Nuclear farnesoid X receptor attenuates acute kidney injury through fatty acid oxidation

Abstract

Acute kidney injury (AKI) is a life-threatening condition that is one of most common side effects of cisplatin therapy. Fatty acid oxidation (FAO) is the main source of energy production in kidney proximal tubular epithelial cells (PTECs) but it is inhibited in AKI. Recent work demonstrated that activation of the farnesoid X receptor (FXR) protects against AKI, but the underlying mechanism remains elusive. Using a model of cisplatin-induced AKI, we found that FXR and FAO-related genes were remarkably downregulated while kidney lipid accumulated. Proximal tubule-specific or whole body FXR knockout worsened, while pharmacological activation attenuated these effects. Conversely, FXR knockout in non-proximal tubules did not. RNA-sequencing of PTECs demonstrated increased transcripts involved in metabolic pathways in cells overexpressing FXR versus control after cisplatin treatment, specifically transcripts associated with FAO and peroxisome proliferator-activated receptor-γ (PPARγ) signaling. Furthermore, FXR overexpression or activation improved FAO and inhibited intracellular lipid accumulation in cisplatin-treated cells. In vivo studies have shown that pharmacological activation of PPARγ can prevent cisplatin-induced lipid accumulation, kidney tubule injury and kidney function decline. However, inhibition of PPARγ eliminated the protective effects of FXR compared to control mice during the cisplatin treatment phase and after ischemia-reperfusion injury. Consistent with findings in vivo, FXR/PPARγ reduced lipid accumulation by improving FAO in cisplatin-treated cells. Furthermore, the inhibition of carnitine palmitoyltransferase 1α abolished the protective effect of FXR in cisplatin-treated mice. Thus, FXR improves FAO and reduced lipid accumulation via PPARγ in PTECs of the kidney. Hence, reconstruction of the FXR/PPARγ/FAO axis may be a novel therapeutic strategy for preventing or treating AKI. Acute kidney injury (AKI) is a life-threatening condition that is one of most common side effects of cisplatin therapy. Fatty acid oxidation (FAO) is the main source of energy production in kidney proximal tubular epithelial cells (PTECs) but it is inhibited in AKI. Recent work demonstrated that activation of the farnesoid X receptor (FXR) protects against AKI, but the underlying mechanism remains elusive. Using a model of cisplatin-induced AKI, we found that FXR and FAO-related genes were remarkably downregulated while kidney lipid accumulated. Proximal tubule-specific or whole body FXR knockout worsened, while pharmacological activation attenuated these effects. Conversely, FXR knockout in non-proximal tubules did not. RNA-sequencing of PTECs demonstrated increased transcripts involved in metabolic pathways in cells overexpressing FXR versus control after cisplatin treatment, specifically transcripts associated with FAO and peroxisome proliferator-activated receptor-γ (PPARγ) signaling. Furthermore, FXR overexpression or activation improved FAO and inhibited intracellular lipid accumulation in cisplatin-treated cells. In vivo studies have shown that pharmacological activation of PPARγ can prevent cisplatin-induced lipid accumulation, kidney tubule injury and kidney function decline. However, inhibition of PPARγ eliminated the protective effects of FXR compared to control mice during the cisplatin treatment phase and after ischemia-reperfusion injury. Consistent with findings in vivo, FXR/PPARγ reduced lipid accumulation by improving FAO in cisplatin-treated cells. Furthermore, the inhibition of carnitine palmitoyltransferase 1α abolished the protective effect of FXR in cisplatin-treated mice. Thus, FXR improves FAO and reduced lipid accumulation via PPARγ in PTECs of the kidney. Hence, reconstruction of the FXR/PPARγ/FAO axis may be a novel therapeutic strategy for preventing or treating AKI. Translational StatementFatty acid oxidation (FAO) is the main energy source for proximal tubular epithelial cells. Acute kidney injury (AKI) causes FAO disorders. Here, we demonstrate that the nuclear receptor farnesoid X receptor (FXR) specifically in the proximal tubule protects against AKI and attenuates lipid accumulation. We further show that these correlate with FAO; FXR and peroxisome proliferator–activated receptor-γ may regulate key enzymes required for FAO. Our results provide new insights into the role of FXR in the prevention or treatment of AKI. Fatty acid oxidation (FAO) is the main energy source for proximal tubular epithelial cells. Acute kidney injury (AKI) causes FAO disorders. Here, we demonstrate that the nuclear receptor farnesoid X receptor (FXR) specifically in the proximal tubule protects against AKI and attenuates lipid accumulation. We further show that these correlate with FAO; FXR and peroxisome proliferator–activated receptor-γ may regulate key enzymes required for FAO. Our results provide new insights into the role of FXR in the prevention or treatment of AKI. Acute kidney injury (AKI) is a life-threatening condition with high morbidity and mortality, occurring in approximately 10%–15% of hospitalized patients, while its incidence has been reported in more than 50% of patients in intensive care admitted to hospital.1Ronco C. Bellomo R. Kellum J.A. Acute kidney injury.Lancet. 