Imbalanced lipid homeostasis caused by membrane αKlotho deficiency contributes to the acute kidney injury to chronic kidney disease transition

Abstract

After acute kidney injury (AKI), renal tubular epithelial cells (RTECs) are pathologically characterized by intracellular lipid droplet (LD) accumulation, which are involved in RTEC injury and kidney fibrosis. However, its pathogenesis remains incompletely understood. The protein, αKlotho, primarily expressed in RTECs, is well known as an anti-aging hormone wielding versatile functions, and its membrane form predominantly acts as a co-receptor for fibroblast growth factor 23. Here, we discovered a connection between membrane αKlotho and intracellular LDs in RTECs. Fluorescent fatty acid (FA) pulse-chase assays showed that membrane αKlotho deficiency in RTECs, as seen in αKlotho homozygous mutated (kl/kl) mice or in mice with ischemia-reperfusion injury (IRI)-induced AKI, inhibited FA mobilization from LDs by impairing adipose triglyceride lipase (ATGL)-mediated lipolysis and lipophagy. This resulted in LD accumulation and FA underutilization. IRI-induced alterations were more striking in αKlotho deficiency. Mechanistically, membrane αKlotho deficiency promoted E3 ligase peroxin2 binding to ubiquitin-conjugating enzyme E2 D2, resulting in ubiquitin-mediated degradation of ATGL which is a common molecular basis for lipolysis and lipophagy. Overexpression of αKlotho rescued FA mobilization by preventing ATGL ubiquitination, thereby lessening LD accumulation and fibrosis after AKI. This suggests that membrane αKlotho is indispensable for the maintenance of lipid homeostasis in RTECs. Thus, our study identified αKlotho as a critical regulator of lipid turnover and homeostasis in AKI, providing a viable strategy for preventing tubular injury and the AKI-to-chronic kidney disease transition. After acute kidney injury (AKI), renal tubular epithelial cells (RTECs) are pathologically characterized by intracellular lipid droplet (LD) accumulation, which are involved in RTEC injury and kidney fibrosis. However, its pathogenesis remains incompletely understood. The protein, αKlotho, primarily expressed in RTECs, is well known as an anti-aging hormone wielding versatile functions, and its membrane form predominantly acts as a co-receptor for fibroblast growth factor 23. Here, we discovered a connection between membrane αKlotho and intracellular LDs in RTECs. Fluorescent fatty acid (FA) pulse-chase assays showed that membrane αKlotho deficiency in RTECs, as seen in αKlotho homozygous mutated (kl/kl) mice or in mice with ischemia-reperfusion injury (IRI)-induced AKI, inhibited FA mobilization from LDs by impairing adipose triglyceride lipase (ATGL)-mediated lipolysis and lipophagy. This resulted in LD accumulation and FA underutilization. IRI-induced alterations were more striking in αKlotho deficiency. Mechanistically, membrane αKlotho deficiency promoted E3 ligase peroxin2 binding to ubiquitin-conjugating enzyme E2 D2, resulting in ubiquitin-mediated degradation of ATGL which is a common molecular basis for lipolysis and lipophagy. Overexpression of αKlotho rescued FA mobilization by preventing ATGL ubiquitination, thereby lessening LD accumulation and fibrosis after AKI. This suggests that membrane αKlotho is indispensable for the maintenance of lipid homeostasis in RTECs. Thus, our study identified αKlotho as a critical regulator of lipid turnover and homeostasis in AKI, providing a viable strategy for preventing tubular injury and the AKI-to-chronic kidney disease transition. Translational StatementRenal tubular epithelial cells (RTECs) are pathologically characterized by lipid droplet (LD) accumulation after acute kidney injury (AKI); however, their pathogenesis remains incompletely understood. Here, we demonstrated an unrecognized link between membrane αKlotho and intracellular LDs in RTECs. Membrane αKlotho deficiency induced by ischemia-reperfusion injury inhibits fatty acid (FA) mobilization by impairing adipose triglyceride lipase (ATGL)–mediated lipolysis and lipophagy, inducing LD accumulation and FA underuse, which contribute to RTEC injury and kidney