Soluble RARRES1 induces podocyte apoptosis to promote glomerular disease progression

Chen, Anqun; Yang, Feng; Lai, Han; Ju, Wenjun; Li, Zhengzhe; Yu, Li; Wang, Andrew; Hong, Quan; Zhong, Fang; Wei, Chengguo; Fu, Jia; Guan, Tianjun; Liu, Bi‐Cheng; Kretzler, Matthias; Lee, Kyung Hwa; He, John Cijiang

doi:10.1172/jci140155

Cited by 51 publications

(54 citation statements)

References 36 publications

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“…Our work provides a mechanistic framework: (a) increased PUFAs, the result of upregulated Rar transcriptional programs and (b) the absence of CoQ protection from PUFA-mediated lipid peroxidation combine to promote podocyte death. This concept of context-dependent Rar podocyte injury is supported by recent work demonstrating expression of retinoic acid receptor responder protein 1 (RAR-RES1) is correlated with kidney injury in FSGS and diabetic kidney disease (84). While our work was focused on mechanisms of kidney injury (Pdss2 kdk/kd mice have isolated kidney disease; ref.…”

Section: Resultsmentioning

confidence: 58%

Targeting a Braf/Mapk pathway rescues podocyte lipid peroxidation in CoQ-deficiency kidney disease

Sidhom¹,

Kim²,

Kost‐Alimova³

et al. 2021

Journal of Clinical Investigation

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Section: Resultsmentioning

confidence: 58%

Targeting a Braf/Mapk pathway rescues podocyte lipid peroxidation in CoQ-deficiency kidney disease

Sidhom¹,

Kim²,

Kost‐Alimova³

et al. 2021

Journal of Clinical Investigation

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“…In addition, our study demonstrated that TNF-a induces the expression of RARRES1. As patients with chronic kidney disease have a marked increase of inflammation, we believe this is the major cause of the high expression of RARRES1 in the kidney of these patients (74). Interestingly, we found that RARRES1 is expressed predominantly in podocytes, as shown by single-cell RNAsequencing analysis of both human and mouse kidneys.…”

Section: Harmful Effects Of Ra In Podocytesmentioning

confidence: 52%

“…We found that mRNA expression of RAR responder protein 1 [RARRES1; also known as tazaroteneinduced gene (TIG1)] correlates significantly with clinical outcomes. However, to our surprise, the higher expression of RARRES1 was associated with worse renal survival, suggesting that RARRES1 is a risk gene for kidney disease (74).…”

Section: Harmful Effects Of Ra In Podocytesmentioning

confidence: 66%

“…In vivo, we validated that RARRES1 wild-type mice developed albuminuria and podocyte injury, whereas RARRES1 cleavage mutant mice, which are unable to generate soluble RARRES1, did not have any renal phenotype (Fig. 2) (74).…”

Section: Harmful Effects Of Ra In Podocytesmentioning

confidence: 80%

“…Our studies suggested that RARRES1, a type 1 membrane protein, can be cleaved and released into supernatants as a highly glycosylated soluble form in cultured podocytes. We mapped the exact cleavage site of RARRES1, and the cleavage is likely mediated by matrix metalloproteinases (74). Soluble RARRES1 can be detected in the urine of mice with diabetic kidney disease and FSGS and is significantly increased in the urine of patients with diabetic kidney disease compared with healthy subjects (unpublished observations).…”

Section: Harmful Effects Of Ra In Podocytesmentioning

confidence: 91%

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Disparate roles of retinoid acid signaling molecules in kidney disease

Chen

Liu

et al. 2021

American Journal of Physiology-Renal Physiology

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RA (Retinoid acid) is synthesized mainly in the liver and has multiple functions in development, cell differentiation and proliferation, and regulation of inflammation. RA has been used to treat multiple diseases such as cancer and skin disorders. The kidney is a major organ for RA metabolism, which is altered in the diseased condition. RA is known to have renal protective effects in multiple animal models of kidney disease. RA has been shown to ameliorate podocyte injury through induction of expression of differentiation markers and regeneration of podocytes from its progenitor cells in animal models of kidney disease. The effects of RA in podocytes are mediated mainly by activation of cAMP/PKA pathway via retinoic acid receptor-α (RARα) and activation of its downstream transcription factor KLF15. Screening of RA signaling molecules in human kidney disease reveals RARRES1 as a risk gene for glomerular disease progression. RARRES1, a podocyte-specific growth arrest gene, is regulated by both high doses of RA and TNFα. Mechanistically, RARRES1 is cleaved by MMPs to generate soluble RARRES1 which then induces podocyte apoptosis through interaction with intracellular RIOK1. Therefore, a high dose of RA may induce podocyte toxicity through the upregulation of RARRES1. Based on the current findings, to avoid potential side effects we propose three strategies to develop future therapies of RA for glomerular disease: 1) develop RARα- and KLF15-specific agonists; 2) use the combination of a low dose of RARα agonist with PDE4 inhibitors; and 3) use the combination of RARα agonist with RARRES1 inhibitors.

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Canonical effects of cytokines on glomerulonephritis: A new outlook in nephrology

Zununi Vahed,

Hosseiniyan Khatibi,

Ardalan

2024

Medicinal Research Reviews

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Glomerulonephritis (GN) is an important cause of renal inflammation resulting from kidney‐targeted adaptive and innate immune responses and consequent glomerular damage. Given the lack of autoantibodies, immune complexes, or the infiltrating immune cells in some forms of GN, for example, focal segmental glomerulosclerosis and minimal change disease, along with paraneoplastic syndrome and a special form of renal involvement in some viral infections, the likeliest causative scenario would be secreted factors, mainly cytokine(s). Since cytokines can modulate the inflammatory mechanisms, severity, and clinical outcomes of GN, it is rational to consider the umbrella term of cytokine GN as a new outlook to reclassify a group of previously known GN. We focus here, particularly, on cytokines that have the central “canonical effect” in the development of GN.

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Soluble RARRES1 induces podocyte apoptosis to promote glomerular disease progression

Cited by 51 publications

References 36 publications

Targeting a Braf/Mapk pathway rescues podocyte lipid peroxidation in CoQ-deficiency kidney disease

Targeting a Braf/Mapk pathway rescues podocyte lipid peroxidation in CoQ-deficiency kidney disease

Disparate roles of retinoid acid signaling molecules in kidney disease

Canonical effects of cytokines on glomerulonephritis: A new outlook in nephrology

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