2019; 394: 1949-1964Google Scholar, 2Bellomo R. Kellum J.A. Ronco C. Acute kidney injury.Lancet. 2012; 380: 756-766Google Scholar, 3Rewa O. Bagshaw S.M. Acute kidney injury-epidemiology, outcomes and economics.Nat Rev Nephrol. 2014; 10: 193-207Google Scholar The major causes of AKI include nephrotoxicity, ischemia/reperfusion (I/R), sepsis, and contrast media.3Rewa O. Bagshaw S.M. Acute kidney injury-epidemiology, outcomes and economics.Nat Rev Nephrol. 2014; 10: 193-207Google Scholar, 4Jang H.R. Rabb H. Immune cells in experimental acute kidney injury.Nat Rev Nephrol. 2015; 11: 88-101Google Scholar, 5Basile D.P. Anderson M.D. Sutton T.A. Pathophysiology of acute kidney injury.Compr Physiol. 2012; 2: 1303-1353Google Scholar Of note, nephrotoxicity is a dose-limiting factor of the chemotherapeutic agent cisplatin. The proximal tubular epithelial cells (PTECs) are the major target for the toxic effects of cisplatin that lead to AKI.6Ozkok A. Edelstein C.L. Pathophysiology of cisplatin-induced acute kidney injury.Biomed Res Int. 2014; 2014: 967826Google Scholar Injured proximal tubular cells suffer from significant changes in metabolic pathways, cellular signaling, and cell cycle.6Ozkok A. Edelstein C.L. Pathophysiology of cisplatin-induced acute kidney injury.Biomed Res Int. 2014; 2014: 967826Google Scholar, 7Liu B.C. Tang T.T. Lv L.L. Lan H.Y. Renal tubule injury: a driving force toward chronic kidney disease.Kidney Int. 2018; 93: 568-579Google Scholar, 8Perazella M.A. Drug-induced acute kidney injury: diverse mechanisms of tubular injury.Curr Opin Crit Care. 2019; 25: 550-557Google Scholar, 9McSweeney K.R. Gadanec L.K. Qaradakhi T. et al.Mechanisms of cisplatin-induced acute kidney injury: pathological mechanisms, pharmacological interventions, and genetic mitigations.Cancers (Basel). 2021; 13: 1572Google Scholar However, there is currently no effective therapeutic option to treat AKI, whose development is therefore crucial.9McSweeney K.R. Gadanec L.K. Qaradakhi T. et al.Mechanisms of cisplatin-induced acute kidney injury: pathological mechanisms, pharmacological interventions, and genetic mitigations.Cancers (Basel). 2021; 13: 1572Google Scholar Although kidneys are not classified as metabolic organs, metabolism plays a key role in the kidneys.10Li X. Zheng S. Wu G. Amino acid metabolism in the kidneys: nutritional and physiological significance.Adv Exp Med Biol. 2020; 1265: 71-95Google Scholar,11Piret S.E. Attallah A.A. Gu X. et al.Loss of proximal tubular transcription factor Kruppel-like factor 15 exacerbates kidney injury through loss of fatty acid oxidation.Kidney Int. 2021; 100: 1250-1267Google Scholar Renal PT cells have a high energy demand, mainly provided by fatty acid oxidation (FAO) and glycolysis.12Kang H.M. Ahn S.H. Choi P. et al.Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development.Nat Med. 2015; 21: 37-46Google Scholar Notably, FAO in the mitochondria and the peroxisomes are major energy sources, essential for supporting cells with high energy demands.13Nieth H. Schollmeyer P. Substrate-utilization of the human kidney.Nature. 1966; 209: 1244-1245Google Scholar, 14Console L. Scalise M. Giangregorio N. et al.The link between the mitochondrial fatty acid oxidation derangement and kidney injury.Front Physiol. 2020; 11: 794Google Scholar, 15Portilla D. Energy metabolism and cytotoxicity.Semin Nephrol. 2003; 23: 432-438Google Scholar During AKI, FAO is inhibited, leading to lipotoxicity and energy deprivation, which is characterized by intracellular lipid accumulation and a decrease of renal adenosine triphosphate (ATP) level, renal tubular cell injury, and death.16Wei Q. Xiao X. Fogle P. Dong Z. Changes in metabolic profiles during acute kidney injury and recovery following ischemia/reperfusion.PLoS One. 2014; 9e106647Google Scholar, 17Yu X. Xu M. Meng X. et al.Nuclear receptor PXR targets AKR1B7 to protect mitochondrial metabolism and renal function in AKI.Sci Transl Med. 2020; 12eaay7591Google Scholar, 18Jang H.S. Noh M.R. Jung E.M. et al.Proximal tubule cyclophilin D regulates fatty acid oxidation in cisplatin-induced acute kidney injury.Kidney Int. 2020; 97: 327-339Google Scholar The carnitine palmitoyltransferase (CPT1) inhibitor etomoxir can exacerbate this process in cisplatin-induced kidney injury.12Kang H.M. Ahn S.H. Choi P. et al.Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development.Nat Med. 2015; 21: 37-46Google Scholar,18Jang H.S. Noh M.R. Jung E.M. et al.Proximal tubule cyclophilin D regulates fatty acid oxidation in cisplatin-induced acute kidney injury.Kidney Int. 2020; 97: 327-339Google Scholar Conversely, the upregulation of FAO attenuated kidney injury. Recent studies have shown that the activation of peroxisome proliferator–activated receptor-γ (PPARγ) and PPAR coactivator-1α increases FAO to reduce the accumulation of free fatty acids (FAs).19Soliman E. Elhassanny A.E.M. Malur A. et al.Impaired mitochondrial function of alveolar macrophages in carbon nanotube-induced chronic pulmonary granulomatous disease.Toxicology. 2020; 445: 152598Google Scholar, 20Legchenko E. Chouvarine P. Borchert P. et al.PPARgamma agonist pioglitazone reverses pulmonary hypertension and prevents right heart failure via fatty acid oxidation.Sci Transl Med. 2018; 10eaao0303Google Scholar, 21Zhao F. Xiao C. Evans K.S. et al.Paracrine Wnt5a-beta-catenin signaling triggers a metabolic that cell 2018; Scholar, Q. Z. F. et axis of through fatty acid 2019; Scholar However, there are no the activation of PPARγ increases FAO in AKI. are transcription by and in the of renal and Z. S.H. and in Int. Scholar nuclear are involved in a of metabolic as and Z. S.H. and in Int. Scholar X receptor (FXR) is a of the nuclear receptor by acids and as intracellular H. A.A. D. E. acids in metabolism in and Exp Med. 2018; Scholar for the and FXR is in the in the proximal tubules X. S. M. et X receptor (FXR) in A. 2014; Scholar FXR is associated with the process of energy metabolism via the of target M.D. of for and 2021; Scholar In the which FAO as cellular of FXR attenuates and by T.T. X. in lipid metabolism and Med. Scholar FXR activation through its as a strategy to treat and L. X receptor is essential for Scholar studies have the of FXR in kidney in acute Choi H.S. et X receptor prevents cisplatin-induced kidney injury by One. 2014; Scholar, Z. L. Xu Z. et X receptor activation protects the kidney from ischemia-reperfusion Scholar, Xu S. et X receptor agonist acid renal and during acute kidney 2018; Scholar However, the role of FXR in FAO in AKI is In this we that FXR improves PPARγ and renal FAO in the of cisplatin AKI. a mechanism by which FXR regulates FAO is activation of FXR is a strategy for the treatment of AKI. for are provided in the were by the and of and were in with the of for the and of FXR knockout and mice were from the The of studies are provided in the a by cells in cell are provided in the were as and were the were provided in the of the changes in the of cisplatin AKI, cisplatin-treated mice were and A. Edelstein C.L. 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Meng X. et al.Nuclear receptor PXR targets AKR1B7 to protect mitochondrial metabolism and renal function in AKI.Sci Transl Med. 2020; 12eaay7591Google N. et of in lipid metabolism and 2018; G. T. M. et of renal fatty acid and and fibrosis in and mice with Scholar studies have the role of FXR in the underlying mechanism remains elusive. In this we demonstrated the new role of FXR in FAO in cisplatin AKI. FXR is downregulated during cisplatin-induced injury, which is a Here, RNA-sequencing metabolism in PTECs with FXR activation or overexpression of FXR the effect of FXR FAO by cisplatin. studies that FXR the of PPARγ during cisplatin AKI. The activation of FXR FAO renal lipid accumulation and these the protective role of FXR in FAO and energy in cisplatin AKI. the mechanism of FXR in renal PT after studies in the and B.C. Tang T.T. Lv L.L. Lan H.Y. Renal tubule injury: a driving force toward chronic kidney disease.Kidney Int. 2018; 93: 568-579Google T. P. et X receptor renal lipid and T. et al.The farnesoid X receptor renal lipid metabolism and renal and Renal Physiol. T. et is by farnesoid X receptor and inhibited by farnesoid X receptor activation in a Scholar, Z. L. C. et of acid and in kidney in 2012; Scholar, S. S. Z. et X receptor is essential for the of renal cells A. 2018; Scholar In of these FXR is the protective effect of has Thus, in the FXR lipid accumulation, and fibrosis in of and T. P. et X receptor renal lipid and T. et al.The farnesoid X receptor renal lipid metabolism and renal and Renal Physiol. T. et is by farnesoid X receptor