Name	Chronic kidney disease
ICD	ICD-11: GB61

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[1]
Response Summary	METTL3 modulated Notch signaling via the m6A modification of Metalloproteinase inhibitor 2 (TIMP2) in IGF2BP2-dependent manner and exerted pro-inflammatory and pro-apoptotic effects. This study suggested that METTL3-mediated m6A modification is an important mechanism of podocyte injury in DN.
Responsed Disease	Chronic kidney disease [ICD-11: GB61.Z]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Up regulation
Pathway Response	Notch signaling pathway			hsa04330
In-vitro Model	MPC-5	Normal	Mus musculus	CVCL_AS87
In-vivo Model	After 7 days of acclimatization, STZ, dissolved in 0.1 M citrate buffer, was intraperitoneally administered daily to mice at a dose of 50 mg/kg after 12 h of food deprivation each day for 5 consecutive days. The type 1 mice diabetic mice were randomly separated into four groups (n = 5-8): AAV9-scramble-control group; AAV9-scramble-STZ; AAV9-shRNA-control; and AAV9-shRNA-STZ group (Hanbio Biotechnology, China). The 50 UL titer of 1 × 1012 virus was injected into the renal pelvis using an insulin needle and maintained there for 2 to 3 s. The type 2 diabetic mice were randomly separated into four groups (n = 5-8): AAV9-scramble-db/m group; AAV9-scramble-db/db group; AAV9-shRNA-db/m group; and AAV9-shRNA-db/db group (Hanbio Biotechnology, China). The 100 UL titer of 1 × 1012 virus was injected into the tail vein using an insulin needle and maintained there for 2 to 3 s. Blood glucose was monitored weekly in mice. At the end of 12 weeks, the 24-h urine samples were collected from the mice kept in metabolic cages.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[2]
Response Summary	Elf3 plays an important role in the process of phenotypic alterations of podocyte induced by the activation of TGF-beta signals. Elf3 protein levels in patients with DN (R2 = 0.7259) were useful as an early non-invasive marker for podocyte injuries in DN. The epithelium-specific transcription factor, Elf3 was induced by AGE stimulation and, subsequently, upregulated RII expression in cultured podocytes. Induction of Elf3 and activation of RII-Mothers against decapentaplegic homolog 3 (SMAD3) signaling, leading to a decrease in WT1 expression, were observed in podocytes in diabetic human kidneys.
Responsed Disease	Chronic kidney disease [ICD-11: GB61.Z]
Target Regulator	ETS-related transcription factor Elf-3 (ELF3)		WRITER	Regulator Info
Pathway Response	TGF-beta signaling pathway			hsa04350
In-vitro Model	Murine podocytes	Normal	Mus musculus	CVCL_5737
In-vivo Model	In the present study, we assessed Smad3 +/- mice for a comparatively long period to examine the effects of Smad3 expression and phosphorylation and to evaluate the involvement of Smad3 in DN. Heterozygous Smad3- knockout mice were kindly provided by Dr. Yasue, University of Tokushima. We attempted to generate Smad3-null mice using pairs of Smad3 mice, but progeny was rarely obtained, and pups were fragile and could not survive for a long period (5 weeks at the most). Therefore, BKS/Cg-m Lepr db (db/db) x Smad3 +/- mice were developed using pairs of Lepr db +/- x Smad3 +/-. Smad3 +/-;db/+ mice were generated by crossing Smad3 +/- and db/+ mice. Moreover, Smad3 +/-;db/db were generated by crossing Smad3 +/-;db/+ and db/+ mice as previously described. Blood glucose concentrations were measured from the tail vein (glucose assay kit; Abbott). The diabetic phenotype was confirmed 4 weeks after birth by blood glucose >300 mg/dl.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[3]
Response Summary	METTL14-regulated PI3K/Akt signaling pathway via Mutated in multiple advanced cancers 1 (PTEN) affected HDAC5-mediated EMT of renal tubular cells in diabetic kidney disease.
Responsed Disease	Chronic kidney disease [ICD-11: GB61.Z]
Target Regulator	Methyltransferase-like 14 (METTL14)		WRITER	Regulator Info
Target Regulation	Down regulation
Pathway Response	PI3K-Akt signaling pathway			hsa04151
Cell Process	Epithelial-mesenchymal transition
In-vitro Model	HK-2 [Human kidney]	Normal	Homo sapiens	CVCL_0302
In-vivo Model	Twenty mice were randomly divided into three groups: normal mice group (N), diabetic mice group (DM), and diabetic mice administrated with TSA group (DM + TSA).

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[4]
Response Summary	TFA could ameliorate HG-induced pyroptosis and injury in podocytes by targeting METTL3-dependent m6A modification via the regulation of NACHT, LRR and PYD domains-containing protein 3 (NLRP3)-inflammasome activation and PTEN/PI3K/Akt signaling. This study provides a better understanding of how TFA can protect podocytes in diabetic kidney disease (DKD).
Responsed Disease	Chronic kidney disease [ICD-11: GB61.Z]
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Target Regulation	Down regulation
Pathway Response	PI3K-Akt signaling pathway			hsa04151
In-vitro Model	MPC-5	Normal	Mus musculus	CVCL_AS87

