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COX-2 inhibitors and renal damage in obesity-related Type II diabetes

01.10.2003


New findings suggest altered kidney regulation of COX-2 occurs at very early stage in obesity-related diabetic nephropathy



In human diabetic patients, an excessive vasoconstrictive and pro-aggregatory thromboxane (TXA2) renal synthesis, along with a decrease in vasodilatory and anti-aggregatory prostaglandin (PGE2) synthesis, has been found to influence kidney function. Prostaglandins and thromboxane are formed by the enzymatic oxidation of arachidonic acid catalyzed by the cyclooxygenases, COX 1 and COX-2. Recently developed non-steroidal anti-inflammatory drugs (NSAIDS) are targeted to inhibit COX-2 and treat inflammation and arthritic pain. It is not known if the use of NSAIDS may be beneficial for the treatment of kidney disease; however, the upregulation of pro-inflammatory COX-2 and increased production of COX-2 derived metabolites have been implicated in diabetic nephropathy. COX-2 regulation and its association with renal damage are not known in the Obese Zucker rat. A new study tests the hypothesis that altered kidney regulation of COX-2 occurs at a very early stage in the progression of kidney disease.

A New Study


The authors of the study entitled, "Renal Microvascular COX-2 Upregulation is Associated with Kidney Damage in Zucker Obese Rats," are Aparajita Dey, Roger S. Williams, David M. Pollock, David W. Stepp and John D. Imig, all from the Vascular Biology Center, Medical College of Georgia, Augusta, GA. They are presenting their findings during the American Physiological Society (APS) (www.the-aps.org) conference, Understanding Renal and Cardiovascular Function Through Physiological Genomics. The scientific conference is being held October 1-4, 2003 at the Radisson Riverfront Hotel and Convention Center, Augusta, GA.

Background

Obesity, a major nutritional disorder in the United States, leads to the development of Type II diabetes, hypertension, atherosclerosis and chronic renal disease, most of which are interdependent factors. Diabetic nephropathy, a kidney disease that develops in as many as 20 to 40 percent of diabetics, is the leading cause of end stage renal disease (ESRD). In addition to diabetes, obesity, hypertension, hyperlipidemia and other risk factors contribute to the development and progression of kidney disease.

The Obese Zucker rat displays all the metabolic characteristics associated with Type II diabetes and hypertension, and develops extensive renal damage. Obese Zucker rats possess a mutant leptin receptor that explains their uncontrolled appetite and, consequently, results in obesity and its associated characteristics (insulin resistance, hypertension, etc.), although the mechanisms responsible for renal damage in the Obese Zucker rat remain unknown.

Methodology

Obese Zucker rats at 10-12 weeks or 20-21 weeks of age were studied. The rats were housed in separate cages and maintained in a temperature and light-controlled room. Throughout the experimental period, animals had access to standard chow and drinking water. Blood pressure was measured in the conscious state utilizing the radiotelemetry method. Blood glucose levels and body weight were measured periodically.

Protein expression of COX-1 and COX-2 in the kidney cortex, renal microvessels and glomeruli was studied. The levels of 6-keto PGF1a, PGF2a, PGE2 and TXB2 in urine were measured using enzyme immunoassays. Urinary albumin excretion, and indicator of kidney damage, was measured. Kidneys were perfusion fixed in 10% buffered formalin solution and embedded in paraffin for light microscopic evaluation.

Results

The researchers found that:
  • the Obese Zucker rats weighed 432 ± 20 g with a blood glucose of 105 ± 5 mg/dl at 10-12 weeks of age and weighed 679 ± 12 g with a blood glucose of 161 ± 13 mg/dl at 20-21 weeks of age. Blood pressure was slightly elevated in the Obese Zucker rat compared to lean rats and averaged 105 ± 5 mmHg;

  • increased COX-2 protein expression was observed in the kidney cortex and microvessels of the Obese Zucker rats at 10-12 and 20-21 weeks of age. The increase in COX-2 protein expression was associated with increases in TXB2 and decreases in PGE2 urinary excretion rates; and

  • increased urinary albumin was evident in the Obese Zucker rat at 10-12 weeks of age and averaged 7±1 mg/d. At 20-21 weeks of age renal vascular and glomerular damage progressed as assessed histologically and urinary albumin excretion increased to 117 ± 10 mg/d in the Obese Zucker rats.

Conclusions

Obesity is a major risk factor that, along with hyperglycemia and hypertension, contributes to the progression of kidney disease. Previous studies in models of Type I diabetes have suggested that COX-2 may contribute to diabetic nephropathy. In this study researchers found increases in renal COX-2 levels and changes in TXA2 and PGE2 levels in the Obese Zucker rat. The changes in TXA2 and PGE2 are similar to those found in the diabetic patient population.

Interestingly, these changes occurred in the Obese Zucker rat at pre-hyperglycemic and pre-hypertensive stages. Renal damage was minimal at 10-12 weeks of age and progressed rapidly towards kidney failure by 20-21 weeks of age. Therefore, during the development of obesity-related diabetes, alternations in COX-2 derived metabolites could contribute to the renal damage associated with this disease. Taken as a whole, these findings suggest that COX-2 inhibitors may be beneficial for the prevention of renal damage in obesity-related type II diabetes.


The American Physiological Society (APS) is one of the world’s most prestigious organizations for physiological scientists. These researchers specialize in understanding the processes and functions by which animals live, and thus ultimately underlie human health and disease. Founded in 1887 the Bethesda, MD-based Society has more than 11,000 members and publishes 3,800 articles in its 14 peer-reviewed journals each year.

EDITOR’S NOTE: Members of the press are invited to attend the conference and interview the researchers in person or by phone. Please contact Donna Krupa at (703) 527-7357 (office); (703) 967-2751 (cell) or djkrupa1@aol.com (email) for more information.

Meeting Dates: October 1-4, 2003
Radisson Riverfront Hotel and Convention Center, Augusta, GA


Donna Krupa | EurekAlert!
Further information:
http://www.faseb.org/aps/

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