and inhibited by farnesoid X receptor activation in a Z. L. C. et of acid and in kidney in 2012; Scholar The activation of FXR increases by renal and protects cells from the that can lead to X. S. M. et X receptor (FXR) in A. 2014; S. S. Z. et X receptor is essential for the of renal cells A. 2018; Scholar effects of FXR were by the and nuclear of the of these mechanisms are in PT Choi H.S. et X receptor prevents cisplatin-induced kidney injury by One. 2014; Scholar, Z. L. Xu Z. et X receptor activation protects the kidney from ischemia-reperfusion Scholar, Xu S. et X receptor agonist acid renal and during acute kidney 2018; Choi et al.The role of FXR is associated with the of and in the of AKI to 2021; et occurring FXR protects against renal ischemia-reperfusion Renal Physiol. 2021; Scholar Of note, PT cells are more FAO as the main energy have energy than cells that are T. Z. to the effects of FXR activation renal proximal tubular 2015; Scholar In the RNA-sequencing in control versus PT cells with it found that the FAO In we that and cisplatin AKI with the of the FAO-related Although cisplatin may to the tubule A.A. et injury of the renal tubule is associated with in Scholar mice did not the of cisplatin AKI. The for this may be that the of FXR in of and with effects D. Q. et regulates genes to Nephrol. 2014; 25: Scholar However, we that lipid accumulation in mice. be to as a cell and in cisplatin AKI. RNA-sequencing we which is to be a of lipid metabolism and a target for FXR to renal tubular cell injury and FAO We that PPARγ be in PPARγ is a nuclear receptor that the of receptor and transcription The factor peroxisome proliferator-activated receptor in and 2015; Scholar PPARγ can genes associated with and as D. A. et al.The role of lipid metabolism in and 2018; Scholar Furthermore, PPARγ agonist pioglitazone can pulmonary hypertension and prevent right heart failure via E. Chouvarine P. Borchert P. et al.PPARgamma agonist pioglitazone reverses pulmonary hypertension and prevents right heart failure via fatty acid oxidation.Sci Transl Med. 2018; 10eaao0303Google Scholar However, there is no that PPARγ can AKI and FAO The PPARγ and FXR is the and triggers the of A. M. et and of peroxisome proliferator-activated by the acid farnesoid X receptor the of Scholar Consistent with the of PPARγ activation reduced cisplatin AKI. demonstrated that of PPARγ by FXR improved the FAO and in renal tubular cells after AKI. that the function of PPARγ is and it is to PPARγ by FXR to the of We have shown that there is a FAO in FXR activation during cisplatin AKI. cisplatin injury, FAO in the mitochondria and peroxisomes were downregulated and in the kidney of mice. are the target in acute tubular cell injury, which are characterized by reduced and as therapeutic targets in acute kidney injury.Curr Opin 25: Scholar FAO is the major energy source of the renal In a decrease in and which are the of energy failure during T. A. et of fatty acids causes the in kidney proximal tubules after Renal Physiol. Scholar Here, we found that the activation of FXR attenuated intracellular lipid accumulation. and mitochondrial FAO were after the of FXR or Furthermore, we that the effect of FXR to its of the the FAO which is to PT cell metabolism through cell metabolic in PT cells. results that activation of the FXR/PPARγ the cisplatin-induced FAO the cisplatin AKI, we the to kidney as AKI. Consistent with the results of mice with cisplatin AKI, the activation of FXR renal function and FAO against acute kidney injury. results further that FXR be as a therapeutic target for AKI. of the is that the of FXR in AKI mainly in cells and but not in human Although a have been not have been or S.H. S.H. et of a inhibitor cisplatin-induced acute kidney injury: for a 2015; Scholar, F. S. S. et of cisplatin from a 2015; Scholar, M. N. M. of the effect of versus cisplatin-induced nephrotoxicity, a 2018; Scholar increases the of lipid in patients, the of FAO in cisplatin E. et phase in patients to the and of a of A. et a in of Scholar studies have shown that the of FXR to the of kidney fibrosis in patients with the of FXR in the Z. L. Xu Z. et X receptor activation protects the kidney from ischemia-reperfusion Scholar The of FXR in against human AKI remains to be further in of In that FXR activation protects against AKI by lipid metabolism via the of The activation of the FXR/PPARγ may be option for AKI Our findings may the for the development of effective and FXR to treat patients with AKI. the no work by the of to the and of the of of and the and and the and and the and the and and the the of the with

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