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Background/aims: In diabetic hypertensive rats, tempol reduces albuminuria by restoring the redox imbalance. Increased formation of reactive oxygen species leading to activation of poly(ADP-ribose) polymerase (PARP)-1 and podocyte loss by apoptosis contribute to albuminuria in diabetes mellitus (DM). In the present study, we investigated the hypothesis that in DM tempol reduces albuminuria by inhibition of PARP-induced podocyte apoptosis., Methods: DM was induced in 4-week-old spontaneously hypertensive rats by streptozotocin. Mouse and human podocyte cell lines were cultured in normal or high-glucose conditions, with or without tempol and/or a PARP-1 inhibitor, PJ34., Results: In diabetic rats, tempol treatment did not affect plasma glucose levels or systolic blood pressure. Albuminuria was higher in diabetic rats, and it was reduced by tempol. DM leads to an elevation of glomerular apoptotic cells and to podocyte loss; both were prevented by tempol treatment. DM increases the expression of poly(ADP-ribose)-modified proteins in isolated glomeruli, and it was reduced by tempol. In vitro, high glucose increased caspase-3 activity and led to a higher number of apoptotic cells that were prevented by tempol and the PARP-1 inhibitor., Conclusion: In DM, tempol reduces albuminuria associated with reduction of podocyte apoptosis and decreasing oxidative stress via PARP signaling., (Copyright © 2012 S. Karger AG, Basel.)

Aims: The presence of hypertension increases renal oxidative stress by increasing NADPH oxidase-dependent superoxide production and by decreasing antioxidant defense in the early stage of experimental diabetes mellitus (DM). In the present study, we investigated whether the administration of an antioxidant mimetic of the superoxide dismutase (SOD) (tempol) corrects the oxidative imbalance and oxidative stress-induced renal injury in the presence of DM and hypertension., Methods: DM was induced in spontaneously hypertensive rats (SHR) by streptozotocin at 4 weeks of age. The diabetic rats either did or did not receive tempol for 20 days. Oxidative-stress parameters and indices of renal injury were evaluated., Results: Tempol reestablished the imbalance in redox status induced by DM. It elevated the expression of renal antioxidant extracellular SOD, p < 0.0001; decreased (p = 0.049) the production of renal NADPH-dependent superoxide production, and diminished (p = 0.016) a marker of oxidative stress-induced DNA damage, 8-hydroxy-2'-deoxyguanosine. Reduction of oxidative stress markers was associated with reduction in renal damage parameters associated with DN. DM-induced albuminuria and elevation in renal expression of collagen IV were reduced to the level observed in control rats., Conclusion: We conclude that an imbalance in renal redox status is associated with markers of renal injury in the early stage of DM and hypertension. Antioxidant treatment reestablished the redox status and prevented oxidative stress-induced renal damage.

Aims: The combination of hypertension and diabetes exacerbates renal oxidative stress. The aim of the present study was therefore to evaluate the pro-oxidant and antioxidant mechanisms responsible for the induction of renal oxidative stress in the presence of hypertension and diabetes mellitus., Methods: Diabetes was induced in spontaneously hypertensive rats (SHR) and their genetically normotensive control Wistar-Kyoto (WKY) rats by streptozotocin at 12 weeks of age. After 10 days, pro-oxidant, antioxidant and oxidative stress parameters were evaluated in the renal tissue., Results: NADPH oxidase-dependent superoxide generation in the renal cortex was significantly elevated in WKY and SHR diabetic (D) groups compared to the respective control (C) groups (p < 0.005, n = 5). However, the highest level of superoxide generation was observed in the SHR-D group compared to all other groups. The expression of the gp91phox subunit of NADPH oxidase was significantly elevated in the SHR-D (p < 0.05, n = 5), but not in the WKY-D group, compared to the respective control groups. The renal cortical extracellular-superoxide dismutase level was found to be markedly decreased in the SHR groups compared to the WKY groups (p < 0.05, n = 5). The antioxidant glutathione level was found to be lower in the SHR-D (p = 0.03, n = 15), but not in the WKY-D group, compared to the respective control groups. Finally, nitrotyrosine and 8-hydroxy-2'-deoxyguanosine, markers of oxidative stress, were found to be similar in the kidneys of WKY-C and WKY-D, but were elevated in the SHR-D compared to the SHR-C group., Conclusion: We therefore conclude that hypertension increases pro-oxidant generation and decreases antioxidant defense, and thereby induces renal oxidative stress in early diabetes., ((c) 2007 S. Karger AG, Basel.)

