Methylation in pericytes after acute injury promotes chronic kidney disease

Chou, Yu‐Hsiang; Pan, Szu-Yu; Shao, Yu-Han; Shih, Hong-Mou; Wei, Shih-Chung; Lai, Chun‐Fu; Chiang, Wen‐Chih; Schrimpf, Claudia; Yang, Kai-Chien; Lai, Liang‐Chuan; Chen, Ming-Fong; Chu, Tzong‐Shinn; Lin, Shuei-Liong

doi:10.1172/jci135773

Cited by 40 publications

(30 citation statements)

References 44 publications

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“…[8][9][10][11][12][13] We have reported that renal pericytes are renal EPO-producing cells (REPCs) who produce EPO through HIF-2a-dependent gene transcription induced by anemia or hypoxia. 14 Pericytes have been demonstrated as the major source of scar-producing myofibroblasts in CKD, 8,10,11,15,16 a finding supported by the other independent reports. 17,18 Although transition to myofibroblasts leads to the repression of Epo transcription, overexpression of HIF-2a partially restores the EPO production in myofibroblasts.…”

Section: Translational Statementsupporting

confidence: 62%

Kidney pericyte hypoxia-inducible factor regulates erythropoiesis but not kidney fibrosis

Pan

Tsai

Chou

et al. 2021

Kidney International

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Prolyl hydroxylase domain enzyme (PHD) inhibitors are effective in the treatment of chronic kidney disease (CKD)associated anemia by stabilizing hypoxia inducible factor (HIF), thereby increasing erythropoietin and consequently erythropoiesis. However, concern for CKD progression needs to be addressed in clinical trials. Although preclinical studies showed an anti-inflammatory effect in kidney disease models, the effect of PHD inhibitors on kidney fibrosis was inconsistent probably because the effects of HIF are cell type and context dependent. The major kidney erythropoietin-producing cells are pericytes that produce erythropoietin through HIF-2a-dependent gene transcription. The concern for the impact of HIF in pericytes on kidney fibrosis arises from the fact that pericytes are the major precursor cells of myofibroblasts in CKD. Since cells expressing Gli1 fulfill the morphologic and anatomic criteria for pericytes, we induced Gli1 þ cellspecific HIF stabilization or knockout to study the impact of HIF in pericytes on kidney pathology of mice with or without fibrotic injury induced by unilateral ureteral obstruction. Compared with the littermate controls, mice with pericyte-specific HIF stabilization due to von Hippel-Lindau protein or PHD2 knockout showed increased serum erythropoietin and polycythemia rather than a discernible difference in kidney fibrosis. Compared with Gli1 þ pericytes sorted from littermate controls, Gli1 þ pericytes sorted from PHD2 knockout mice showed increased erythropoietin gene expression rather than discernible changes in Col1a1 or Acta2 expression. Furthermore, pericyte-specific knockout of HIF-1a or HIF-2a did not affect kidney fibrosis. Thus, our study supports the absence of negative effects of PHD inhibitors on kidney fibrosis of mice despite HIF stabilization in pericytes.

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Section: Translational Statementsupporting

confidence: 62%

Kidney pericyte hypoxia-inducible factor regulates erythropoiesis but not kidney fibrosis

Pan

Tsai

Chou

et al. 2021

Kidney International

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“…Potentially fibroblasts include any ECM-producing cell in the connective tissue stroma. Consistent with their diversity, multiple cellular origins for the fibroblast have been suggested including epithelial- and endothelial-to-mesenchymal transition, infiltration of bone marrow precursors and macrophages (Duffield et al, 2013 ), along with a resident quiescent mesenchymal stem cell precursor, often simply referred to as a pericyte (Chou et al, 2020 ).…”

Section: What Is a Fibroblast?mentioning

confidence: 99%

A Metabolic Reprogramming of Glycolysis and Glutamine Metabolism Is a Requisite for Renal Fibrogenesis—Why and How?

Hewitson

Smith

2021

Front. Physiol.

