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 NO and tubuloglomerular feedback (TGF) mediate the effect. However, a recent study with a neuronal NO synthase-alpha knockout model refuted this mechanism and concluded that neither neuronal NO synthase nor TGF response is involved in the protein-induced hyperfiltration. To examine the discrepancy, this study tested a hypothesis that neuronal NO synthase-beta in the macula densa mediates the high-protein diet-induced glomerular hyperfiltration via TGF mechanism. We examined the effects of high protein intake on NO generation at the macula densa, TGF response, and glomerular filtration rate in wild-type and macula densa-specific neuronal NO synthase KO mice. In wild-type mice, high-protein diet increased kidney weight, glomerular filtration rate, and renal blood flow, while reduced renal vascular resistance. TGF response in vivo and in vitro was blunted, and NO generation in the macula densa was increased following high-protein diet, associated with upregulations of neuronal NO synthase-beta expression and phosphorylation at Ser1417. In contrast, these high-protein diet-induced changes in NO generation at the macula densa, TGF response, renal blood flow, and glomerular filtration rate in wild-type mice were largely attenuated in macula densa-specific neuronal NO synthase KO mice. In conclusion, we demonstrated that high-protein diet-induced glomerular hyperfiltration is dependent on neuronal NO synthase beta in the macula densa via TGF response.