Background and Aims: Several lines of clinical evidence support the concept that the reduction of blood pressure may be useful in the prevention of diabetic kidney disease. In young diabetic spontaneously hypertensive rats (SHR), prevention of hypertension reduces several early renal abnormalities including albuminuria. However, the contribution of nephrin loss to albuminuria in this early stage of experimental diabetes is unknown. Therefore, we investigated whether elevation of albuminuria in young diabetic SHR is associated with nephrin loss, and if prevention of hypertension, with or without inhibition of the renin-angiotensin system, precludes these abnormalities., Methods: Diabetes was induced by streptozotocin injection in 4-week-old still normotensive SHR and their genetically normotensive control, Wistar-Kyoto rats. Diabetic SHR were randomized for no treatment, or treatment with captopril, losartan, or triple therapy (hydrochlorothiazide, reserpine and hydralazine) for 20 days., Results: The increase in systolic blood pressure was equally prevented by all treatments. Albuminuria was higher in diabetic SHR and similarly reduced (p < 0.05) by captopril, losartan, and triple therapy. Glomerular expression of nephrin was significantly reduced in diabetic SHR in comparison with non-diabetic controls. The antihypertensive treatment prevented the reduction in glomerular expression of nephrin., Conclusions: These results demonstrate that the loss of nephrin is associated with albuminuria in a model of genetic hypertension and diabetes, and that the prevention of development of hypertension restores nephrin and prevents albuminuria. This finding suggests a crucial role of blood pressure in diabetes as determinant of nephrin expression and albuminuria., ((c) 2007 S. Karger AG, Basel.)

Background/aims: Previous partial hepatectomy (HPTX) can attenuate glycerol-induced acute kidney injury (Gly-AKI). The aim of this study was to explore the pathophysiological mechanisms and the role of hepatocyte growth factor (HGF) in kidney protection., Methods: Rats were subjected to HPTX 24 h before glycerol administration. Renal function, acute tubular necrosis, apoptosis, leukocyte infiltration, and the expression of HGF, c-met, monocyte chemoattractant protein-1, interleukin-1beta, and heme oxygenase-1 were evaluated 24 h after glycerol injection. The regenerative response was analyzed from 6 to 72 h after glycerol injection (BrdU incorporation). In a separate series of experiments, Gly-AKI+HPTX rats were treated with anti-HGF antibody., Results: Gly-AKI+HPTX rats showed an increased expression of renal HGF and c-met as well as an improved creatinine clearance and reduced acute tubular necrosis and apoptosis, cytokine expression, and leukocyte infiltration. The regenerative response was less intense 24 and 72 h after glycerol administration in this group. The anti-HGF treatment disclosed an important role of HGF in the reduction of tubular injury, particularly apoptosis. Overexpression of heme oxygenase-1 was observed in Gly-AKI+HPTX rats, but was not associated with HPTX-induced renal protection., Conclusion: We conclude that Gly-AKI+HPTX rats have a reduced susceptibility to renal injury instead of an increased regenerative response and that endogenous HGF overexpression is responsible for suppression of tubular apoptosis., (Copyright 2007 S. Karger AG, Basel.)

Background: The combination of diabetes and hypertension increases the incidence and severity of kidney disease in an additive manner. Inflammatory and oxidative stress mechanisms contribute to renal damage in both diabetes and hypertension. Therefore, we investigated whether renal macrophage infiltration and oxidative stress events are additive from the beginning in diabetic animals with coexisting hypertension., Methods: Diabetes was induced in spontaneously hypertensive rats (SHRs) and their genetically normotensive control Wistar Kyoto (WKY) rats by streptozotocin injection at 12 weeks of age for 10 days, and the effects of hyperglycemia on renal macrophage infiltration and oxidative stress were evaluated., Results: Blood pressure was higher in SHR than in WKY groups. Markers of oxidative stress-induced DNA and protein modification, 8-hydroxy- 2'-deoxyguanosine (8-OHdG) and nitrotyrosine, respectively, and the antioxidant glutathione levels were found to be similar in WKY-control and WKY-diabetic groups. However, 8-OHdG was significantly elevated (p = 0.014), the nitrotyrosine level tended to be elevated (p = 0.068) and the glutathione level was significantly reduced (p = 0.034) in the SHR-diabetic group compared to the SHR-control group. On the other hand, glomerular and tubulointerstitial macrophage infiltration was significantly higher in both WKY-diabetic and SHR-diabetic groups than the respective control groups., Conclusions: A short duration of diabetes mellitus induces renal oxidative stress in the presence of hypertension; however, renal macrophage infiltration becomes evident in early diabetes regardless of the presence or absence of hypertension. We conclude that the combination of diabetes and hypertension adversely affects oxidative stress in the kidney, but the combination has no additive effect on renal macrophage infiltration, at least in early diabetes., (Copyright (c) 2006 S. Karger AG, Basel.)

