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Review
. 2024 Aug;14(8):100933.
doi: 10.1016/j.jpha.2024.01.001. Epub 2024 Jan 3.

Renal tubular epithelial cell quality control mechanisms as therapeutic targets in renal fibrosis

Yini Bao  1 , Qiyuan Shan  1 , Keda Lu  2 , Qiao Yang  1 , Ying Liang  1 , Haodan Kuang  1 , Lu Wang  1 , Min Hao  1 , Mengyun Peng  1 , Shuosheng Zhang  3 , Gang Cao  1   2
Affiliations
Review

Renal tubular epithelial cell quality control mechanisms as therapeutic targets in renal fibrosis

Yini Bao et al. J Pharm Anal. 2024 Aug.

Abstract

Renal fibrosis is a devastating consequence of progressive chronic kidney disease, representing a major public health challenge worldwide. The underlying mechanisms in the pathogenesis of renal fibrosis remain unclear, and effective treatments are still lacking. Renal tubular epithelial cells (RTECs) maintain kidney function, and their dysfunction has emerged as a critical contributor to renal fibrosis. Cellular quality control comprises several components, including telomere homeostasis, ubiquitin-proteasome system (UPS), autophagy, mitochondrial homeostasis (mitophagy and mitochondrial metabolism), endoplasmic reticulum (ER, unfolded protein response), and lysosomes. Failures in the cellular quality control of RTECs, including DNA, protein, and organelle damage, exert profibrotic functions by leading to senescence, defective autophagy, ER stress, mitochondrial and lysosomal dysfunction, apoptosis, fibroblast activation, and immune cell recruitment. In this review, we summarize recent advances in understanding the role of quality control components and intercellular crosstalk networks in RTECs, within the context of renal fibrosis.

Keywords: Autophagy; Mitochondria; Quality control; Renal fibrosis; Renal tubular epithelial cells; Telomere homeostasis.

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Conflict of interest statement

The authors declare that there are no conflicts of interest.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Cellular quality control in renal tubular epithelial cells (RTECs). Maintenance of telomere homeostasis (DNA), ubiquitin-proteasome system (UPS) and autophagy (protein), endoplasmic reticulum (ER), mitochondrion, and lysosome (organelle) are essential for cellular homeostasis. TIN2: TRF1 interacting nuclear factor 2; RAP1: repressor/activator protein 1; TPP1: telomere protection protein 1; POT1: protection of telomeres 1; TRF1: telomeric repeat-binding factor 1; TRF2: telomeric repeat-binding factor 2; TERT: telomerase reverse transcriptase; NHP2: H/ACA ribonucleoprotein complex subunit 2; NOP10: H/ACA ribonucleoprotein complex subunit 3; GAR1: H/ACA ribonucleoprotein complex subunit 1; E1: ubiquitin-activating enzyme; E2: ubiquitin-conjugating enzyme; E3: ubiquitin ligase; Ub: ubiquitin; LC3: microtubule-associated protein 1 light chain 3; p62: sequestosome 1; PERK: protein kinase RNA-like ER kinase; ATF6: activating transcription factor 6; IRE1α: inositol-requiring protein 1α; UPR: unfolded protein response; PINK1: phosphatase and tensin homolog on chromosome ten (PTEN)-induced putative kinase 1; TFEB: transcription factor EB; TFEC: transcription factor EC.
Fig. 2
Fig. 2
DNA quality control in fibrotic renal tubular epithelial cells (RTECs). Telomere dysfunction can be induced by irreparable DNA damage and telomere shortening. Persistent damage and telomere shortening inhibit DNA damage repair in fibrotic RTECs, trigger persistent DNA damage responses (DDRs), and induce cell cycle arrest and cellular senescence, all of which ultimately lead to renal fibrosis. TIN2: TRF1 interacting nuclear factor 2; RAP1: repressor/activator protein 1; TRF1: telomeric repeat-binding factor 1; TRF2: telomeric repeat-binding factor 2; TPP1: telomere protection protein 1; POT1: protection of telomeres 1; TERT: telomerase reverse transcriptase; NHP2: H/ACA ribonucleoprotein complex subunit 2; NOP10: H/ACA ribonucleoprotein complex subunit 3; GAR1: H/ACA ribonucleoprotein complex subunit 1; TERC: telomerase RNA component; p16: cyclin dependent kinase inhibitor 2A; p21: cyclin-dependent kinase inhibitor 1A; SASP: senescence-associated secretory phenotype.
Fig. 3
Fig. 3
Protein quality control in renal tubular epithelial cells (RTECs). Misfolded and damaged protein can be degraded by ubiquitin-proteasome system (UPS) and autophagy system. The collaboration between UPS and autophagy is critical for protein homeostasis in RTECs. The majority of aberrant proteins are targeted to 26S proteasome for degradation in UPS. When UPS is inhibited, the autophagy system can be activated to remove incremental aberrant proteins. Ub: ubiquitin; E1: ubiquitin-activating enzyme; E2: ubiquitin-conjugating enzyme; E3: ubiquitin ligase; p62: sequestosome 1; LC3: microtubule-associated protein 1 light chain 3.
Fig. 4
Fig. 4
Organelle quality control in fibrotic renal tubular epithelial cells (RTECs). The core elements of organelle quality control network in RTECs include the homeostasis of endoplasmic reticulum (ER), mitochondria, and lysosome. Upon ER stress, RTECs exert complementary adaptive mechanisms, namely, unfolded protein response (UPR), to deal with protein-folding alterations. Upon irreversible ER stress, UPR further promotes RTEC apoptosis. An increased UPR can be found in fibrotic RTECs. In addition, lysosome dysfunction suppresses normal mitophagy, and mitochondrial damage results in defective fatty acid β-oxidation in RTECs, both of which promote renal fibrosis. PERK: protein kinase RNA-like ER kinase; eIF2α: factor 2 subunit-α; ATF4: activating transcription factor 4; ATF6: activating transcription factor 6; S1P: site-1 protease; S2P: site-2 protease; ATF6f: fragment of ATF6; IRE1α: inositol-requiring protein 1α; XBP-1: X-box binding protein 1; XBP-1s: spliced form of XBP1; JNK: c-Jun N-terminal kinase; CHOP: CCAAT/enhancer-binding protein-homologous protein; TCA: tricarboxylic acid; ATP: adenosine triphosphate; LMP: lysosomal membrane permeabilization; PINK1: phosphatase and tensin homolog on chromosome ten (PTEN)-induced putative kinase 1; Ub: ubiquitin; LC3: microtubule-associated protein 1 light chain 3.
Fig. 5
Fig. 5
Crosstalk of renal tubular epithelial cells (RTECs) with effector cells in renal fibrosis. Injured RTECs produce various cytokines to promote the crosstalk among RTECs, fibroblasts/myofibroblasts, and immune cells, accelerate epithelial-to-mesenchymal transition (EMT) and apoptosis program, and further contribute to excessive extracellular matrix (ECM) deposition and promote renal fibrosis. TGF-β: transforming growth factor-β; CTGF: connective tissue growth factor.
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