fibrosis. Mechanistically, αKlotho normalizes FA mobilization by protecting ATGL expression from peroxin2-mediated ubiquitination degradation. Our findings provide novel insights into the pathogenesis of LD accumulation in RTECs after AKI and present a viable therapeutic strategy for preventing tubular injury and AKI–to–chronic kidney disease transition. Renal tubular epithelial cells (RTECs) are pathologically characterized by lipid droplet (LD) accumulation after acute kidney injury (AKI); however, their pathogenesis remains incompletely understood. Here, we demonstrated an unrecognized link between membrane αKlotho and intracellular LDs in RTECs. Membrane αKlotho deficiency induced by ischemia-reperfusion injury inhibits fatty acid (FA) mobilization by impairing adipose triglyceride lipase (ATGL)–mediated lipolysis and lipophagy, inducing LD accumulation and FA underuse, which contribute to RTEC injury and kidney fibrosis. Mechanistically, αKlotho normalizes FA mobilization by protecting ATGL expression from peroxin2-mediated ubiquitination degradation. Our findings provide novel insights into the pathogenesis of LD accumulation in RTECs after AKI and present a viable therapeutic strategy for preventing tubular injury and AKI–to–chronic kidney disease transition. Acute kidney injury (AKI), a common and severe emergency associated with high morbidity, mortality, and health care costs, is a substantial risk for the occurrence and development of chronic kidney disease (CKD) and kidney failure.1Vijayan A. Tackling AKI: prevention, timing of dialysis and follow-up.Nat Rev Nephrol. 2021; 17: 87-88Crossref PubMed Scopus (40) Google Scholar,2Kellum J.A. Romagnani P. Ashuntantang G. et al.Acute kidney injury.Nat Rev Dis Primers. 2021; 7: 52Crossref PubMed Scopus (382) Google Scholar Even mild AKI can progress to kidney fibrosis, which acts as the common pathway for various terminal kidney diseases.3Dong Y. Zhang Q. Wen J. et al.Ischemic duration and frequency determines AKI-to-CKD progression monitored by dynamic changes of tubular biomarkers in IRI mice.Front Physiol. 2019; 10: 153Crossref PubMed Scopus (77) Google Scholar As a result, developing reliable strategies to inhibit AKI-to-CKD transition is critical. The AKI-to-CKD transition is complicated, involving various mechanisms, such as persistent chronic inflammation, epigenetic modification, and so on.4Guo X. Xu L. Velazquez H. et al.Kidney-targeted renalase agonist prevents cisplatin-induced chronic kidney disease by inhibiting regulated necrosis and inflammation.J Am Soc Nephrol. 2022; 33: 342-356Crossref PubMed Scopus (21) Google Scholar,5Sun Y. Fan Y. Wang Z. et al.S100A16 promotes acute kidney injury by activating HRD1-induced ubiquitination and degradation of GSK3β and CK1α.Cell Mol Life Sci. 2022; 79: 184Crossref PubMed Scopus (3) Google Scholar However, current interventions targeting these mechanisms have not effectively delayed the onset of CKD, suggesting that other pathologic mechanisms may exist. Ischemia or toxic injury impairs mitochondrial oxidative phosphorylation in renal cells; this deficit occurs more frequently in renal tubular epithelial cells (RTECs).6Liu B.C. Tang T.T. Lv L.L. et al.Renal tubule injury: a driving force toward chronic kidney disease.Kidney Int. 2018; 93: 568-579Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar As high-energy–demanding cells, RTECs heavily rely on fatty acid (FA) β-oxidation (FAO) for energy supply rather than glycolysis, rendering themselves particularly vulnerable to AKI.7Takaori K. Nakamura J. Yamamoto S. et al.Severity and frequency of proximal tubule injury determines renal prognosis.J Am Soc Nephrol. 2016; 27: 2393-2406Crossref PubMed Scopus (178) Google Scholar Recent have demonstrated that RTECs from to after AKI, to to the Z. S. X. The of in tubular epithelial cells the progression of acute kidney Mol Life Sci. 2021; PubMed Scopus Google H. et and proximal tubule after Am Soc Nephrol. 