Urinary and renal interstitial concentrations of TNF-alpha increase prior to the rise in albuminuria in diabetic rats.
BACKGROUND
The development of diabetic nephropathy has been linked to the release of vasoactive hormones and growth factors. Currently the role of inflammatory cytokines in this pathogenic process is not clear.


METHODS
We utilized the microdialysis technique to monitor early changes in tumor necrosis-alpha (TNF-alpha) levels in the renal interstitial fluid and urine of conscious Sprague-Dawley rats (N = 8) before and after induction of diabetes with streptozotocin (STZ). Measurement of the urinary albumin excretion (UAE) was utilized to monitor the development and progression of diabetic nephropathy.


RESULTS
UAE increased from 0.56 +/- 0.20 microg/min to 8.14 +/- 2.98 microg/min 17 days after induction of diabetes (P = 0.01). Renal interstitial fluid TNF-alpha increased from 11.96 +/- 5.32 pg/mL at baseline to 45.02 +/- 11.69 pg/mL 5 days after induction of diabetes (P = 0.03). Renal interstitial fluid TNF-alpha levels remained elevated throughout the remainder of the study period. Urinary TNF-alpha also increased significantly compared to baseline 3 days after induction of diabetes (294.18 +/- 36.94 pg/mL vs. 16.05 +/- 6.07 pg/mL, P < 0.002). There was a second significant rise in urinary TNF-alpha concentration to 638.16 +/- 36.94 pg/mL 21 days after induction of diabetes (P < 0.001). Serum TNF-alpha levels were undetectable before STZ injection and remained undetectable by the end of the study. Urinary and renal interstitial fluid TNF-alpha in the control rats (N = 5) did not change throughout the study.


CONCLUSIONS
We found an early rise in renal TNF-alpha levels after induction of diabetes with STZ, which precedes the rise in UAE by about 2 weeks. These findings suggest a possible contribution of TNF-alpha in the complicated pathogenic process resulting in microalbuminuria in diabetes.
Kalantarinia
Kambiz
K
Department of Medicine, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
Awad
Alaa S
AS
Siragy
Helmy M
HM
D000419:Albuminuria / Q000209:etiology* / Q000652:urine; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism* / Q000652:urine; D007668:Kidney / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009994:Osmolar Concentration; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000652:urine
D001786:Blood Glucose; D014409:Tumor Necrosis Factor-alpha