Background/aims: This study tested the hypothesis that prevention of the development of hypertension, and not the class of antihypertensive agent, inhibits the increase in renal fibronectin and albuminuria in experimental diabetes., Methods: Four-week-old spontaneously hypertensive rats (SHR), with diabetes induced by streptozotocin, were randomized for no treatment, or treatment with captopril, amlodipine, an association of captopril and amlodipine (Cap+A) or an association of captopril and verapamil (Cap+V) for 12 weeks., Results: Systolic blood pressure increased similarly in control (187 +/- 5 mm Hg, mean +/- SE) and diabetic (186 +/- 4) SHR and was kept within the normal range by amlodipine (131 +/- 3), captopril (127 +/- 3), Cap+A (134 +/- 4) and Cap+V (134 +/- 9, p < 0.0001). In diabetic rats, albuminuria was higher than in control SHR [geometric mean (variance), 1,213 (953-1,708) vs. 512 (213-850), p < 0.0001] and was reduced to a similar extent by amlodipine [573 (353-744), p < 0.0001], captopril [562 (238-771), p < 0.0001], Cap+A [679 (442-971), p < 0.0001] and Cap+V [748 (581-848) microg/24 h, p = 0.0002]. Renal fibronectin increased in diabetic rats (24.0 +/- 3.3 densitometric units, mean +/- SE) compared to control rats (9.6 +/- 1.8, p = 0.0005) and was normalized by amlodipine (9.9 +/- 1.0, p = 0.0001), captopril (11.2 +/- 0.4, p = 0.0016), Cap+A (9.9 +/- 2.0, p = 0.0004) and Cap+V (14.7 +/- 4.9, p = 0.0159)., Conclusion: In this model, tight blood pressure control rather than the class of antihypertensive agent was the main determinant factor in attenuating of nephropathy., (Copyright 2004 S. Karger AG, Basel)

Background/aim: The aim of this study was to evaluate the effect of preventing hypertension on renal disease in a model of genetic hypertension and diabetes., Methods: Four-week-old spontaneously hypertensive rats (SHR) with streptozotocin-induced diabetes were randomized for no treatment, or for treatment with captopril, losartan or triple therapy (hydrochlorothiazide, reserpine and hydralazine) for 16 weeks., Results: Increase in systolic blood pressure was equally prevented by captopril (128 +/- 3 mm Hg), losartan (128 +/- 2) and triple therapy (129 +/- 2, p < 0.0001). Albuminuria was similarly reduced by captopril (499 (404-659)), losartan (622 (470-976)) and triple therapy (479 (362-600) microg/24 h (p < 0.0001)). Renal fibronectin expression increased in diabetic SHR (125 +/- 13 densitometric unit) as compared to the controls (51 +/- 9, p < 0.0001), and decreased (p < 0.0001 vs. diabetic SHR) with captopril (32 +/- 8), losartan (27 +/- 4) and triple therapy (35 +/- 6)., Conclusion: The prevention of hypertension in diabetic SHR by captopril, losartan or triple therapy was equally efficacious in impeding increase of albuminuria and the expression of renal fibronectin. Under these conditions, tight blood pressure control was the main determinant in attenuating nephropathy., (Copyright 2003 S. Karger AG, Basel)

