Empagliflozin reduces podocyte lipotoxicity in experimental Alport syndrome

被引:25
|
作者
Ge, Mengyuan [1 ,2 ]
Molina, Judith [1 ,2 ]
Kim, Jin-Ju [1 ,2 ]
Mallela, Shamroop K. [1 ,2 ]
Ahmad, Anis [3 ]
Varona Santos, Javier [1 ,2 ]
Al-Ali, Hassan [1 ,2 ]
Mitrofanova, Alla [1 ,2 ]
Sharma, Kumar [4 ]
Fontanesi, Flavia [5 ]
Merscher, Sandra [1 ,2 ]
Fornoni, Alessia [1 ,2 ]
机构
[1] Univ Miami, Dept Med, Miller Sch Med, Katz Family Div Nephrol & Hypertens, Miami, FL 33136 USA
[2] Univ Miami, Peggy & Harold Katz Family Drug Discovery Ctr, Miller Sch Med, Miami, FL 33136 USA
[3] Univ Miami, Dept Radiat Oncol, Miller Sch Med, Miami, FL USA
[4] Univ Texas Hlth San Antonio, Ctr Precis Med, Sch Med, San Antonio, TX USA
[5] Univ Miami, Dept Biochem & Mol Biol, Miami, FL USA
来源
ELIFE | 2023年 / 12卷
基金
美国国家卫生研究院;
关键词
Alport syndrome; lipid; energy substrate; SGLT2; inhibitor; Mouse; COTRANSPORTER; 2; INHIBITION; FATTY-ACID OXIDATION; DIABETIC KIDNEY; CELL-LINES; SGLT2; METABOLISM; EXPRESSION; MUTATIONS; APOPTOSIS; DISEASE;
D O I
10.7554/eLife.83353
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are anti-hyperglycemic agents that prevent glucose reabsorption in proximal tubular cells. SGLT2i improves renal outcomes in both diabetic and non-diabetic patients, indicating it may have beneficial effects beyond glycemic control. Here, we demonstrate that SGLT2i affects energy metabolism and podocyte lipotoxicity in experimental Alport syndrome (AS). In vitro, we found that the SGLT2 protein was expressed in human and mouse podocytes to a similar extent in tubular cells. Newly established immortalized podocytes from Col4a3 knockout mice (AS podocytes) accumulate lipid droplets along with increased apoptosis when compared to wild-type podocytes. Treatment with SGLT2i empagliflozin reduces lipid droplet accumulation and apoptosis in AS podocytes. Empagliflozin inhibits the utilization of glucose/pyruvate as a metabolic substrate in AS podocytes but not in AS tubular cells. In vivo, we demonstrate that empagliflozin reduces albuminuria and prolongs the survival of AS mice. Empagliflozin-treated AS mice show decreased serum blood urea nitrogen and creatinine levels in association with reduced triglyceride and cholesterol ester content in kidney cortices when compared to AS mice. Lipid accumulation in kidney cortices correlates with a decline in renal function. In summary, empagliflozin reduces podocyte lipotoxicity and improves kidney function in experimental AS in association with the energy substrates switch from glucose to fatty acids in podocytes.
引用
收藏
页数:22
相关论文
共 50 条
  • [1] Empagliflozin Reduces Renal Lipotoxicity in Alport Syndrome
    Ge, Mengyuan
    David, Judith T. Molina
    Kim, Jin Ju
    Santos, Javier T. Varona
    Fontanesi, Flavia
    Merscher, Sandra M.
    Fornoni, Alessia
    JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2022, 33 (11): : 413 - 413
  • [2] Comprehensive lipidomic analysis reveals further insights into the molecular mechanism of podocyte lipotoxicity in Alport syndrome
    Shabaka, Amir
    Requena, Belen Fernandez
    Gonzalez-Riano, Carolina
    Lanzon, Borja
    Martinez, Sara
    Gradillas, Ana
    Carrillo, Isabel Galan
    Bosch, Teresa Bada
    Sevillano, Angel
    Medina-Gomez, Gema
    Barbas, Coral
    Juarez, Gema Maria Fernandez
    NEPHROLOGY DIALYSIS TRANSPLANTATION, 2024, 39
  • [3] Discoidin domain receptor 1 activation links extracellular matrix to podocyte lipotoxicity in Alport syndrome
    Kim, Jin-Ju
    David, Judith M.
