Enhanced angiotensin II (AngII) action has been implicated in endothelial dysfunction that is characterized as decreased nitric oxide availability. Although endothelial cells have been reported to express AngII type 1 (AT1) receptors, the exact role of AT1 in regulating endothelial NO synthase (eNOS) activity remains unclear. We investigated the possible regulation of eNOS through AT1 in bovine aortic endothelial cells (BAECs) and its functional significance in rat aortic vascular smooth muscle cells (VSMCs). In BAECs infected with adenovirus encoding AT1 and in VSMCs infected with adenovirus encoding eNOS, AngII rapidly stimulated phosphorylation of eNOS at Ser1179. This was accompanied with increased cGMP production. These effects were blocked by an AT1 antagonist. The cGMP production was abolished by a NOS inhibitor as well. To explore the importance of eNOS phosphorylation, VSMCs were also infected with adenovirus encoding S1179A-eNOS. AngII did not stimulate cGMP production in VSMCs expressing S1179A. However, S1179A was able to enhance basal NO production as confirmed with cGMP production and enhanced vasodilator-stimulated phosphoprotein phosphorylation. Interestingly, S1179A prevented the hypertrophic response similar to wild type in VSMCs. From these data, we conclude that the AngII/AT1 system positively couples to eNOS via Ser1179 phosphorylation in ECs and VSMCs if eNOS and AT1 coexist. However, basal level NO production may be sufficient for prevention of AngII-induced hypertrophy by eNOS expression. These data demonstrate a novel molecular mechanism of eNOS regulation and function and thus provide useful information for eNOS gene therapy under endothelial dysfunction.

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Great attention has been drawn toward the recently defined IgG4 related sclerosing disease, an entity incorporating autoimmune pancreatitis and other organ involvements, hypergammaglobulinemia and deposition of IgG4 in affected tissues. We demonstrate an index case of this disease with multiple organ involvements and an excellent response to corticosteroid treatment. A 69-year-old white man was diagnosed with IgG4 related sclerosing disease with involvement of lungs, pancreas, submandibular glands, lymph nodes, and kidney. In addition, the patient had polyclonal IgG hypergammaglobulinemia and hypocomplementemia. A renal biopsy showed tubulointerstitial nephritis with extensive lymphoplasmacytic infiltrate. Biopsy of the lung showed "inflammatory pseudotumor" with lymphocyte and plasma cell infiltration. IgG4 positive plasma cells were seen in the biopsy of submandibular gland and the kidney. Immuno-staining of the renal biopsy specimen showed vascular deposition of complement split product C4d. Corticosteroid treatment of 2 months showed complete resolution of the disease process. We demonstrate deposition of C4d in the IgG4 related tubulointerstitial nephritis for the first time.