Unlabelled: Interleukin-6 stimulates tubular regeneration in rats with glycerol-induced acute renal failure., Background: Interleukin 6 (IL-6) is a pleiotropic cytokine released after endotoxemia, trauma and organ injury. IL-6 may act in cellular proliferation activating transduction signals and Ras/Map cascade or the HGF/c-met axis. We tested the effect of IL-6 in the regeneration of tubular epithelia after acute tubular necrosis (ATN) in rats., Methods: Rats with glycerol-induced acute renal failure (Gly-ARF) were treated with IL-6 200 microg/kg/day. Functional, histological and immunohistochemical tests were done 24 and 72 h after Gly-ARF to localise mitotic cells (BrdU). The renal expression of c-met (Western-Blot) and circulating levels of HGF (ELISA) were also determined., Results: Rats with Gly-ARF had reduced creatinine clearance that was not influenced by IL-6. The histological appearance of ATN was also unaffected by IL-6. The IL-6 treated rats showed a significant increase in tubular cell proliferation in cortex and medulla, as well as in the expression of c-met protein in the renal cortex, compared to untreated Gly-ARF rats. The plasma HGF concentration was equally elevated in treated and untreated Gly-ARF rats., Discussion: IL-6 stimulates tubular regeneration after Gly-ARF and increases the expression of c-met in the renal cortex. Gly-ARF rats have high circulating levels of HGF that is targeted to act in the injured kidneys by the IL-6 overexpressed renal c-met., (Copyright 2002 S. Karger AG, Basel)

Insulin-dependent diabetes mellitus (IDDM) patients may have an increased intrarenal angiotensin II activity. In diabetic patients, captopril increases the renal hemodynamic response to an amino acid infusion. We investigated the effects of two salt diets on arterial pressure and renal response to a protein load in 10 normotensive (blood pressure < 140/90 mm Hg) IDDM patients (aged 30 +/- 3 years) who had diabetes for 7 +/- 4 years and normoalbuminuria levels [albumin excretion rate 4.8 (2.5-19.1) microg/min]. After 1 week of normal (approximately 100 mmol/day; approximately 100 mEq/l) and 1 week of high (approximately 300 mmol/day; approximately 300 mEq/l) salt intake, renal hemodynamic studies were performed at baseline and after a protein load (meat meal) of 100 g/1.73 m2. The mean 24-hour urinary sodium excretion levels were 99 +/- 27 and 293 +/- 80 mmol (mEq) with normal and high salt intake, respectively. No significant changes were seen in plasma sodium and glucose control with the normal and high salt diets, respectively: plasma sodium 135 +/- 3 vs. 137 +/- 1 mmol/l (mEq/l), (p = 0.08) and glycated hemoglobin 9.1 +/- 1.9 vs. 9.4 +/- 2.1% (p = 0.36). The body weight (70.9 +/- 12 vs. 71.8 +/- 13 kg; p = 0.015) was significantly higher with a high salt diet. The mean arterial pressure was similar with both diets (normal vs. high salt diet 91 +/- 9 vs. 89 +/- 6 mm Hg, p = 0.25). The plasma renin concentration [28 +/- 15 vs. 16 +/- 6 microU/ml(168 +/- 90 vs. 96 +/- 36 pmol/l), p = 0.013] and angiotensin II [8.8 +/- 4.4 vs. 6.4 +/- 3.5 pg/ml (0.052 +/- 0.025 vs. 0.038 +/- 0.021 nmol/l), p = 0.016] were significantly lower with the high salt diet. Following protein loading, the glomerular filtration rate increased with both diets: normal salt diet 114 +/- 26 vs. 128 +/- 30 ml/min/1.73 m2(1.9 +/- 0.43 vs. 2.13 +/- 0.50 ml/s/1.73 m2), p = 0.04; high salt diet 118 +/- 23 vs. 127 +/- 29 ml/min/1.73 m2 (1.97 +/- 0.38 vs. 2.12 +/- 0.48 ml/s/1.73 m2), p = 0.13. The change in renal plasma flow was similar to that of the glomerular filtration rate with normal and high salt intake, respectively: 566 +/- 94 vs. 617 +/- 142 ml/min/1.73 m2 (9.44 +/- 1.57 vs. 10.29 +/- 2.37 ml/s/173 m2), p = 0.0017; 572 +/- 125 vs. 600 +/- 110 ml/min/1.73 m2 (9.54 +/- 2.08 vs. 10.00 +/- 1.83 ml/s/1.73 m2), p = 0.057. In this subset of normotensive normoalbuminuric IDDM patients, a high salt intake did not promote an exaggerated renal response to the protein load despite inhibition of the renin-angiotensin system.