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Proteinuria is preceded by decreased nitric oxide synthesis and prevented by a NO donor in cholesterol-fed rats
Diana M Attia1, Zhenmin N Ni, Peter Boer
1Department of Nephrology and Hypertension, Utrecht University Medical Center, Utrecht, The Netherlands.
Background:
Hypercholesterolemia decreases nitric oxide (NO) availability in the circulation and induces podocyte activation and renal injury in rats. It is unknown whether hypercholesterolemia decreases renal NO availability. To dissociate the injury-independent effect of hypercholesterolemia on renal NO availability from secondary effects of proteinuria, increasing concentrations of cholesterol were administered. To determine whether podocyte activation and renal injury were associated with NO deficiency, molsidomine, an exogenous NO donor, was administered to hypercholesterolemic rats.
Methods:
Female rats were fed 0, 0.5, 1, or 2% cholesterol for 24 weeks. Rats fed 2% cholesterol were also studied for two weeks. In addition rats fed 0 or 1% cholesterol received 120 mg molsidomine/L drinking water. Renal NO availability was determined by measuring renal NO synthesis and superoxide activity. Podocyte activation was monitored by desmin staining.
Results:
Hypercholesterolemia dose-dependently increased proteinuria. In the absence of proteinuria, hypercholesterolemia decreased renal NO synthesis (4.2 +/- 0.5 in 0.5% cholesterol vs. 6.8 +/- 0.6 pmol/min/mg protein in controls; P < 0.05). With the exception of neuronal nitric oxide synthase (nNOS), renal NOS protein mass remained unaffected. Renal superoxide activity was dose-dependently increased, thus further lowering renal NO availability. Podocyte injury was dose-dependently increased even in the absence of proteinuria (score, 40 +/- 4 in 0.5% cholesterol vs. 9 +/- 4 in controls; P < 0.05). After two weeks, hypercholesterolemia caused no proteinuria, but did cause some podocyte injury. Renal NOS activity was decreased, but glomerular endothelial NOS (eNOS) staining was unchanged. Molsidomine prevented proteinuria, podocyte activation, and all further renal injury.
Conclusions:
Hypercholesterolemia decreases renal NO synthesis, and induces podocyte activation before proteinuria appears. Renal superoxide activity is increased once rats are proteinuric, further lowering renal NO availability. All of these changes can be prevented by a NO donor.
Insights
High cholesterol in rats reduces kidney nitric oxide (NO) availability and damages podocytes early. Supplementing with an NO donor prevented these negative effects, indicating NO
Area of Science:
- Nephrology
- Cardiovascular Science
- Biochemistry
Background:
- Hypercholesterolemia is known to reduce nitric oxide (NO) availability and cause renal injury in rats.
- The direct impact of hypercholesterolemia on renal NO availability, independent of proteinuria, was previously unknown.
- This study aimed to investigate hypercholesterolemia's effect on renal NO and podocyte injury, and whether NO supplementation could mitigate these effects.
Purpose of the Study:
- To determine if hypercholesterolemia decreases renal nitric oxide (NO) availability.
- To investigate the association between podocyte activation, renal injury, and NO deficiency.
- To assess the protective effects of an exogenous NO donor (molsidomine) against hypercholesterolemia-induced renal damage.
Main Methods:
- Rats were fed varying concentrations of cholesterol (0-2%) for 24 weeks.
- Renal nitric oxide (NO) synthesis and superoxide activity were measured to assess NO availability.
- Podocyte activation was evaluated using desmin staining, and the effects of molsidomine were examined.
Main Results:
- Hypercholesterolemia dose-dependently increased proteinuria and podocyte injury, even before proteinuria was evident.
- Renal NO synthesis was decreased in hypercholesterolemic rats, with increased renal superoxide activity.
- Molsidomine administration completely prevented proteinuria, podocyte activation, and subsequent renal injury.
Conclusions:
- Hypercholesterolemia impairs renal nitric oxide (NO) synthesis and initiates podocyte activation prior to proteinuria.
- Increased renal superoxide activity exacerbates NO deficiency in proteinuric hypercholesterolemic rats.
- Exogenous NO donors effectively counteract hypercholesterolemia-induced renal damage, highlighting the role of NO.
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