Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis
Verónica Miguel, … , Ricardo Ramos, Santiago Lamas
Verónica Miguel, … , Ricardo Ramos, Santiago Lamas
Published January 19, 2021
Citation Information: J Clin Invest. 2021;131(5):e140695. https://doi.org/10.1172/JCI140695.
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Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis

Abstract

Chronic kidney disease (CKD) remains a major epidemiological, clinical, and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) present a persistent inflammatory and profibrotic response. Fatty acid oxidation (FAO), the main source of energy for TECs, is reduced in kidney fibrosis and contributes to its pathogenesis. To determine whether gain of function in FAO (FAO-GOF) could protect from fibrosis, we generated a conditional transgenic mouse model with overexpression of the fatty acid shuttling enzyme carnitine palmitoyl-transferase 1A (CPT1A) in TECs. Cpt1a-knockin (CPT1A-KI) mice subjected to 3 models of renal fibrosis (unilateral ureteral obstruction, folic acid nephropathy [FAN], and adenine-induced nephrotoxicity) exhibited decreased expression of fibrotic markers, a blunted proinflammatory response, and reduced epithelial cell damage and macrophage influx. Protection from fibrosis was also observed when Cpt1a overexpression was induced after FAN. FAO-GOF restored oxidative metabolism and mitochondrial number and enhanced bioenergetics, increasing palmitate oxidation and ATP levels, changes that were also recapitulated in TECs exposed to profibrotic stimuli. Studies in patients showed decreased CPT1 levels and increased accumulation of short- and middle-chain acylcarnitines, reflecting impaired FAO in human CKD. We propose that strategies based on FAO-GOF may constitute powerful alternatives to combat fibrosis inherent to CKD.

Authors

Verónica Miguel, Jessica Tituaña, J. Ignacio Herrero, Laura Herrero, Dolors Serra, Paula Cuevas, Coral Barbas, Diego Rodríguez Puyol, Laura Márquez-Expósito, Marta Ruiz-Ortega, Carolina Castillo, Xin Sheng, Katalin Susztak, Miguel Ruiz-Canela, Jordi Salas-Salvadó, Miguel A. Martínez González, Sagrario Ortega, Ricardo Ramos, Santiago Lamas

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Figure 7

CPT1A upregulation after FA-induced renal disease mitigates FAN-associated kidney function deterioration, renal fibrosis, and FAO defects.

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CPT1A upregulation after FA-induced renal disease mitigates FAN-associat...
(A) Representative microphotographs of H&E (upper panels) and Sirius red (lower panels) staining of kidneys from WT and Pax8-CPT1A mice subjected to FAN prior to doxycycline (Dox) (Supplemental figure 12A). Scale bars: 50 μm. Quantification of Sirius red staining represents the mean ± SEM, n = 6 mice. **P < 0.05 compared with FAN kidneys in WT mice. (B and C) Serum BUN (B) and creatinine (C) levels of WT and Pax8-CPT1A mice subjected to FAN as in A. Data represent the mean ± SEM (n = 6 mice). *P < 0.05, ***P < 0.001 compared with respective control (CT) condition; #P < 0.05 compared with WT mice with the same condition. (D) mRNA levels of α-SMA, Col1α1, FN, CPT1A, and Ppargc1a determined by qRT-PCR in kidneys of WT and Pax8-CPT1A mice subjected to FAN as in A. Bar graphs represent the mean ± SEM of fold changes (n = 6 mice). *P < 0.05, **P < 0.01 compared with corresponding CT kidneys; #P < 0.05, ##P < 0.01 compared with kidneys from WT mice with the same condition. (E and F) ATP production rate of TECs from WT and Pax8-CPT1A mice subjected to FAN as in A. ***P < 0.001 compared with TECs from WT mice with the same condition. (F) Oxygen consumption rate (OCR) of TECs from WT and Pax8-CPT1A mice subjected to FAN as in A. Bar graphs (right panel) show the rates of OCR as in Figure 4C. **P < 0.01 compared with their corresponding control (CT) TECs; #P < 0.05 and ##P < 0.01 compared with TECs from WT mice with the same condition. Statistical significance between 2 independent groups was determined using nonparametric 2-tailed Mann-Whitney U test; more than 2 groups were compared with Kruskal-Wallis test.