2016; 27: PubMed Scopus Google Z. J. Z. et of acute kidney injury to chronic kidney of 2022; Full Text Full Text PDF Scopus Google Scholar However, of is to RTECs as a of for to renal injury and Z. S. X. The of in tubular epithelial cells the progression of acute kidney Mol Life Sci. 2021; PubMed Scopus Google Scholar intracellular lipid droplet (LD) accumulation, resulting from the of FA thereby energy S. J. acid in by lipid droplet and mitochondrial Full Text Full Text PDF PubMed Scopus Google Scholar LDs in the kidney AKI et of promotes Int. 2019; Full Text Full Text PDF PubMed Scopus Google Y. A. et and contribute to in the Am Soc Nephrol. PubMed Scopus Google Z. A. et lipid accumulation the progression of acute kidney injury by the 2021; PubMed Scopus Google Scholar the of targeting LDs as an strategy for inhibiting AKI-to-CKD transition. However, the current of LD accumulation in RTECs primarily on mitochondrial with interventions intracellular lipid lipid homeostasis on the between LD and are and as in which can into et of lipid in disease in and PubMed Scopus Google H. et mechanisms for lipid mobilization from 2021; PubMed Scopus Google Scholar cells from LDs and of lipolysis and lipophagy, lipolysis and of the Rev Mol PubMed Scopus Google Scholar such as adipose triglyceride lipase and to from thereby the of into are on to supply by intracellular LDs or with S. Wang Y. et lipid PubMed Scopus Google Scholar these mechanisms from to in intracellular and with to LD and impairing FA a S. J. acid in by lipid droplet and mitochondrial Full Text Full Text PDF PubMed Scopus Google Scholar lipolysis and may the for lipid that of lipolysis or the kidney from or cisplatin-induced Z. A. et lipid accumulation the progression of acute kidney injury by the 2021; PubMed Scopus Google A. S. et triglyceride lipase renal in a of chronic kidney 2021; PubMed Scopus Google K. et renal tubular lipid in with by inhibiting lipid and PubMed Scopus (40) Google Scholar the mechanisms of these and their in RTECs have not well after AKI. αKlotho, a primarily expressed and by RTECs, as a The in health and Rev Nephrol. 2019; PubMed Scopus Google Scholar Recent have identified other of αKlotho, such as in K. et growth factor and and of an of Rev Physiol. PubMed Scopus Google X. in chronic kidney disease and disease.Kidney Dis PubMed Google Scholar and energy H. and 2021; Full Text Full Text PDF PubMed Scopus Google Scholar an of have and in the of αKlotho homozygous mutated (kl/kl) Y. et and in the a novel for Full Text PDF PubMed Scopus Google K. K. et of an energy homeostasis in PubMed Scopus Google Scholar the adipose of the with adipose lipid in adipose and K. K. et of an energy homeostasis in PubMed Scopus Google Scholar that αKlotho may a in or intracellular lipid of αKlotho in mice LD S. J. et and for and by inhibiting J. PubMed Scopus (40) Google Scholar the of LD accumulation by αKlotho in the However, the between αKlotho and intracellular lipid homeostasis in RTECs, as well as their mechanisms, remains to this we discovered an unrecognized link between αKlotho and lipid homeostasis in RTECs. that membrane αKlotho deficiency in RTECs, in mice or ischemia-reperfusion injury AKI FA mobilization the of lipolysis and lipophagy, to LD accumulation and FA IRI-induced alterations are more striking in αKlotho deficiency. Mechanistically, membrane αKlotho deficiency promotes E3 ligase peroxin2 binding to ubiquitin-conjugating enzyme E2 resulting in degradation of which as a common molecular basis for lipolysis and lipophagy. Overexpression of membrane αKlotho FA mobilization by preventing ATGL ubiquitination, thereby LD accumulation in RTECs, tubular and kidney fibrosis after AKI. membrane αKlotho is an that lipid homeostasis in RTECs. This study the membrane αKlotho in intracellular lipid after AKI, providing a viable strategy to tubular injury and AKI-to-CKD transition. and were by the and of mice were from and the mice were from αKlotho mice were from mice were from of and of The of these and IRI are in the FA cells were with and from and with an to αKlotho lipophagy, cells with were with of RTECs from mice were with and The of these are in the are expressed as and were between were an of were by of with the and and tubular injury triglyceride and and assays are in the αKlotho deficiency LD accumulation in RTECs. 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