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D-Serine activates glycolysis via mTOR pathway in kidney remodeling and suppresses onset of diabetes

ABSTRACT: D-Serine, a long-term undetected enantiomer of serine1,2, is a novel biomarker that reflects kidney function and disease activity3-5 and has unclear physiological functions. Here we show that D-serine is a physiological molecule that promotes tissue remodeling and suppresses the onset of diabetes. D-serine is quickly and dominantly distributed to the kidney upon injection in mice, suggesting that the kidney is a key target organ. Unilateral nephrectomy in human living kidney donors decreases urinary excretion and thus increases the blood level of D-serine, which in turn promotes the compensatory enlargement of the remnant kidney in mouse model. D-Serine activates cell cycle for tissue remodeling through an mTOR-related pathway, which promotes metabolic reprograming to glycolytic activation. In rodent diabetic model, D-serine promotes glycolysis in the kidney and suppresses the surge of blood glucose levels. D-Serine has physiological activity that influences kidney function and maintains metabolic homeostasis to reduce diabetic propensity.

ORGANISM(S): Mus musculus

PROVIDER: GSE155475 | GEO | 2022/04/07

REPOSITORIES: GEO

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Project description:MicroRNAs (miRNAs) are small regulatory RNA molecules that modulate the activity of specific mRNA targets and play important roles in a wide range of physiologic and pathologic processes. We hypothesized that miRNAs might be involved in the progression of CKD. In our previous studies we found chronic renal damages developed progressively in rats with 5/6 nephrectomy. L-mimosine(L-Mim) intervention from wk 5 to wk 12 improved renal function and resulted in additional accumulation of HIF-1 M-NM-1 and -2 M-NM-1 at wk 12. In the current study we found miR-29c was up-regulated in the L-Mim treated group compared with the control using Agilent miRNA microarrays. Of the microRNAs and proteins that exhibited reciprocal changes in expression following the L-Mim treatment, miR-29c and tropomyosin 1M-NM-1 (TPM1), which is involved in stress fiber function, met the sequence criteria for microRNA-target interaction, were later confirmed by 3'-untranslated region reporter analysis. TGFM-NM-21 treatment (3 ng/ml, 24 hours) decreased miR-29c expression and up-regulated protein expression of TPM1 in human renal epithelial cells. Overexpression of miR-29c significantly attenuated TGF-M-NM-21 induced increase in TPM1 in vitro. Moreover, intrarenal expression of miR-29c was decreased in IgAN patients with moderate to severe tubulointerstital fibrosis (TIF), compared with IgAN patients without TIF, and intrarenal protein expression of TMP1 was significantly increased in IgAN patients with TIF. The results suggest that intrarenal expression of miR-29c was down-regulated while its predicted target, TPM1 was up-regulated in the progression of CKD. Short term stabilizing of HIF up-regulates miR-29c and attenuates CKD in the remnant kidney model. Four weeks after 5/6 nephrectomy, rats were treated with intraperitoneal injections of vehicle or L-mimosine (L-Mim, Calbiochem), a prolyl 4-hydroxylase inhibitor (PHD), at a dosage of 50 mg/kg every other day. At the end of wk 12 after 5/6 nephrectomy, all rats (n=4, for each group) were sacrificed and blood samples were collected via cardiac puncture. Renal tissue were harvested, one piece of which was fixed in neutral formalin and then embedded in paraffin. The remaining kidney tissue was dissected in ice-cold PBS to, remove medulla, and then snap-frozen in liquid nitrogen before transferring to storage at -80M-BM-0C until further analysis.

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D-Serine activates glycolysis via mTOR pathway in kidney remodeling and suppresses onset of diabetes

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