Mechanism of ochratoxin A-induced reduction of glomerular filtration rate in rats

M Gekle and S Silbernagl

Department of Physiology, University of Wurzburg, Germany.

The nephrotoxin ochratoxin A (OTA) causes a reduction of glomerular filtration rate (GFR) and of para-aminohippuric acid (PAH) clearance. We determined renal plasma flow (RPF), filtration fraction (FF) and total renal vascular resistance (TRVR). Using furosemide, we investigated the role of tubuloglomerular feedback (TGF) for GFR reduction. Using enalapril and the angiotensin II antagonist DUP 753 we investigated the role of angiotensin II for GFR reduction. Six days' application of 0.5 mg/kg b.wt. of OTA i.p. to male Wistar rats leads to RPF reduction from 3.98 +/- 0.18 to 1.97 +/- 0.18 ml/(min.g kidney wet weight) and GFR reduction from 1.08 +/- 0.06 to 0.69 +/- 0.04 ml/(min.g kidney wet weight) (n = 6, P < .05 for both). FF increased to 130% of control and TRVR to 202% of control (n = 6, P < .05 for both). The application of furosemide (30 mg/(h.kg b.wt.) after pretreatment with OTA had no effect on the reduction of GFR indicating that TGF is not involved. Pretreatment with OTA and enalapril [0.5 mg/(d.kg) b.wt.] blunted the effect of OTA alone significantly (GFR only dropped to 88% of control). Pretreatment with OTA and DUP 753 [20 mg/(d.kg) b.wt.] blunted the effect of OTA alone significantly: GFR and RPF only dropped to 89 and 91% of control, respectively. FF and TRVR were no longer different from control. Acute application of DUP 753 (2 mg/kg b.wt. i.v.) after pretreatment with OTA blunted the effect of OTA to a lesser extend. Our conclusions are: 1) Reduction of PAH clearance and of GFR is in part due to reduced RPF. 2) The increase in TRVR is at least in part caused by an increase of the efferent resistance. 3) Activation of the TGF is not involved in GFR reduction. 4) The increase in TRVR and the decrease of GFR are mainly mediated by angiotensin II.

Volume 267, Issue 1, pp. 316-321, 10/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics