Role of Src homology 2 domain‐containing protein B in the regulation of GFR and renal afferent arteriole responsiveness (1088.12)

Abstract

BACKGROUND: Src homology 2 domain‐containing protein B (Shb) is an adapter protein which regulates several signal transduction cascades and endothelial cell functions. We used Shb‐knockout (Shb‐/‐) and wild‐type (Shb+/+) mice to investigate the role of Shb in regulating glomerular filtration rate (GFR), vascular resistance and tubuloglomerular feedback.METHODS: GFR was measured in conscious Shb‐/‐ and Shb+/+ mice using FITC‐inulin. Isotonic contractions were measured in isolated and perfused renal afferent arterioles from Shb‐/‐ and Shb+/+ mice. Concentration responses to Ang II (10‐12 to 10‐6M; 2 minutes each) doses, low‐dose Ado (10‐8 mol/l; 15 min) alone or Nω‐nitro‐l‐arginine methyl ester (L‐NAME; 10‐4 mol/l; 15 min) alone, as well as Ado (10‐8 mol/l) or nitric oxide (NO) synthase inhibitor L‐NAME (10‐4 mol/l) in combination with cumulative application of Ang II (10‐12 to 10‐6 mol/l; 2 minutes each) were studied in both genotypes.RESULTS: There was a significantly increased GFR (371 ± 12 µl/min, n=11) in Shb‐/‐ comparing to Shb+/+ (321 ± 11 µl/min, n=8) mice. The maximal arteriolar contraction to Ang II was remarkably larger in Shb‐/‐ (87 %, n=8) than in Shb+/+ (54 %, n=8) mice. Low‐dose Ado contracted afferent arterioles in both genotypes (6% in Shb‐/‐ and 7% in Shb+/+). Ado significantly enhanced Ang II constriction in afferent arterioles in both genotypes (to 93% in Shb‐/‐ and to 72 % in Shb+/+). L‐NAME reduced arteriolar diameters significantly more in Shb‐/‐ (14 %, n=7) than in wild types (9 %, n=7) and remarkably augmented ANG II responses in both genotypes. L‐NAME with Ang II almost fully constricted renal afferent arterioles in Shb‐/‐ (98 %), while contracted 64% in Shb+/+ mice.CONCLUSION: The absence of Shb markedly increases GFR. Both low‐dose adenosine and L‐NAME treatments significantly augment Ang II arteriolar constriction effectiveness, which indicates Ado‐Ang II and NO‐Ang II interactions in both Shb‐/‐ and Shb+/+ mice. The underlying mechanisms remain to be resolved.