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Macula Densa SGLT1-NOS1-Tubuloglomerular Feedback Pathway, a New Mechanism for Glomerular Hyperfiltration During Hyperglycemia

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Macula Densa SGLT1-NOS1-Tubuloglomerular Feedback Pathway, a New Mechanism for Glomerular Hyperfiltration During Hyperglycemia BASIC RESEARCH www.jasn.org Macula Densa SGLT1-NOS1-Tubuloglomerular Feedback Pathway, a New Mechanism for Glomerular Hyperfiltration during Hyperglycemia Jie Zhang,1 Jin Wei,1 Shan Jiang,1 Lan Xu,2 Lei Wang,1 Feng Cheng,3 Jacentha Buggs,4 Hermann Koepsell,5 Volker Vallon,6 and Ruisheng Liu1 1Department of Molecular Pharmacology and Physiology, College of Medicine, 2Department of Biostatistics, College of Public Health, and 3Department of Pharmaceutical Science, College of Pharmacy, University of South Florida, Tampa, Florida; 4Advanced Organ Disease & Transplantation Institute, Tampa General Hospital, Tampa, Florida; 5Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany; and 6Division of Nephrology and Hypertension, Department of Medicine, University of California, San Diego, La Jolla, California ABSTRACT Background Glomerular hyperfiltration is common in early diabetes and is considered a risk factor for later diabetic nephropathy. We propose that sodium-glucose cotransporter 1 (SGLT1) senses increases in luminal glucose at the macula densa, enhancing generation of neuronal nitric oxide synthase 1 (NOS1)– dependent nitric oxide (NO) in the macula densa and blunting the tubuloglomerular feedback (TGF) response, thereby promoting the rise in GFR. Methods We used microperfusion, micropuncture, and renal clearance of FITC–inulin to examine the effects of tubular glucose on NO generation at the macula densa, TGF, and GFR in wild-type and macula densa–specificNOS1knockoutmice. Results Acute intravenous injection of glucose induced hyperglycemia and glucosuria with increased GFR in mice. We found that tubular glucose blunts the TGF response in vivo and in vitro and stimulates NO generation at the macula densa. We also showed that SGLT1 is expressed at the macula densa; in the presence of tubular glucose, SGLT1 inhibits TGF and NO generation, but this action is blocked when the SGLT1 inhibitor KGA-2727 is present. In addition, we demonstrated that glucose increases NOS1 expression and NOS1 phosphorylation at Ser1417 in mouse renal cortex and cultured human kidney tissue. In macula densa–specific NOS1 knockout mice, glucose had no effect on NO generation, TGF, and GFR. Conclusions We identified a novel mechanism of acute hyperglycemia–induced hyperfiltration wherein increases in luminal glucose at the macula densa upregulate the expression and activity of NOS1 via SGLT1, blunting the TGF response and promoting glomerular hyperfiltration. J Am Soc Nephrol 30: 578–593, 2019. doi: https://doi.org/10.1681/ASN.2018080844 More than 30 million Americans have diabetes. Di- Received August 20, 2018. Accepted January 27, 2019. abetic nephropathy is a major complication of di- abetes mellitus1–3 and the leading cause of ESRD. An J.Z. and J.W. contributed equally to this work. increase in GFR or glomerular hyperfiltration has Published online ahead of print. Publication date available at www.jasn.org. been observed in about 70% of patients with type 1 diabetes4,5 and 50% of patients with type 2 diabe- Correspondence: Dr. Jie Zhang, Department of Molecular Pharmacology and Physiology, University of South Florida Col- 5–8 tes, andisassociatedwithanincreasedrisk lege of Medicine, 12901 Bruce B. Downs Boulevard, MDC 8 for diabetic nephropathy and worse prognosis.4,7–9 Tampa, FL 33612. Email: [email protected] The pathogenesis of glomerular hyperfiltration in Copyright © 2019 by the American Society of Nephrology 578 ISSN : 1046-6673/3004-578 J Am Soc Nephrol 30: 578–593, 2019 www.jasn.org BASIC RESEARCH diabetes has not been fully elucidated. Several mechanisms have Significance Statement been implicated, primarily including vascular and tubular theo- ries. According to the vascular mechanism, glomerular hyperfil- Although glomerular hyperfiltration is common in early diabetes and tration results from an imbalance between vasoconstrictive fac- considered a risk factor for later diabetic nephropathy, the mech- fi tors and vasodilatory factors.4,5,10 The tubular theory proposes anisms underlying glomerular hyper ltration have not been fully clarified. The authors identified a novel mechanism of acute hy- that tubular growth and the upregulated sodium-glucose co- perglycemia–induced hyperfiltration in which increases in luminal transporter 2 (SGLT2) enhance proximal tubular reabsorp- glucose at the macula densa upregulate the expression and activity tion, which reduces sodium chloride (NaCl) delivery to the of neuronal nitric oxide synthase 1 (NOS1) via sodium-glucose co- macula densa and increases GFR via the tubuloglomerular transporter 1 (SGLT1); this blunts the tubuloglomerular