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Tubular insulin-induced gene 1 deficiency promotes NAD+ consumption and exacerbates kidney fibrosis

ABSTRACT:

Profibrotic proximal tubular (PT) were identified as a unique phenotype of PTCs in renal fibrosis by single-cell RNA sequencing (scRNA-seq). Controlling the process of renal fibrosis requires understanding how to manage the S1 subset's branch to the S3 subset rather than to the profibrotic PT subset. Insulin-induced gene 1 (Insig1) is one of the branch-dependent genes involved in controlling this process, although its role in renal fibrosis is unknown. Here, we discovered that tubular Insig1 deficiency, rather than fibroblast Insig1 deficiency, play a detrimental role in the pathogenesis of renal fibrosis in vivo and in vitro. Overexpression of Insig1 profoundly inhibited renal fibrosis. Mechanistically, Insig1 deletion in PTCs boosted SREBP1 nuclear localization, increasing Aldh1a1 transcriptional activity, causing excessive NAD+ consumption and ER enlargement, as well as accelerating renal fibrosis. We also identified nicardipine as a selective inhibitor of Aldh1a1, which could restore NAD+ and maintain ER homeostasis, as well as improve renal fibrosis. Together, our findings support tubular Insig1 as a new therapeutic target for chronic kidney disease (CKD).

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

SUBMITTER: xiaowen yu

PROVIDER: MTBLS9985 | MetaboLights | 1970-01-01

REPOSITORIES: MetaboLights

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			Action	DRS
	MTBLS9985	Other
	FILES	Other
	a_MTBLS9985_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS9985_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt

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PFKFB3-mediated glycolysis boosts fibroblast activation and subsequent kidney fibrosis

Project description:<p>Renal fibrosis, a hallmark of chronic kidney diseases, is driven by the activation of renal fibroblasts. Recent studies have highlighted the role of glycolysis in this process. Nevertheless, one critical glycolytic activator, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), remains unexplored in renal fibrosis. Upon reanalyzing the single-cell sequencing data from Dr. Humphreys' lab, we noticed an upregulation of glycolysis, gluconeogenesis, and TGFβ signaling pathway in myofibroblasts from fibrotic kidneys after unilateral ureter obstruction (UUO) or kidney ischemia/reperfusion. Furthermore, our experiments showed significant induction of PFKFB3 in mouse kidneys following UUO or kidney ischemia/reperfusion. To delve deeper into the role of PFKFB3, we generated mice with Pfkfb3 deficiency specifically in myofibroblasts (Pfkfb3f/fPostnMCM). Following UUO or kidney ischemia/reperfusion, a substantial decrease of fibrosis in injured kidneys of Pfkfb3f/fPostnMCM mice was identified compared to their wild-type littermates. Additionally, in cultured renal fibroblast NRK-49F cells, PFKFB3 was elevated upon exposure to TGFβ1, accompanied by the increase of α-SMA and fibronectin. Notably, this upregulation was significantly diminished with PFKFB3 knockdown, correlated with a glycolysis suppression. Mechanistically, the glycolytic metabolite lactate promoted the fibrotic activation of NRK-49F. In conclusion, our study demonstrates the critical role of PFKFB3 in driving fibroblast activation and subsequent renal fibrosis.</p>

2024-03-12 | MTBLS8281 | MetaboLights

Deficiency of ERO1 and activation of protein translation synergistically impair breast tumor resilience

Project description:Endoplasmic reticulum (ER) stress triggers an adaptive response which fosters tumor cell survival and resilience to stress conditions. Activation of the endoplasmic reticulum stress response, through its PERK branch, promotes the phosphorylation of the α-subunit of translation initiation factor eIF2alpha, thereby repressing general protein translation and selectively augmenting the translation of ATF4 with the downstream CHOP transcription factor and the protein disulfide oxidase ERO1. Here, we show that ISRIB, a small molecule, which inhibits the action of the phosphorylated α-subunit of eIF2, thereby activating protein translation, synergistically interacts with the genetic deficiency of protein disulfide oxidase ERO1 enfeebling tumor growth and spreading. ISRIB represses CHOP signal but surprisingly does not inhibit ERO1. Mechanistically, ISRIB increases the ER protein load with a prominent perturbing effect on ERO1 deficient Triple-Negative breast cells, which have adapted to live with low client protein load, while ERO1 deficiency selectively impairs VEGF-dependent angiogenesis. Strikingly, ERO1-deficient Triple Negative Breast Cancer xenografts have augmented ER stress response and PERK branch. In vivo, ISRIB synergistically with ERO1 deficiency inhibits the growth of Triple-Negative Breast cancer xenografts by impairing proliferation and angiogenesis, while it is not effective on the xenograft counterparts with ERO1. In summary, these results demonstrate that ISRIB together with ERO1 deficiency synergistically shatters a feature of the adaptive ER stress response while ERO1 deficiency selectively impairs angiogenesis in tumors, thereby together promoting tumor cytotoxicity. Therefore, our findings suggest two surprising findings in breast tumors: ERO1 is not regulated via CHOP and ISRIB represents a therapeutic option to efficiently inhibit tumor progression in those tumors with limited ERO1 and high PERK.

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Sirtuin 3 regulates mitochondrial protein acetylation and metabolism in tubular epithelial cells during renal fibrosis

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RTN1 IS A NOVEL MEDIATOR FOR PROGRESSION OF KIDNEY DISEASE

Project description:Gene expression profiling of kidneys from the murine model of HIV-associated nephropathy (HIVAN) identified an association between the expression of an endoplasmic reticulum (ER)-associated protein reticulon-1, RTN1, and the severity of kidney disease. Of the three known RTN1 isoforms, only RTN1A protein expression was increased in kidneys of murine models of HIVAN, diabetic nephropathy (DN), and renal fibrosis and humans with HIVAN and DN. Both mRNA and protein expression of RTN1-A in the kidneys correlated inversely with estimated glomerular filtration rate (eGFR) in patients with DN. In kidney cells, RTN1 overexpression induced ER stress/apoptosis, whereas RTN1 knockdown attenuated tunicamycin-, and hyperglycemia-induced ER stress/apoptosis. Incubation of kidney cells with high glucose media induced RTN1A expression likely through oxidative pathway, while knockdown of RTN1A inhibited high glucose-induced apoptosis. RTN1A interacts with PERK and mutation of its N- or C-terminal domain abolished its effects on ER stress/apoptosis. In vivo, knockdown of Rtn1a expression either before or after kidney injury attenuated renal fibrosis in mice with unilateral ureteral obstruction (UUO) and tubular epithelial cell-specific knockdown of Rtn1a also ameliorated ER stress and renal fibrosis in the UUO mice. Finally, knockdown of Rtn1a also attenuated proteinuria, glomerular hypertrophy, and mesangial expansion in STZ-induced diabetic mice, which were associated with suppression of ER stress markers. Taken together, these data suggest that RTN1 is a mediator of kidney disease progression that exacerbates kidney injury through ER stress and apoptosis.

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