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Kidney alkalization increases macula densa NOS1β expression and improves transplanted renal graft function
Author(s) -
Wang Lei
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06208
Subject(s) - macula densa , nos1 , tubuloglomerular feedback , transplantation , renal function , kidney transplantation , kidney , medicine , endocrinology , chemistry , nitric oxide synthase , renin–angiotensin system , nitric oxide , blood pressure
Ischemia‐reperfusion injury (IRI) is a major hurdle for the survival of transplanted grafts. Currently, there are no effective strategies for prevention and treatment of IRI during kidney transplantation (KTX). Neuronal NO synthase beta (NOS1β) is the primary splice variant of NOS1 in macula densa (MD) and contributes to most of the MD‐NO generation, which blunts tubuloglomerular feedback (TGF) response and increase GFR, which is one of the important factors in evaluation of renal function. While TGF response modulated by NOS1β has been demonstrated to play an essential role in the long‐term control of hemodynamics, the role of NOS1 in the MD in the prevention of IRI and protection of transplanted graft function remains unknown. KTX was performed in C57BL/6 mice. The expression of NOS1 and graft function were evaluated. To test the response of NOS1 to the tubular pH, the mice were given bicarbonate or NH 4 Cl for two weeks. Blood, urine pH and expression of NOS1 were measured. KTX were performed after the treatment. Graft injury and function were evaluated again. To further investigate the role of the NOS1 in the protection of the graft function, we repeated the above experiments in kidney specific NOS1 knockout (KO) mice and compared the results with C57BL/6 mice. The control recipients showed moderate graft injury with plasma creatinine (Pcr) of 0.68 ± 0.13 mg/dl and reduced graft function indicated by 23% decrease in GFR at 5 days after KTX. NOS1β expression decreased by 60%. TGF response was measured by micropuncture which was 4.1 ± 0.3 mmHg for sham‐operated mice and 7.2 ± 0.9 mmHg for KTX mice. These data indicated that decreased NOS1β expression may contribute to the decrease of GFR and deterioration in graft function by enhanced TGF response. KO recipients showed more severe graft injury with the Pcr of 1.07±0.14mg/dl which demonstrated that deletion of NOS1 from macula densa significantly aggravated renal graft injury. The pH‐NOS activity response curve showed that NOS1 was sensitive to tubular pH with the optimal pH of 8.0. Bicarbonate treatment increased NOS1 expression in macula densa by 65% while NH4Cl intake decreased the NOS1 expression by 40%. KTX were performed in C57BL/6 and KO mice after two weeks treatment of bicarbonate or NH 4 Cl. Pcr levels were about 30% and 100% lower in bicarbonate‐treated group than H 2 O and NH4Cl groups, respectively, indicating that bicarbonate treatment significantly alleviated graft injury. However, there were no significant differences in the graft injury for the KO mice among different groups. In summary, NOS1β expression in the macula densa decreases after KTX, which enhances TGF responsiveness and contributes to the decrease in GFR and decline of graft function. Rescue of NOS1β in the macula densa by renal alkalization decreases kidney injury and improves transplanted graft functions.