Relevance of serum phosphorus changes on renal prognosis in patients with essential hypertension

renal microvascular responses, we generated several unique p66 Shc mutant rat strains based on the genetic background of Dahl salt-sensitive (SS) rats using CompoZr ZFNs targeting exon 2 of the Shc1 gene. The juxtamedullary vasculature was isolated from these genetically modified rats and afferent arteriolar responses to vasoactive compounds were monitored by videomicroscopy. We have demonstrated that p66 Shc knockout restores vasoconstrictor responses to ATP and increased perfusion pressure, which are impaired in SS rats. In patch clamp electrophysiology experiments carried out with primary smooth muscle cells (SMC) isolated from renal vessels of p66 Shc rat knockouts we established that p66 Shc deficiency results in a dramatic increase in TRPC channels activity in response to Endothelin-1 (ET-1). Correspondingly, ET-1-mediated cytosolic Ca2+ mobilization and activation of [Ca2+]i-dependent cytoplasmic tyrosine kinase Pyk2 were also increased in SMC derived from p66 Shc knockout rats, when compared with SMC derived from their WT littermates. Moreover, p66 Shc knockout promoted cellular contractility in primary rat SMC. Our data suggest that p66 Shc restrains activity of TRPC channels, attenuating changes in cytosolic Ca2+ concentration, contributing to reduction of autoregulatory responses of juxtamedullary afferent arterioles. These results establish a role for the adaptor protein p66 Shc in the regulation of renal vascular tone and promotion of renal vascular dysfunction.