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. 2021 Dec;78(6):1760-1770.
doi: 10.1161/HYPERTENSIONAHA.121.17643. Epub 2021 Oct 18.

Knockout of Macula Densa Neuronal Nitric Oxide Synthase Increases Blood Pressure in db/db Mice

Jie Zhang #  1 , Ximing Wang #  1   2 , Yu Cui #  3 , Shan Jiang  1 , Jin Wei  1 , Jenna Chan  1 , Anish Thalakola  1 , Thanh Le  1 , Lan Xu  4 , Liang Zhao  3 , Lei Wang  1 , Kun Jiang  5 , Feng Cheng  6 , Trushar Patel  7 , Jacentha Buggs  8 , Volker Vallon  9 , Ruisheng Liu  1
Affiliations

Knockout of Macula Densa Neuronal Nitric Oxide Synthase Increases Blood Pressure in db/db Mice

Jie Zhang et al. Hypertension. 2021 Dec.

Abstract

[Figure: see text].

Keywords: diabetes mellitus; glomerular filtration rate; hemodynamics; hypertension; kidney; nitric oxide; nitric oxide synthase.

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Figures

Figure 1.
Figure 1.. Blood glucose, GFR and TGF responsiveness in db/db mice.
(A) The blood glucose concentration in db/db and db/+ mice. n=12; *P<0.01 vs db/+. (B) The GFR in db/db and db/+ mice. n=10; *P<0.01 vs db/+. (C and D) The TGF response in vivo in db/db and db/+ mice. n=18 tubules/6 mice per group; *P<0.01 vs db/+. (E and F) The TGF response in vitro in Akita and WT mice. n=16 nephrons/group; *P<0.01 vs db/+, *P<0.01 vs db/+. Statistical difference in (A and B) was calculated by two-way repeated measures ANOVA followed by Sidak multiple comparisons test. Statistical difference in (C-F) was calculated by t-test.
Figure 2.
Figure 2.. Macula densa NOS1 expression and activity in db/db mice.
(A) The TGF-induced NO generation at the macula densa in db/db and db/+ mice. n=15; *P<0.01 vs 10 mM, #P<0.01 vs db/+. (B) The immunoblots of renal cortical NOS1, P-NOS1, and loading control of β-actin in db/db and db/+ mice. (C and D) The renal cortical NOS1 and P-NOS1/NOS1 levels in db/db and db/+ mice. n=8; *P<0.01 vs db/+. Statistical difference in (A) was calculated by two-way ANOVA followed by Sidak multiple comparisons test. Statistical difference in (C-D) was calculated by t-test.
Figure 3.
Figure 3.. Characterization of db/db MD-NOS1KO mouse model.
(A) The blood glucose concentration in db/+ NOS1flox/flox, db/db NOS1flox/flox, db/+ MD-NOS1KO and db/db MD-NOS1KO mice. n=10; *P<0.01 vs db/+. (B) The double immunofluorescence staining of NOS1 and NKCC2 in the kidney slices of db/db NOS1flox/flox and db/db MD-NOS1KO mice. Red: NOS1; Green: NKCC2; Blue: nucleus; Arrow: macula densa. Statistical difference in (A) was calculated by two-way repeated measures ANOVA followed by Sidak multiple comparisons test.
Figure 4.
Figure 4.. Effect of macula densa NOS1 deletion on TGF responsiveness as well as GFR in db/db mice.
(A and B) The TGF response in vivo in db/+ NOS1flox/flox, db/db NOS1flox/flox, db/+ MD-NOS1KO and db/db MD-NOS1KO mice. n=17 tubules/5 mice per group; *P<0.01 vs db/+; #P<0.01 vs NOS1flox/flox. (C and D) The TGF response in vitro in db/+ NOS1flox/flox, db/db NOS1flox/flox, db/+ MD-NOS1KO and db/db MD-NOS1KO mice. n=14 nephrons/group; *P<0.05 vs db/+; #P<0.01 vs NOS1flox/flox. (E) The GFR in db/+ NOS1flox/flox, db/db NOS1flox/flox, db/+ MD-NOS1KO and db/db MD-NOS1KO mice. n=10; *P<0.01 vs db/+; #P<0.01 vs NOS1flox/flox. Statistical difference in (A and C) was calculated by t-test. Statistical difference in (B and D) was calculated by two-way ANOVA followed by Sidak multiple comparisons test. Statistical difference in (E) was calculated by two-way repeated measures ANOVA followed by Sidak multiple comparisons test.
Figure 5.
Figure 5.. Effect of macula densa NOS1 deletion on natriuresis as well as blood pressure in db/db mice.
(A) The FENa in db/+ NOS1flox/flox, db/db NOS1flox/flox, db/+ MD-NOS1KO and db/db MD-NOS1KO mice. n=10; *P<0.05 vs db/+; #P<0.01 vs NOS1flox/flox. (B) The MAP in db/+ NOS1flox/flox, db/db NOS1flox/flox, db/+ MD-NOS1KO and db/db MD-NOS1KO mice. *P<0.05 vs db/+; #P<0.05 vs NOS1flox/flox. Statistical difference in (A) was calculated by two-way ANOVA followed by Sidak multiple comparisons test. Statistical difference in (B) was calculated by two-way repeated measures ANOVA followed by Sidak multiple comparisons test.
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