TY - JOUR
T1 - Nitric oxide production by glomerular podocytes
AU - Palygin, Oleg
AU - Ilatovskaya, Daria V.
AU - Levchenko, Vladislav
AU - Endres, Bradley T.
AU - Geurts, Aron M.
AU - Staruschenko, Alexander
N1 - Funding Information:
This research was supported by the National Institutes of Health grants R35 HL135749 (to A. Staruschenko), DP2 OD008396 (to A. Geurts), K99 DK105160 (to D. Ilatovskaya) and DRTC P30 DK020595 Pilot & Feasibility project (O. Palygin), American Heart Association 17SDG33660149 (O. Palygin), American Diabetes Association 1-15-BS-172 , and Juvenile Diabetes Research Foundation 1-INO-2016-223-A-N (to A. Staruschenko).
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2018/1/30
Y1 - 2018/1/30
N2 - Nitric Oxide (NO), a potent vasodilator and vital signaling molecule, has been shown to contribute to the regulation of glomerular ultrafiltration. However, whether changes in NO occur in podocytes during the pathogenesis of salt-sensitive hypertension has not yet been thoroughly examined. We showed here that podocytes produce NO, and further hypothesized that hypertensive animals would exhibit reduced NO production in these cells in response to various paracrine factors, which might contribute to the damage of glomeruli filtration barrier and development of proteinuria. To test this, we isolated glomeruli from the kidneys of Dahl salt-sensitive (SS) rats fed a low salt (LS; 0.4% NaCl) or high salt (HS; 4% NaCl, 3 weeks) diets and loaded podocytes with either a combination of NO and Ca2+ fluorophores (DAF-FM and Fura Red, respectively) or DAF-FM alone. Changes in fluorescence were observed with confocal microscopy in response to adenosine triphosphate (ATP), angiotensin II (Ang II), and hydrogen peroxide (H2O2). Application of Ang II resulted in activation of both NO and intracellular calcium ([Ca2+]i) transients. In contrast, ATP promoted [Ca2+]i transients, but did not have any effects on NO production. SS rats fed a HS diet for 3 weeks demonstrated impaired NO production: the response to Ang II or H2O2 in podocytes of glomeruli isolated from SS rats fed a HS diet was significantly reduced compared to rats fed a LS diet. Therefore, glomerular podocytes from hypertensive rats showed a diminished NO release in response to Ang II or oxidative stress, suggesting that podocytic NO signaling is dysfunctional in this condition and likely contributes to the development of kidney injury.
AB - Nitric Oxide (NO), a potent vasodilator and vital signaling molecule, has been shown to contribute to the regulation of glomerular ultrafiltration. However, whether changes in NO occur in podocytes during the pathogenesis of salt-sensitive hypertension has not yet been thoroughly examined. We showed here that podocytes produce NO, and further hypothesized that hypertensive animals would exhibit reduced NO production in these cells in response to various paracrine factors, which might contribute to the damage of glomeruli filtration barrier and development of proteinuria. To test this, we isolated glomeruli from the kidneys of Dahl salt-sensitive (SS) rats fed a low salt (LS; 0.4% NaCl) or high salt (HS; 4% NaCl, 3 weeks) diets and loaded podocytes with either a combination of NO and Ca2+ fluorophores (DAF-FM and Fura Red, respectively) or DAF-FM alone. Changes in fluorescence were observed with confocal microscopy in response to adenosine triphosphate (ATP), angiotensin II (Ang II), and hydrogen peroxide (H2O2). Application of Ang II resulted in activation of both NO and intracellular calcium ([Ca2+]i) transients. In contrast, ATP promoted [Ca2+]i transients, but did not have any effects on NO production. SS rats fed a HS diet for 3 weeks demonstrated impaired NO production: the response to Ang II or H2O2 in podocytes of glomeruli isolated from SS rats fed a HS diet was significantly reduced compared to rats fed a LS diet. Therefore, glomerular podocytes from hypertensive rats showed a diminished NO release in response to Ang II or oxidative stress, suggesting that podocytic NO signaling is dysfunctional in this condition and likely contributes to the development of kidney injury.
KW - Angiotensin II
KW - DAF-FM
KW - Dahl salt-sensitive rat
KW - Hydrogen peroxide
KW - Hypertension
KW - Nitric oxide
UR - http://www.scopus.com/inward/record.url?scp=85034073816&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85034073816&partnerID=8YFLogxK
U2 - 10.1016/j.niox.2017.11.005
DO - 10.1016/j.niox.2017.11.005
M3 - Article
C2 - 29128399
AN - SCOPUS:85034073816
SN - 1089-8603
VL - 72
SP - 24
EP - 31
JO - Nitric Oxide - Biology and Chemistry
JF - Nitric Oxide - Biology and Chemistry
ER -