Insulin resistance, oxidative stress, and podocyte injury: role of rosuvastatin modulation of filtration barrier injury.
OBJECTIVE
There is an emerging relationship between insulin resistance/hyperinsulinemia, oxidative stress, and glomerular injury manifesting as albuminuria. HMG-CoA reductase inhibitors (statins) have been shown to reduce oxidative stress in the vasculature as well as albuminuria in animal models and in human studies. The glomerular filtration barrier is emerging as a critical determinant of albumin filtration. We investigated the effects of insulin resistance and rosuvastatin or placebo on the glomerular filtration barrier.


METHODS
Young Zucker obese and Zucker lean rats (6-7 weeks old) were treated with the HMG-CoA reductase inhibitor rosuvastatin (10 mg/kg/day) or placebo for 21 days.


RESULTS
In the Zucker obese rats, homeostasis model assessment-insulin resistance index, oxidative markers (NADPH oxidase activity, reactive oxygen species, and urine isoprostane formation), podocyte foot process effacement, and albuminuria were increased as compared with Zucker lean controls, independent of increases in systolic blood pressure. Albuminuria correlated with podocyte foot process effacement (r(2) = 0.61) and insulin level (r(2) = 0.69). Rosuvastatin treatment improved albuminuria, filtration barrier indices, and oxidative stress via copper/zinc superoxide dismutase.


CONCLUSIONS
These data indicate that hyperinsulinemia together with insulin resistance is associated with podocyte injury and albuminuria independent of the systolic blood pressure. Further, rosuvastatin modulates filtration barrier injury and albuminuria and improves oxidative stress measures via copper/zinc superoxide dismutase.
Whaley-Connell
Adam
A
Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, MO 65212, USA. whaleyconnella@health.missouri.edu
DeMarco
Vincent G
VG
Lastra
Guido
G
Manrique
Camila
C
Nistala
Ravi
R
Cooper
Shawna A
SA
Westerly
Blair
B
Hayden
Melvin R
MR
Wiedmeyer
Charles
C
Wei
Yongzhong
Y
Sowers
James R
JR
D000419:Albuminuria / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001786:Blood Glucose; D001835:Body Weight / Q000187:drug effects; D005464:Fluorobenzenes / Q000494:pharmacology*; D005919:Glomerular Filtration Rate; D006706:Homeostasis; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D046529:Microscopy, Electron, Transmission; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D050199:Podocytes / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism
D001786:Blood Glucose; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007328:Insulin; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D013482:Superoxide Dismutase