Empagliflozin reduces podocyte lipotoxicity in experimental Alport syndrome

被引:34
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
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 66 条
[1]   Bioenergetic characterization of mouse podocytes [J].
Abe, Yoshifusa ;
Sakairi, Toru ;
Kajiyama, Hiroshi ;
Shrivastav, Shashi ;
Beeson, Craig ;
Kopp, Jeffrey B. .
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2010, 299 (02) :C464-C476
[2]   Empagliflozin reduces the levels of CD36 and cardiotoxic lipids while improving autophagy in the hearts of Zucker diabetic fatty rats [J].
Aragon-Herrera, Alana ;
Feijoo-Bandin, Sandra ;
Santiago, Manuel Otero ;
Barral, Luis ;
Campos-Toimil, Manuel ;
Gil-Longo, Jose ;
Pereira, Thiago M. Costa ;
Garcia-Caballero, Tomas ;
Rodriguez-Segade, Santiago ;
Rodriguez, Javier ;
Tarazon, Estefania ;
Rosello-Lleti, Esther ;
Portoles, Manuel ;
Gualillo, Oreste ;
Ramon Gonzalez-Juanatey, Jose ;
Lago, Francisca .
BIOCHEMICAL PHARMACOLOGY, 2019, 170
[3]   IDENTIFICATION OF MUTATIONS IN THE COL4A5 COLLAGEN GENE IN ALPORT SYNDROME [J].
BARKER, DF ;
HOSTIKKA, SL ;
ZHOU, J ;
CHOW, LT ;
OLIPHANT, AR ;
GERKEN, SC ;
GREGORY, MC ;
SKOLNICK, MH ;
ATKIN, CL ;
TRYGGVASON, K .
SCIENCE, 1990, 248 (4960) :1224-1227
[4]   Lifelong effect of therapy in young patients with the COL4A5 Alport missense variant p.(Gly624Asp): a prospective cohort study [J].
Boeckhaus, Jan ;
Hoefele, Julia ;
Riedhammer, Korbinian M. ;
Nagel, Mato ;
Beck, Bodo B. ;
Choi, Mira ;
Gollasch, Maik ;
Bergmann, Carsten ;
Sonntag, Joseph E. ;
Troesch, Victoria ;
Stock, Johanna ;
Gross, Oliver .
NEPHROLOGY DIALYSIS TRANSPLANTATION, 2022, 37 (12) :2496-2504
[5]   Anaerobic Glycolysis Maintains the Glomerular Filtration Barrier Independent of Mitochondrial Metabolism and Dynamics [J].
Brinkkoetter, Paul T. ;
Bork, Tillmann ;
Salou, Sarah ;
Liang, Wei ;
Mizi, Athanasia ;
Oezel, Cem ;
Koehler, Sybille ;
Hagmann, H. Henning ;
Ising, Christina ;
Kuczkowski, Alexander ;
Schnyder, Svenia ;
Abed, Ahmed ;
Schermer, Bernhard ;
Benzing, Thomas ;
Kretz, Oliver ;
Puelles, Victor G. ;
Lagies, Simon ;
Schlimpert, Manuel ;
Kammerer, Bernd ;
Handschin, Christoph ;
Schell, Christoph ;
Huber, Tobias B. .
CELL REPORTS, 2019, 27 (05) :1551-+
[6]   SGLT2 inhibitor dapagliflozin limits podocyte damage in proteinuric nondiabetic nephropathy [J].
Cassis, Paola ;
Locatelli, Monica ;
Cerullo, Domenico ;
Corna, Daniela ;
Buelli, Simona ;
Zanchi, Cristina ;
Villa, Sebastian ;
Morigi, Marina ;
Remuzzi, Giuseppe ;
Benigni, Ariela ;
Zoja, Carlamaria .
JCI INSIGHT, 2018, 3 (15)
[7]   Renal Hemodynamic Effect of Sodium-Glucose Cotransporter 2 Inhibition in Patients With Type 1 Diabetes Mellitus [J].
Cherney, David Z. I. ;
Perkins, Bruce A. ;
Soleymanlou, Nima ;
Maione, Maria ;
Lai, Vesta ;
Lee, Alana ;
Fagan, Nora M. ;
Woerle, Hans J. ;
Johansen, Odd Erik ;
Broedl, Uli C. ;
von Eynatten, Maximilian .
CIRCULATION, 2014, 129 (05) :587-597
[8]   Off-target effects of sodium-glucose co-transporter 2 blockers: empagliflozin does not inhibit Na+/H+ exchanger-1 or lower [Na+]i in the heart [J].
Chung, Yu Jin ;
Park, Kyung Chan ;
Tokar, Sergiy ;
Eykyn, Thomas R. ;
Fuller, William ;
Pavlovic, Davor ;
Swietach, Pawel ;
Shattock, Michael J. .
CARDIOVASCULAR RESEARCH, 2021, 117 (14) :2794-2806
[9]   The Link Between the Mitochondrial Fatty Acid Oxidation Derangement and Kidney Injury [J].
Console, Lara ;
Scalise, Mariafrancesca ;
Giangregorio, Nicola ;
Tonazzi, Annamaria ;
Barile, Maria ;
Indiveri, Cesare .
FRONTIERS IN PHYSIOLOGY, 2020, 11
[10]  
Cummings BS, 2021, CURR PROTOC, V1, DOI [10.1002/cpz1.210, 10.1002/0471141755.ph1208s25]