Troglitazone halts diabetic glomerulosclerosis by blockade of mesangial expansion.
BACKGROUND
Renal complications of long-term, poorly controlled type 2 diabetes mellitus include glomerulosclerosis and interstitial fibrosis. The onset and progression of these complications are influenced by underlying pathophysiologies such as hyperglycemia, hypertriglyceridemia, and hypercholesterolemia. Troglitazone, a thiazolidinedione, has been shown to ameliorate these metabolic defects. However, it was not known whether therapeutic intervention with troglitazone would prevent the onset and progression of glomerulosclerosis.


METHODS
Sixty male ZDF/Gmitrade mark rats and 30 age-matched Zucker lean rats were in the study. The ZDF/Gmitrade mark rats were divided into two groups, one in which blood glucose levels were uncontrolled (30 animals) and another (30) in which blood glucose was controlled via dietary administration of troglitazone. Ten animals from each group were sacrificed at one, three, and six months into the study. The kidneys were harvested and processed for immunostaining with BM-CSPG, a marker for mesangial matrix. Images of 200 glomeruli per animal were captured using digital imaging microscopy, and the index of mesangial expansion (total area mesangium/total area of tuft) per glomerular section was measured.


RESULTS
The administration of troglitazone ameliorated the metabolic defects associated with type 2 diabetes mellitus. Moreover, the glomeruli from tissue sections of animals given troglitazone showed no mesangial expansion when compared with normoglycemic control animals, whereas the uncontrolled diabetic animals showed significant mesangial expansion at all time intervals.


CONCLUSIONS
Therapeutic intervention with the thiazolidinedione troglitazone halts the early onset and progression of mesangial expansion in the ZDF/Gmitrade mark rat, preventing the development of glomerulosclerosis in this animal model of type 2 diabetes mellitus.
McCarthy
K J
KJ
School of Medicine, Louisiana State University Medical Center, Shreveport, Louisiana 71130-3932, USA. kmccar2@lsuhsc.edu
Routh
R E
RE
Shaw
W
W
Walsh
K
K
Welbourne
T C
TC
Johnson
J H
JH
D000818:Animals; D001485:Basement Membrane / Q000737:chemistry / Q000473:pathology; D001835:Body Weight; D011508:Chondroitin Sulfate Proteoglycans / Q000032:analysis; D002839:Chromans / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005355:Fibrosis; D005920:Glomerular Mesangium / Q000737:chemistry / Q000473:pathology*; D006943:Hyperglycemia / Q000188:drug therapy / Q000473:pathology; D006946:Hyperinsulinism / Q000188:drug therapy / Q000473:pathology; D015228:Hypertriglyceridemia / Q000188:drug therapy / Q000473:pathology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000473:pathology; D051381:Rats; D011924:Rats, Zucker; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone
D011508:Chondroitin Sulfate Proteoglycans; D002839:Chromans; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D000077288:Troglitazone