    Wilbon, Sydney S.
    Santos, Javier, V
    Patel, Devang M.
    Ahmad, Anis
    Mitrofanova, Alla
    Liu, Xiaochen
    Mallela, Shamroop K.
    Ducasa, Gloria M.
    Ge, Mengyuan
    Sloan, Alexis J.
    Al-Ali, Hassan
    Boulina, Marcia
    Mendez, Armando J.
    Contreras, Gabriel N.
    Prunotto, Marco
    Sohail, Anjum
    Fridman, Rafael
    Miner, Jeffrey H.
    Merscher, Sandra
    Fornoni, Alessia
    EBIOMEDICINE, 2021, 63
  • [4] Comprehensive lipidomic analysis reveals further insights into the molecular mechanism of podocyte lipotoxicity in Alport syndrome
    Shabaka, Amir
    Fernandez Requena, Belen
    Gonzalez-Riano, Carolina
    Lanzon, Borja
    Martinez, Sara
    Gradillas, Ana
    Galan Carrillo, Isabel
    Bada Bosch, Teresa
    Sevillano, Angel
    Medina-Gomez, Gema
    Barbas, Coral
    Fernandez Juarez, Gema Maria
    NEPHROLOGY DIALYSIS TRANSPLANTATION, 2024, 39 : I403 - I404
  • [5] Podocyte p53 Limits the Severity of Experimental Alport Syndrome
    Fukuda, Ryosuke
    Suico, Mary Ann
    Kai, Yukari
    Omachi, Kohei
    Motomura, Keishi
    Koga, Tomoaki
    Komohara, Yoshihiro
    Koyama, Kosuke
    Yokota, Tsubasa
    Taura, Manabu
    Shuto, Tsuyoshi
    Kai, Hirofumi
    JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2016, 27 (01): : 144 - 157
  • [6] Podocyte Depletion in Thin GBM and Alport Syndrome
    Wickman, Larysa
    Hodgin, Jeffrey B.
    Wang, Su Q.
    Afshinnia, Farsad
    Kershaw, David
    Wiggins, Roger C.
    PLOS ONE, 2016, 11 (05):
  • [7] Progress in therapeutic targets on podocyte for Alport syndrome
    Zheng, Qimin
    Gu, Xiangchen
    He, John Cijiang
    Xie, Jingyuan
    JOURNAL OF TRANSLATIONAL INTERNAL MEDICINE, 2024, 12 (02) : 129 - 133
  • [8] Mechanisms and Implications of Podocyte Autophagy in Alport Syndrome
    Njeim, Rachel
    Ficarella, Maria
    Fontanella, Antonio Miguel
    Gye, Haley
    Kim, Jin Ju
    Mitrofanova, Alla
    Ali, Hassan
    Merscher, Sandra M.
    Fornoni, Alessia
    JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2024, 35 (10):
  • [9] Podocyte Lipotoxicity in CKD
    Kim, Jin-Ju
    Wilbon, Sydney S.
    Fornoni, Alessia
    KIDNEY360, 2021, 2 (04): : 755 - 762
  • [10] Accelerated podocyte detachment and progressive podocyte loss from glomeruli with age in Alport Syndrome
    Ding, Fangrui
    Wickman, Larysa
    Wang, Su Q.
    Zhang, Yanqin
    Wang, Fang
    Afshinnia, Farsad
    Hodgin, Jeffrey
    Ding, Jie
    Wiggins, Roger C.
    KIDNEY INTERNATIONAL, 2017, 92 (06) : 1515 - 1525