethanol vs. 7.04 +/- 1.78 in 1,25(OH)2D3 treated SNX]. In parallel, there was significantly (P < 0.01) less glomerulosclerosis [glomerulosclerosis index 1.16 +/- 0.14 in the ethanol treated SNX vs. 0.80 +/- 0.16 in SNX treated with 1,25(OH)2D3] in the eight week experiment. Albuminuria was significantly (P < 0.01) lower in 1,25(OH)2D3 treated than in ethanol treated SNX (mean 0.785 mg/24 hr, range 0.43 to 1.80, vs. 3.75 mg/24 hr, 1.29 to 14.2). The morphological data were directionally analogous in a second 16 week experiment. Only slight changes of the vascular sclerosis index and tubulointerstitial index were seen in SNX and were not affected by 1,25(OH)2D3 further. To prove that the effect of 1,25(OH)2D3 was independent of PTH, parathyreoidectomized SNX rats without or with 1,25(OH)2D3 treatment were examined seven days post-SNX. PCNA staining showed suppression of cell proliferation. Furthermore, in situ hybridization for transforming growth factor-B (TGF-beta) showed less vascular and tubular expression in 1,25(OH)2D3 treated rats. We conclude that 1,25(OH)2D3 has antiproliferative actions during the compensatory growth of nephrons in response to subtotal nephrectomy. These effects are independent of PTH. The data document that 1,25(OH)2D3 reduces renal cell proliferation and glomerular growth as well as glomerulosclerosis and albuminuria as indicators of progressive glomerular damage.
Animals↗
The renoprotective effect of angiotensin-converting enzyme inhibitors in experimental chronic renal failure is not dependent on enhanced kinin activity.
BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors have been shown to ameliorate the progression of glomerulosclerosis both in experimental models of uraemia and in patients with renal failure. It has not been documented, however, whether this is due to a decrease in angiotensin II generation or is a consequence of elevated local level of bradykinin. METHODS: Morphometric investigation of renal tissue was performed in 5/6 nephrectomized (SNx) rats, i.e. untreated or treated with the ACE inhibitor ramipril (SNx-RAM), the B2 kinin receptor antagonist HOE 140 (SNx-HOE), or a combination of both (SNx-RAM + HOE) over 8 weeks. A further group of SNx received delayed treatment with ramipril from week 5 onward (SNx-RAMD). In addition, a sham-operated (SHAM) control group was studied. RESULTS: Systolic blood pressure was significantly lower in both SNx-RAM and SNx-RAM + HOE groups compared to (untreated) SNx. The glomerulosclerosis index (GSI) was substantially higher in the (untreated) SNx group (0.24 +/- 0.04) vs SHAM (0.02 +/- 0.01). A significantly higher GSI was found in the SNx-HOE group (0.45 +/- 0.08) as compared to (untreated) SNx. However, in the SNx-RAM, SNx-RAM + HOE, and SNx-RAMD groups, the GSI was lowered to a similar extent (0.1 +/- 0.02, 0.09 +/- 0.02, and 0.07 +/- 0.01 respectively). In addition, a concomitant attenuation of tubulointerstitial damage was noted in all the above groups. CONCLUSION: Increased kinin activity does not appear to play a major role in the renoprotective effect of ACE inhibitors in the remnant kidney model.
Angiotensin Receptor Antagonists↗
Nephroprotection of an ET(A)-receptor blocker (LU 135252) in salt-loaded uninephrectomized stroke-prone spontaneously hypertensive rats.
The present study was designed to assess whether the orally active and highly specific endothelin A (ET(A)) receptor antagonist LU 135252 affects progressive renal dysfunction in a hypertensive rat model of renal damage, ie, the uninephrectomized (UNX) stroke-prone spontaneously hypertensive rat (SHRsp). The animals were examined on a normal salt (0.25%) diet and, to sensitize the kidney to hypertensive injury, also on a high salt (3%) diet. Stereological methods were used to quantify indices of glomerulosclerosis, vascular damage, and tubulointerstitial damage. Treatment with LU 135252 (100 mg/kg body wt) did not affect systolic blood pressure (BP) in animals on a normal salt diet during the whole period of the experiment (18 weeks) or in salt-loaded animals until week 10; subsequently, BP was slightly but significantly lower in salt-loaded UNX-SHRsp given LU 135252. Between weeks 6 and 12, 40% of the untreated UNX-SHRsp on a high salt diet, but none on a standard salt diet, died; such mortality was completely prevented by LU 135252. Indices of renal damage were more abnormal in salt-loaded UNX-SHRsp compared with UNX-SHRsp on a normal salt diet. Development of glomerulosclerosis and tubulointerstitial and vascular damage in UNX-SHRsp on high salt was completely prevented by LU 135252. The respective indices were no longer significantly different from those of salt-loaded sham-operated SHRsp controls. In the less severely damaged kidneys of UNX-SHRsp on normal salt, treatment with LU 135252 tended to ameliorate the indices, but the difference was not statistically significant. The results document a role of the ET system, specifically of ET(A) receptors, in the development of progressive renal injury in salt-loaded UNX-SHRsp. LU 135252 completely prevented death and renal damage resulting from salt loading.
