High-Protein Diet-Induced Glomerular Hyperfiltration Is Dependent on Neuronal Nitric Oxide Synthase β in the Macula Densa via Tubuloglomerular Feedback Response

It is well-known that high protein intake increases glomerular filtration rate. Evidence from several studies indicated that nitric oxide and tubuloglomerular feedback mediate the effect. However, a recent study with a neuronal nitric oxide synthase α knockout model refuted this mechanism and concluded that neither neuronal nitric oxide synthase nor tubuloglomerular feedback response is involved in the protein-induced hyperfiltration. To examine the discrepancy, this study tested a hypothesis that neuronal nitric oxide synthase β in the macula densa mediates the high protein diet-induced glomerular hyperfiltration via tubuloglomerular feedback mechanism. We examined the effects of high protein intake on nitric oxide generation at the macula densa, tubuloglomerular feedback response, and glomerular filtration rate in wild-type and macula densa–specific neuronal nitric oxide synthase knockout mice. In wild-type mice, high protein diet increased kidney weight, glomerular filtration rate and renal blood flow, while reduced renal vascular resistance. Tubuloglomerular feedback response in vivo and in vitro were blunted and nitric oxide generation in the macula densa was increased following high protein diet, associated with upregulations of neuronal nitric oxide synthase β expression and phosphorylation at Ser1417. In contrast, these high protein diet-induced changes in nitric oxide generation at the macula densa, tubuloglomerular feedback response, renal blood flow and glomerular filtration rate in wild-type mice were largely attenuated in macula densa–specific neuronal nitric oxide synthase knockout mice. In conclusion, we demonstrated that high protein diet-induced glomerular hyperfiltration is dependent on neuronal nitric oxide synthase β in the macula densa via tubuloglomerular feedback response.