RESUMO
The calcium-sensing receptor (CaSR) is a G-coupled protein expressed in renal juxtaglomerular (JG) cells. Its activation stimulates calcium-mediated decreases in cAMP content and inhibits renin release. The postreceptor pathway for the CaSR in JG cells is unknown. In parathyroids, CaSR acts through G(q) and/or G(i). Activation of G(q) stimulates phospholipase C (PLC), and inositol 1,4,5-trisphosphate (IP(3)), releasing calcium from intracellular stores. G(i) stimulation inhibits cAMP formation. In afferent arterioles, the ryanodine receptor (RyR) enhances release of stored calcium. We hypothesized JG cell CaSR activation inhibits renin via the PLC/IP(3) and also RyR activation, increasing intracellular calcium, suppressing cAMP formation, and inhibiting renin release. Renin release from primary cultures of isolated mouse JG cells (n = 10) was measured. The CaSR agonist cinacalcet decreased renin release 56 ± 7% of control (P < 0.001), while the PLC inhibitor U73122 reversed cinacalcet inhibition of renin (104 ± 11% of control). The IP(3) inhibitor 2-APB also reversed inhibition of renin from 56 ± 6 to 104 ± 11% of control (P < 0.001). JG cells were positively labeled for RyR, and blocking RyR reversed CaSR-mediated inhibition of renin from 61 ± 8 to 118 ± 22% of control (P < 0.01). Combining inhibition of IP(3) and RyR was not additive. G(i) inhibition with pertussis toxin plus cinacalcet did not reverse renin inhibition (65 ± 12 to 41 ± 8% of control, P < 0.001). We conclude stimulating JG cell CaSR activates G(q), initiating the PLC/IP(3) pathway, activating RyR, increasing intracellular calcium, and resulting in calcium-mediated renin inhibition.
Assuntos
Inositol 1,4,5-Trifosfato/metabolismo , Sistema Justaglomerular/metabolismo , Receptores de Detecção de Cálcio/metabolismo , Renina/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Transdução de Sinais/fisiologia , Fosfolipases Tipo C/metabolismo , Animais , Calcimiméticos/farmacologia , Cálcio/metabolismo , Células Cultivadas , Cinacalcete , AMP Cíclico/metabolismo , Inibidores Enzimáticos/farmacologia , Estrenos/farmacologia , Sistema Justaglomerular/citologia , Sistema Justaglomerular/efeitos dos fármacos , Camundongos , Modelos Animais , Naftalenos/farmacologia , Toxina Pertussis/farmacologia , Pirrolidinonas/farmacologia , Receptores de Detecção de Cálcio/agonistas , Receptores de Detecção de Cálcio/efeitos dos fármacos , Fosfolipases Tipo C/antagonistas & inibidoresRESUMO
We present here a rare case of synchronous adrenocortical carcinoma (ACC) and renal cell carcinoma (RCC). A 27-year-old woman presented with gradual abdominal distension, hematuria, and loss of weight of 3-months duration. She gave a history of treatment for hypertension. The computed axial tomography (CT) scan revealed a large retroperitoneal mass. Her urinary VMA was slightly elevated. Her 24-h urinary metanephrine level was normal. The patient underwent left adrenalectomy, left nephrectomy, spleenectomy, and distal pancreactomy with segmental colonic resection. Postoperative pathology revealed ACC of left suprarenal measuring 22 × 19 × 18 cm(3) and RCC involving the left upper pole of kidney measuring 3 × 2 × 1 cm(3).
RESUMO
Recent studies have demonstrated that orally administered thiazolidinedione ligands of the peroxisome proliferator-activated receptor-gamma can ameliorate clinical features of psoriasis in humans. Thiazolidinediones also inhibit the proliferation of psoriatic keratinocytes in monolayer and organ culture, and at least one of these agents (troglitazone) inhibits epidermal hyperplasia of human psoriatic skin transplanted to severe-combined immunodeficient (SCID) mice. In the present study, we show that a novel, synthetic, thiazoladinedione derivative, BP-1107 ({2-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenoxy]-ethyl}-methyl-amide), is capable of inhibiting psoriatic hyperplasia in the SCID mouse transplant model after topical application. Like other thiazolidinediones, BP-1107 inhibits proliferation of rapidly growing keratinocytes in monolayer culture, but compared with these agents, the effective dose of BP-1107 needed to suppress keratinocyte proliferation is much lower. Concentrations of BP-1107 that effectively inhibit keratinocyte function have no detrimental effect on dermal fibroblasts. These data suggest that effective topical antipsoriatic therapy may be provided with this agent.