Animals↗
Rats with moderate renal failure show capillary deficit in heart but not skeletal muscle.
In previous studies on experimental renal failure, hypertrophy of cardiomyocytes, diminished capillarization, and increased intercapillary distances had been observed, abnormalities that will expose the heart to reduced ischemia tolerance. It has not been established, however, whether such structural alterations are unique for the heart (eg, as a consequence of left ventricular hypertrophy) or are demonstrable in other tissues as well. Clarification of this point is important to test hypotheses on some potential mechanisms for cardiac undercapillarization. To address this issue further, we compared capillary length density (by stereologic techniques) in perfusion-fixed skeletal muscle (m. psoas) and hearts of subtotally nephrectomized (SNX) rats with moderate renal failure to those in sham-operated pair-fed controls. The duration of renal failure was 8 weeks. SNX rats had significantly higher mean systolic blood pressure (128 mm Hg v 109 mm Hg), serum creatinine, and urea levels. Despite pair feeding, the mean body weight was significantly lower in the SNX rats (409 g v 471 g), but the left ventricular weight to body weight ratio tended to be higher than in the sham-operated controls (2.39 mg/g v 2.13 mg/g). In the heart, myocyte mean cross-sectional area (675 +/- 112 microm2 v 545 +/- 111 microm2) and volume density of nonvascular interstitial tissue (3.47 +/- 1.04 v 1.33 +/- 0.22) were significantly higher in the SNX rats than in the controls. In parallel, myocardial capillary length density was significantly reduced after subtotal nephrectomy (3,036 +/- 535 mm/mm3 v 3,916 +/- 615 mm/mm3). In contrast, in skeletal muscle, myocyte cross-sectional area (3,109 +/- 783 microm2 v 3,042 +/- 639 microm2), capillary length density (718 +/- 248 mm/mm3 v 717 +/- 184 mm/mm3), and three-dimensional capillary fiber ratio (2.10 +/- 0.26 v 2.13 +/- 0.4) were similar in SNX and control rats. These data document a selective defect of capillarization in the heart of animals with moderate renal failure, pointing to tissue-specific abnormalities of cardiac capillarogenesis.
Animals↗
The renal risks of smoking.
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Albuminuria↗
Bacterial infections in diabetes mellitus: are calcium channel blockers beneficial?
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Animals↗
Angiotensin converting enzyme inhibitors, calcium channel blockers, and their combination in the treatment of glomerular disease.
BACKGROUND: Glomerular diseases may progress to end-stage renal failure via the development of glomerulosclerosis. Systemic hypertension and intraglomerular hypertension are important, although not the only, determinants of this process. Proteinuria (albuminuria) is a surrogate marker for glomerular damage and renal prognosis. EFFICACY OF ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS: In animal experiments and in controlled clinical studies, ACE inhibitors have proved to be effective in reducing proteinuria and in preventing glomerulosclerosis or progression to end-stage renal failure, possibly more than can be explained by their effects on blood pressure. EFFICACY OF CALCIUM CHANNEL BLOCKERS: In contrast to the uniform efficacy of ACE inhibitors, the effect of calcium channel blockers is less uniform. It depends on the model of renal damage used, the extent of the fall in systemic blood pressure and the type of calcium channel blocker used. Nevertheless, clinical studies have shown a reduction in proteinuria and at least an attenuation of progression with the use of long-acting calcium channel blockers. RATIONALE FOR THE COMBINATION OF ACE INHIBITORS AND CALCIUM CHANNEL BLOCKERS: If angiotensin II influences the progression of renal failure, as is universally accepted, then the combination of an ACE inhibitor (reducing the generation of angiotensin II) and a calcium channel blocker (reducing target-organ responsiveness to angiotensin II) appears a promising one. EVIDENCE FOR THE EFFECTIVENESS OF THIS COMBINATION: In animal experiments, co-administration of an ACE inhibitor and a calcium channel blocker caused a more marked reduction in glomerulosclerosis, and this was seen in the stroke-prone spontaneously hypertensive rat model even at non-antihypertensive doses. In human diabetic nephropathy at least, proteinuria (measured as a surrogate marker of the illness) was lowered more effectively by the combination of an ACE inhibitor and a calcium channel blocker than either drug used as monotherapy despite a similar fall in blood pressure.
Angiotensin-Converting Enzyme Inhibitors↗
Inhibitory effect of calcium channel blockers on human mesangial cell growth: evidence for actions independent of L-type Ca2+ channels.
