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Acta Physiologica 2009; Volume 195, Supplement 669
The 88th Annual Meeting of The German Physiological Society
3/22/2009-3/25/2009
Giessen, Germany
IMPAIRED RENAL BLOOD FLOW AUTOREGULATION DUE TO COMPROMISED TUBULOGLOMERULAR FEEDBACK IN MICE LACKING CONNEXIN 40
Abstract number: O298
Just1 A., Kurtz2 L., Wit3 C., Wagner1 C., Kurtz2 A., Arendshorst4 W. J.
1Physiologisches Institut 1, Universitt Freiburg, Freiburg i. Br.
2Institut fr Physiologie, Universitt Regensburg, Regensburg
3Institut fr Physiologie, Universitt Lbeck, Lbeck
4Dept. of Cell and Molecular Physiology, University of North Carolina, Chapel Hill, United States of America
BACKGROUND: Connexin (Cx40) is highly expressed in endothelial cells as well as in the renal juxtaglomerular apparatus and plays a prominent role in conducted vasodilator responses in skeletal muscle arterioles and also in renin release and arterial pressure control. We studied the role of Cx40 in renal blood flow (RBF) autoregulation, autoregulatory mechanisms, and agonist-induced vasomotor responses in mice lacking Cx40 (Cx40-ko) and mice with Cx40 replaced by Cx45 (Cx40-ki45).
RESULTS:
Cx40 (Cx40-ko), had impaired steady-state autoregulation (722% of perfect vs. 10211% in wild-type (wt), p<0.01) to a sudden step increase in renal perfusion pressure. Dynamic analysis of the three main mechanisms revealed markedly reduced tubuloglomerular feedback (TGF) in Cx40-ko (188 vs. 7510%, p<0.01), while the most rapid myogenic response (MR, 237 vs. 226) and slowest third component (187 vs. 277%) were not consistently altered. In mice with Cx40 replaced by Cx45 (Cx40-ki45) steady-state autoregulation (6617%) and TGF (4011%) were weaker than in wt and tended to be stronger than in Cx40-ko. L-NAME augmented MR similarly in all genotypes, maintaining impaired overall autoregulation (2930 vs. 1025%, Cx40-ko vs. wt, p<0.05). Responses of renovascular resistance and arterial pressure to norepinephrine (NE, 75 mg iv) and acetylcholine (ACh, 25 mg) were similar in all genotypes before or after L-NAME. Systemic and renal vasoconstrictor responses to L-NAME were also similar in all genotypes. Immunhistochemistry showed Cx37, Cx40, and Cx43 in preglomerular endothelial, renin-producing, and mesangial cells. In Cx40-ko and Cx40-ki45, expression of Cx40 was absent.
CONCLUSIONS:
We conclude that Cx40 contributes to RBF autoregulation and is critical for TGF-mediated signal transduction to the afferent arteriole. This Cx40 function can partly be substituted by Cx45 and is independent of NO. The modulation of the renal MR by NO does not require Cx40, nor does acute renal vasoconstriction elicited by NE or vasodilation by ACh or NO.
Supported by NIH (R01HL002334) and German Research Foundation (SFB 699 and WI2071/2-1).
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Acta Physiologica 2009; Volume 195, Supplement 669 :O298