Influence of Connexin40 on the renal myogenic response in murine afferent arterioles

Abstract

Renal autoregulation consists of two main mechanisms; the myogenic response and the tubuloglomerular feedback mechanism (TGF). Increases in renal perfusion pressure activate both mechanisms causing a reduction in diameter of the afferent arteriole (AA) resulting in stabilization of the glomerular pressure. It has previously been shown that connexin-40 (Cx40) is essential in the renal autoregulation and mediates the TGF mechanism. The aim of this study was to characterize the myogenic properties of the AA in wild-type and connexin-40 knockout (Cx40KO) mice using both in situ diameter measurements and modeling. We hypothesized that absence of Cx40 would not per se affect myogenic properties as Cx40 is expressed primarily in the endothelium and as the myogenic response is known to be present also in isolated, endothelium-denuded vessels. Methods used were the isolated perfused juxtamedullary nephron preparation to allow diameter measurements of the AA. A simple mathematical model of the myogenic response based on experimental parameters was implemented. Our findings show that the myogenic response is completely preserved in the AA of the Cx40KO and if anything, the stress sensitivity of the smooth muscle cell in the vascular wall is increased rather than reduced as compared to the WT. These findings are compatible with the view of the myogenic response being primarily a local response to the local transmural pressure.

Keywords: Afferent arteriole; autoregulation; connexin; myogenic.

Figure 1

Theoretical examples of (A) activation as a function of increasing wall stress at high (gray) and low (black) stress sensitivity of the vascular wall. (B) Diameter as a function of increasing perfusion pressure at high (gray) and low (black) stress sensitivity. (C) Diameter as a function of increasing perfusion pressure at low (gray) and high (black) wall thickness.

Figure 2

Changes in afferent arteriolar diameter in wild-type mice at increasing renal perfusion pressures during perfusion without (black, active curve) and during perfusion with a vasodilator (nifedipine/papaverine; gray, passive curve). (A) experimental data. (B) data from the mathematical model. Thin black lines show the pressure range (95–195 mm Hg) measured in the renal artery. Gray vertical lines indicate the estimated pressure range found in the mid to late AA. *P < 0.05 versus 95 mm Hg. #P < 0.05 versus active.

Figure 3

Changes in afferent arteriolar diameter in papillectomized wild-type mice at increasing renal perfusion pressures during perfusion without (black, active curve) and during perfusion with a vasodilator (nifedipine; gray, passive curve). (A) experimental data. (B) data from the mathematical model. Thin black lines show the pressure range (95–195 mm Hg) measured in the renal artery. Gray vertical lines indicate the estimated pressure range found in the mid to late AA. *P < 0.05 versus 95 mm Hg. #P < 0.05 versus papillectomy, active.

Figure 4

Changes in afferent arteriolar diameter in Cx40 knockout mice at increasing renal perfusion pressures during perfusion without (black, active curve) and during perfusion with a vasodilator (nifedipine/papaverine; gray, passive curve). (A) experimental data. (B) data from the mathematical model. Thin black lines show the pressure range (95–195 mm Hg) measured in the renal artery. Gray vertical lines indicate the estimated pressure range found in the mid to late AA. *P < 0.05 versus 95 mm Hg. #P < 0.05 versus active.