Calcium channel blockers (CCB) are known to affect the outcome of glomerulosclerosis in vivo and to suppress mesangial cell proliferation and cytokine production in vitro. It is uncertain, however, whether (i) human adult mesangial cells (HMC) express L-type Ca2+ channels and (ii) whether the effect of CCB on HMC is mediated by inhibition of L-type Ca2+ channels. In single cell preparations of HMC, the L-type Ca2+ channel agonist Bay K 8644 and K+-depolarization of the cell membrane caused a transient increase of cytosolic free Ca2+ ([Ca2+]i) in 60 to 80% of the cells. The CCB verapamil and nifedipine partially inhibited the effect of Bay K 8644 and K+-depolarization on [Ca2+]i. Binding experiments confirmed these functional studies by showing specific binding at the phenylalkylamine binding site of L-Type Ca2+ channels. Quiescent HMC were stimulated with fetal calf serum (FCS) or growth factors (platelet derived growth factor A/B, epidermal growth factor, angiotensin II, endothelin 1) in the presence of various concentrations (10(-10) to 10(-5) M) of different CCB: either (R)-verapamil, (S)-verapamil or the raceme of verapamil, and nifedipine or diltiazem, respectively. In addition, the enantiomers of devapamil were studied, because their action on the L-type Ca2+ channel is more stereoselective than that of the enantiomers of verapamil. At high concentrations (10(-6) to 10(-5) M) (R,S)-verapamil decreased cell numbers in cultures of quiescent HMC, increased LDH in the supernatant, and caused loss of trypan blue exclusion (cytotoxicity). At lower concentrations (R,S)-verapamil showed no cytotoxicity, but had two effects: (1.) concentration dependent (down to 10(-8) M) inhibition of indices of cell proliferation, that is, (i) stimulated (FCS or growth factor) 3H-thymidine incorporation and (ii) increment in cell number; and (2.) inhibition of indices of cell or matrix protein synthesis, that is, (i) stimulated 3H-methionine incorporation and (ii) 3H-proline incorporation. At equimolar concentrations the dihydropyridine nifedipine was equipotent with verapamil, whereas the benzothiazepine diltiazem was conspicuously less effective. Even at the lowest effective concentration (10(-8) M) comparison of (R)- and (S)-verapamil showed no significant difference between the enantiomer with weak or with strong effect on L-type Ca2+ channels, and this was true even when the more stereoselective enantiomers of devapamil were tested. These observations argue against the notion that effects of CCB result from specific interaction with L-type Ca2+ channels. The data are more consistent with the idea that interactions with targets other than L-type Ca2+ channels are involved.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Angiotensin II induces hypertrophy and hyperplasia in adult human mesangial cells.
Several experimental studies point to a potential role of angiotensin II (Ang II) in the progression of glomerulosclerosis even in the absence of glomerular hypertension. We tested the hypothesis that Ang II acts as a growth factor for adult human mesangial cells (AHMC). AHMC were isolated from noninvolved parts of tumor nephrectomy specimens and grown in RPMI medium with the addition of fetal calf serum (FCS). All studies were performed with growth-arrested cells. Proliferation studies were done in serum-free standard growth medium (SF) with the addition of either various concentrations of insulin, plasma-derived serum, or FCS. Ang II (10(-10) to 10(-6) M) dose dependently increased the 3H-thymidine uptake of AHMC up to 57 +/- 13% over solvent controls (p < 0.01). In parallel, the DNA content was 36 +/- 10% higher (p < 0.05) than in solvent controls after 2 days of culture. The cell numbers were higher up to 47 +/- 8% in Ang II (10(-6) M) stimulated cultures after 4 days of incubation (p < 0.01). The effect of Ang II was specific, since it was almost completely obliterated by the AT1 receptor antagonist DuP753. The effect of Ang II was particularly marked when cultures were incubated with SF plus high concentrations (1.7 x 10(-6) M) of insulin or SF plus 10% plasma-derived serum. In contrast, the effect was not significant when cultures were incubated with SF plus 10% FCS. Ang II, when added to platelet-derived growth factor at various concentrations, did not further increase the proliferation. The effect on protein synthesis was assessed in growth-arrested AHMC by 3H-methionine uptake and protein/DNA ratio in cell lysates. Ang II (10(-10) to 10(-6) M) dose dependently increased the 3H-methionine uptake of AHMC up to 47 +/- 10% over solvent controls (p < 0.01). In parallel Ang II (10(-8) to 10(-6) M) dose dependently increased the 3H-methionine uptake of the protein/DNA ratio by 24 +/- 6% after 48 h of incubation. DuP753 obliterated the stimulatory effect of Ang II. Ang II (10(-6) M) also increased the mRNA of the immediate-early growth-related gene Egr-1. We conclude that Ang II induces hypertrophy and proliferation in adult human mesangial cells. This result is of interest with respect to a potential role of Ang II in the pathogenesis of glomerulosclerosis in humans.
Adult↗