TY - JOUR
T1 - Renal Glomerular Mitochondria Function in Salt-Sensitive Hypertension
AU - Domondon, Mark
AU - Polina, Iuliia
AU - Nikiforova, Anna B.
AU - Sultanova, Regina F.
AU - Kruger, Claudia
AU - Vasileva, Valeriia Y.
AU - Fomin, Mikhail V.
AU - Beeson, Gyda C.
AU - Nieminen, Anna Liisa
AU - Smythe, Nancy
AU - Maldonado, Eduardo N.
AU - Stadler, Krisztian
AU - Ilatovskaya, Daria V.
N1 - Funding Information:
This study was supported by the National Institutes of Health (NIDDK) R00 DK105160 (to DI), 1R01 DK115749 (to KS), and NIH/NCI Grants R01 CA184456 to EM; Dialysis Clinic Inc. Reserve Fund, the MUSC SCTR support program via NIH/NCATS UL1TR001450 (DI); and the APS Research Career Enhancement and Lazaro J. Mandel awards to DI.
Funding Information:
The authors would like to thank Dr. Monika Gooz and Kareem Heslop (MUSC) for help with initial imaging experiments, and the MUSC Histology & Immunohistochemistry Laboratory and Research Electron Microscopy Service Laboratory for assistance with preparation of sample and staining of tissues for histology and TEM. Funding. This study was supported by the National Institutes of Health (NIDDK) R00 DK105160 (to DI), 1R01 DK115749 (to KS), and NIH/NCI Grants R01 CA184456 to EM; Dialysis Clinic Inc. Reserve Fund, the MUSC SCTR support program via NIH/NCATS UL1TR001450 (DI); and the APS Research Career Enhancement and Lazaro J. Mandel awards to DI. The work was also partially supported by the P20-GM103542 South Carolina COBRE in Oxidants, Redox Balance, and Stress Signaling.
Publisher Copyright:
© Copyright © 2020 Domondon, Polina, Nikiforova, Sultanova, Kruger, Vasileva, Fomin, Beeson, Nieminen, Smythe, Maldonado, Stadler and Ilatovskaya.
PY - 2020/2/4
Y1 - 2020/2/4
N2 - Salt-sensitive (SS) hypertension is accompanied with an early onset of proteinuria, which results from the loss of glomerular podocytes. Here, we hypothesized that glomerular damage in the SS hypertension occurs in part due to mitochondria dysfunction, and we used a unique model of freshly isolated glomeruli to test this hypothesis. In order to mimic SS hypertension, we used Dahl SS rats, an established animal model. Animals were fed a 0.4% NaCl (normal salt, NS) diet or challenged with a high salt (HS) 4% NaCl diet for 21 days to induce an increase in blood pressure (BP). Similar to previous studies, we found that HS diet caused renal hypertrophy, increased BP, glomerulosclerosis, and renal lesions such as fibrosis and protein casts. We did not observe changes in mitochondrial biogenesis in the renal cortex or isolated glomeruli fractions. However, Seahorse assay performed on freshly isolated glomeruli revealed that basal mitochondrial respiration, maximal respiration, and spare respiratory capacity were lower in the HS compared to the NS group. Using confocal imaging and staining for mitochondrial H2O2 using mitoPY1, we detected an intensified response to an acute H2O2 application in the podocytes of the glomeruli isolated from the HS diet fed group. TEM analysis showed that glomerular mitochondria from the HS diet fed group have structural abnormalities (swelling, enlargement, less defined cristae). Therefore, we report that glomerular mitochondria in SS hypertension are functionally and structurally defective, and this impairment could eventually lead to loss of podocytes and proteinuria. Thus, the glomerular–mitochondria axis can be targeted in novel treatment strategies for hypertensive glomerulosclerosis.
AB - Salt-sensitive (SS) hypertension is accompanied with an early onset of proteinuria, which results from the loss of glomerular podocytes. Here, we hypothesized that glomerular damage in the SS hypertension occurs in part due to mitochondria dysfunction, and we used a unique model of freshly isolated glomeruli to test this hypothesis. In order to mimic SS hypertension, we used Dahl SS rats, an established animal model. Animals were fed a 0.4% NaCl (normal salt, NS) diet or challenged with a high salt (HS) 4% NaCl diet for 21 days to induce an increase in blood pressure (BP). Similar to previous studies, we found that HS diet caused renal hypertrophy, increased BP, glomerulosclerosis, and renal lesions such as fibrosis and protein casts. We did not observe changes in mitochondrial biogenesis in the renal cortex or isolated glomeruli fractions. However, Seahorse assay performed on freshly isolated glomeruli revealed that basal mitochondrial respiration, maximal respiration, and spare respiratory capacity were lower in the HS compared to the NS group. Using confocal imaging and staining for mitochondrial H2O2 using mitoPY1, we detected an intensified response to an acute H2O2 application in the podocytes of the glomeruli isolated from the HS diet fed group. TEM analysis showed that glomerular mitochondria from the HS diet fed group have structural abnormalities (swelling, enlargement, less defined cristae). Therefore, we report that glomerular mitochondria in SS hypertension are functionally and structurally defective, and this impairment could eventually lead to loss of podocytes and proteinuria. Thus, the glomerular–mitochondria axis can be targeted in novel treatment strategies for hypertensive glomerulosclerosis.
KW - glomeruli
KW - hypertension
KW - kidney
KW - mitochondria
KW - podocyte
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U2 - 10.3389/fphys.2019.01588
DO - 10.3389/fphys.2019.01588
M3 - Article
AN - SCOPUS:85079673649
SN - 1664-042X
VL - 10
JO - Frontiers in Physiology
JF - Frontiers in Physiology
M1 - 1588
ER -