feedback fi feedback (TGF) response (SGLT2-NaCl pathway).11–13 (TGF) response and promotes glomerular hyper ltration. This novel SGLT1-NOS1-TGF pathway mediates the glomerular hyperfiltration The TGF response describes a mechanism by which an in- observed in response to acute hyperglycemia. These findings estab- crease in NaCl delivery to the macula densa promotes the re- lish a critical role of macula densa NOS1 and SGLT1 as key determi- lease and formation of ATP and/or adenosine,14–17 which then nants of, and potential therapeutic targets for, acute hyperglycemia– constricts the afferent arteriole (Af-Art) and induces a tonic associated glomerular hyperfiltration, and possibly for diabetes as well. inhibition of single-nephron GFR.18–20 neuronal nitric oxide fl fl synthase (NOS1) is the predominant nitric oxide synthase knockout (MD-NOS1KO) mice (NKCC2cre/NOS1 ox/ ox) 21,22 (NOS) isoform expressed in macula densa cells, and nitric were generated by crossing an NKCC2-Cre line with oxide (NO) generated by the macula densa blunts TGF re- NOS1-floxed mice as described previously.28 All protocols 23–26 sponse. Recently, several studies from our laboratory were approved by the Institutional Animal Care and Use demonstrated the decisive role of macula densa NOS1 in the Committee at the University of South Florida, College of TGF response and the long-term control of GFR, sodium ex- Medicine (IS00003816 and IS00004119). All chemicals 27–29 cretion, and BP. Mice with deletion of NOS1 from the were purchased from Sigma (St. Louis, MO), except as macula densa exhibit enhanced TGF responsiveness and de- indicated. velop salt-sensitive hypertension.28 Although many previous studies have assessed the TGF response and renal NO produc- Induction of Acute Hyperglycemia tion in diabetes,11,30–33 whether macula densa NOS1 is a To determine the intravenous dose of glucose that is able to causal factor for diabetic hyperfiltration remains elusive. increase blood glucose levels over the renal threshold of glucose More than 99% of filteredglucose in the kidney is reabsorbed by (corresponding to blood glucose concentration of approxi- sodium-glucose cotransporter 1 (SGLT1) and SGLT2 in the prox- mately .180 mg/dl in humans and .250 mg/dl in ro- imal tubules. SGLT2 is present in the S1 and S2 segments of dents37,38), we applied a bolus injection of 50 ml of glucose proximal tubules and mediates approximately 97% of glucose (2.5 or 5 M in saline) in lightly anesthetized mice via the retro- resorption, whereas SGLT1 is present in the S3 segment of prox- orbital venous sinus, and the blood glucose levels were measured imal tubules and accounts for the remaining 2%–3% of the at 3, 10, 20, 40, 60, and 80 minutes after glucose injection, by filtered glucose.34 The luminal glucose concentration at the mac- Precision Xtra Glucose Meter K (Fisher Scientific, Waltham, ula densa is usually negligible under normoglycemic conditions. MA). Mice injected with 50 ml saline (0 M glucose) served as Luminal glucose concentration at the macula densa rises, how- controls. ever, when the amount of filtered glucose exceeds the maximal capacity of reabsorption by proximal tubules in hyperglycemic Measurement of Glucose Concentration in Urine and states. Moreover, SGLT1has recently been detected on the apical Early Distal Tubule membrane of macula densa cells in mouse35 and rat kidneys36 To determine the effect of hyperglycemia on glucose concen- with a custom-made antibody. However, the role of macula tration at macula densa, the glucose concentration in urine and densa SGLT1 in the control of TGF and GFR in a hyperglycemic early distal tubule fluid were measured. Micropuncture prep- setting is not known and has not been investigated. aration was performed as previously described.28,39,40 Briefly, In this study, we tested a novel hypothesis that the increase in mice were anesthetized with inactin (80 mg/ml, intraperito- luminal glucose concentration at the macula densa enhances neal injection) and ketamine (50 mg/ml, intramuscular injec- NOS1-dependent NO formation via SGLT1, thereby inhibiting tion). A tracheostoma was placed to facilitate breathing and TGF responsiveness and promoting glomerular hyperfiltration femoral artery was catheterized for BP measurement. The in hyperglycemia (SGLT1-NOS1 pathway). femoral vein was catheterized for infusion of saline with 1% BSA at the rate of 1 ml/h per 100 g body wt throughout the experiment. After an abdominal incision, the left ureter was METHODS catheterized for the collection of urine and the left kidney was exposed and immobilized in a kidney holder cup. The Animal kidney orientation was positioned so that superficial tubules C57BL/6 mice (male, 13–15 weeks old) were purchased from could be clearly visualized under the microscope (SZX16; Jackson Laboratory. The macula densa–specific NOS1 Olympus, Tokyo, Japan). The segment of early distal tubule J Am Soc Nephrol
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