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Chronic Kidney Disease (CKD) is characterized by organ remodeling and fibrosis due to failed wound repair after on-going or severe injury. Key to this process is the continued activation and presence of matrix-producing renal fibroblasts. In cancer, metabolic alterations help cells to acquire and maintain a malignant phenotype. More recent evidence suggests that something similar occurs in the fibroblast during activation. To support these functions, pro-fibrotic signals released in response to injury induce metabolic reprograming to meet the high bioenergetic and biosynthetic demands of the (myo)fibroblastic phenotype. Fibrogenic signals such as TGF-β1 trigger a rewiring of cellular metabolism with a shift toward glycolysis, uncoupling from mitochondrial oxidative phosphorylation, and enhanced glutamine metabolism. These adaptations may also have more widespread implications with redirection of acetyl-CoA directly linking changes in cellular metabolism and regulatory protein acetylation. Evidence also suggests that injury primes cells to these metabolic responses. In this review we discuss the key metabolic events that have led to a reappraisal of the regulation of fibroblast differentiation and function in CKD.

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“…Generally, AKI occurs in patients with renal hypoperfusion, cardiovascular disease, sepsis, major surgery, radiocontrast exposure, and pharmacological treatments (3)(4)(5)(6)(7)(8). As an important complication, the incidence of AKI in hospitalized patients is almost 10-15% and in patients in the intensive care unit (ICU) its prevalence can sometimes exceed 50% (9)(10)(11). Development of AKI in hospital is associated with an extended length of stay, accelerated onset of end-stage renal disease, increased costs and increased mortality (12).…”

Section: Introductionmentioning

confidence: 99%

“…Development of AKI in hospital is associated with an extended length of stay, accelerated onset of end-stage renal disease, increased costs and increased mortality (12). Moreover, kidney dysfunction or damage can occur over a longer period and accelerate progression of underlying chronic kidney disease (CKD) (10,(13)(14)(15). Despite recent insights into the causes and underlying mechanisms, no interventions beyond supportive treatment have been developed to improve outcomes of established AKI (16,17).…”

Section: Introductionmentioning

confidence: 99%

Aldehyde dehydrogenase 2 protects against acute kidney injury by regulating autophagy via Beclin-1 pathway

Xu¹,

Guo²,

Wei³

et al. 2021

JCI Insight

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The mitochondrial enzyme acetaldehyde dehydrogenase 2 (ALDH2) catalyzes the detoxification of acetaldehyde and endogenous lipid aldehydes. Approximately 40% of East Asians, accounting for 8% of the human population, carry the E504K mutation in ALDH2 that leads to accumulation of toxic reactive aldehydes and increases the risk for cardiovascular disease (CVD), cancer and Alzheimer's, among other diseases. However, the role of ALDH2 in acute kidney injury (AKI) remains poorly defined and is therefore the subject of the present study using various cellular and organismal sources. In murine models in which AKI was induced by either the contrast agent Iohexol or renal ischemia/reperfusion, knockout and activation/overexpression of ALDH2 was associated with increased and decreased renal injury, respectively. In murine renal tubular epithelial cells (RTECs), ALDH2 upregulated Beclin-1 expression, promoted autophagy activation and eliminated reactive oxygen species (ROS). In vivo and in vitro, both 3-MA and Beclin-1 siRNAs inhibited autophagy and abolished ALDH2 mediated renoprotection. In mice with Iohexol induced AKI, ALDH2 knockdown in RTECs using AAV-shRNA impaired autophagy activation and aggravated renal injury. In human renal proximal tubular epithelial HK-2 cells exposed to Iohexol, ALDH2 activation potentiated autophagy and attenuated apoptosis. In mice with AKI induced by renal ischemia ischemia/reperfusion, ALDH2 overexpression or pretreatment regulated autophagy mitigating apoptosis of RTECs and renal injury. Our data collectively substantiate a critical role of ALDH2 in AKI via autophagy activation involving the Beclin-1 pathway.

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Methylation in pericytes after acute injury promotes chronic kidney disease

Cited by 40 publications

References 44 publications

Kidney pericyte hypoxia-inducible factor regulates erythropoiesis but not kidney fibrosis

Kidney pericyte hypoxia-inducible factor regulates erythropoiesis but not kidney fibrosis

A Metabolic Reprogramming of Glycolysis and Glutamine Metabolism Is a Requisite for Renal Fibrogenesis—Why and How?

Aldehyde dehydrogenase 2 protects against acute kidney injury by regulating autophagy via Beclin-1 pathway

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