Macula Densa Nitric Oxide Synthase 1β Protects against Salt-Sensitive Hypertension

[摘要] Nitric oxide (NO) is an important negative modulator of tubuloglomerular feedback responsiveness. We recently found that macula densa expresses α -, β -, and γ -splice variants of neuronal nitric oxide synthase 1 (NOS1), and NOS1 β expression in the macula densa increases on a high-salt diet. This study tested whether upregulation of NOS1 β expression in the macula densa affects sodium excretion and salt-sensitive hypertension by decreasing tubuloglomerular feedback responsiveness. Expression levels of NOS1 β mRNA and protein were 30- and five-fold higher, respectively, than those of NOS1 α in the renal cortex of C57BL/6 mice. Furthermore, macula densa NO production was similar in the isolated perfused juxtaglomerular apparatus of wild-type (WT) and nitric oxide synthase 1 α -knockout (NOS1 α KO) mice. Compared with control mice, mice with macula densa–specific knockout of all nitric oxide synthase 1 isoforms (MD-NOS1KO) had a significantly enhanced tubuloglomerular feedback response and after acute volume expansion, significantly reduced GFR, urine flow, and sodium excretion. Mean arterial pressure increased significantly in MD-NOS1KO mice ( P <0.01) but not NOS1flox/flox mice fed a high-salt diet. After infusion of angiotensin II, mean arterial pressure increased by 61.6 mmHg in MD-NOS1KO mice versus 32.0 mmHg in WT mice ( P <0.01) fed a high-salt diet. These results indicate that NOS1 β is a primary NOS1 isoform expressed in the macula densa and regulates the tubuloglomerular feedback response, the natriuretic response to acute volume expansion, and the development of salt-sensitive hypertension. These findings show a novel mechanism for salt sensitivity of BP and the significance of tubuloglomerular feedback response in long-term control of sodium excretion and BP.

[学科分类] 泌尿医学