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[5]
Response Summary	The elevated m6A RNA levels and the most upregulated METTL14 expression in kidneys of mice with adriamycin and diabetic nephropathy. METTL14-dependent RNA m6A modification contributes to podocyte injury through posttranscriptional regulation of NAD-dependent protein deacetylase sirtuin-1 (SIRT1) mRNA, which provide a potential approach for the diagnosis and treatment of podocytopathies.
Responsed Disease	Chronic kidney disease [ICD-11: GB61.Z]
Responsed Drug	Doxil		Approved	Drug Info
Target Regulator	Methyltransferase-like 14 (METTL14)		WRITER	Regulator Info
Target Regulation	Down regulation
Cell Process	Cell apoptosis
In-vitro Model	Conditionally immortalized human podocytes (Podocytes)
In-vivo Model	To establish mice model with ADR nephropathy, adult male C57BL/6J mice (8-12 weeks of age) were purchased from Animal Center of Fudan University and injected with 19.5 mg/kg ADR (D1515, Sigma-Aldrich, St-Louis, MO, USA) intravenously via tail vein.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[6]
Response Summary	Mechanistically, the FTO/Suppressor of cytokine signaling 1 (SOCS1)/JAK-STAT axis promotes diabetic kidney disease(DKD) pathogenesis via promoting inflammation. Moreover, FTO expression is significantly decreased in DKD, and overexpression of FTO can dramatically alleviate kidney inflammation.
Responsed Disease	Chronic kidney disease [ICD-11: GB61.Z]
Target Regulator	Fat mass and obesity-associated protein (FTO)		ERASER	Regulator Info
Target Regulation	Up regulation
Pathway Response	JAK-STAT signaling pathway			hsa04630
In-vitro Model	HEK293T	Normal	Homo sapiens	CVCL_0063
	hMC	Normal	Homo sapiens	CVCL_9Q61
	HK-2 [Human kidney]	Normal	Homo sapiens	CVCL_0302
In-vivo Model	FTO over-expression db/db mice were generated through injecting the tail vein with Fto-overexpression lentivirus at 12 weeks.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[7]
Response Summary	METTL14 could aggravated high glucose-induced glomerular endothelial cell injury and diabetic nephropathy through m6A modification of alpha-klotho. METTL14 silence decreased the levels of ROS, Tumor necrosis factor (TNF/TNF-alpha) and IL-6 and cell apoptosis.
Responsed Disease	Chronic kidney disease [ICD-11: GB61.Z]
Target Regulator	Methyltransferase-like 14 (METTL14)		WRITER	Regulator Info
Target Regulation	Up regulation
Pathway Response	NF-kappa B signaling pathway			hsa04064
	AGE-RAGE signaling pathway in diabetic complications			hsa04933
	Apoptosis			hsa04210
Cell Process	Cell apoptosis
In-vitro Model	HRGECs cell line (Human glomerular microvascular endothelial cells)
In-vivo Model	After adaptive feeding for 1 week, db/db mice were randomly divided into five groups (n = 6): db/db group, db/db + rAAV group, db/db + rAAV-METTL14 group, db/db + rAAV-klotho group, and db/db + rAAV-METTL14 + rAAV-klotho group. Except db/db group, the other four groups were injected with recombinant adeno-associated virus (rAAV) control, rAAV mediated delivery of METTL14 (rAAV-METTL14), or/and rAAV mediated delivery of klotho (rAAV-klotho) respectively via tail vein. Six db/m mice were chosen as the normal control.

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[2]
Response Summary	Elf3 plays an important role in the process of phenotypic alterations of podocyte induced by the activation of TGF-beta signals. Elf3 protein levels in patients with DN (R2 = 0.7259) were useful as an early non-invasive marker for podocyte injuries in DN. The epithelium-specific transcription factor, Elf3 was induced by AGE stimulation and, subsequently, upregulated RII expression in cultured podocytes. Induction of Elf3 and activation of RII-Smad3 signaling, leading to a decrease in Wilms tumor protein (WT1) expression, were observed in podocytes in diabetic human kidneys.
Responsed Disease	Chronic kidney disease [ICD-11: GB61.Z]
Target Regulator	ETS-related transcription factor Elf-3 (ELF3)		WRITER	Regulator Info
Pathway Response	TGF-beta signaling pathway			hsa04350
In-vitro Model	Murine podocytes	Normal	Mus musculus	CVCL_5737

In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Disease Response by This Target Gene				[8]
Response Summary	Renal fibrosis is a key factor in chronic kidney disease (CKD). Metastasis associated lung adenocarcinoma transcript 1 (MALAT1)/miR-145/FAK pathway was involved in the effect of dihydroartemisinin (DHA) on TGF-beta1-induced renal fibrosis in vitro and in vivo.
Responsed Disease	Chronic kidney disease [ICD-11: GB61]
Responsed Drug	Artenimol		Approved	Drug Info
Target Regulator	Methyltransferase-like 3 (METTL3)		WRITER	Regulator Info
Cell Process	Epithelial-mesenchymal transition
In-vitro Model	HK-2 [Human kidney]	Normal	Homo sapiens	CVCL_0302
	HK2	Normal	Acipenser baerii	CVCL_YE28
In-vivo Model	For the unilateral ureteral obstruction (UUO) model, male C57BL/6J mice at 8 weeks of age (20-22 g body weight) were first anaesthetized with pentobarbital sodium (50 mg/kg) via intraperitoneal injection. Then, the left ureter was ligated using 3-0 silk and a left lateral incision.

Ref 1	METTL3-mediated m(6)A modification of TIMP2 mRNA promotes podocyte injury in diabetic nephropathy. Mol Ther. 2022 Apr 6;30(4):1721-1740. doi: 10.1016/j.ymthe.2022.01.002. Epub 2022 Jan 4.
Ref 2	Involvement of Elf3 on Smad3 activation-dependent injuries in podocytes and excretion of urinary exosome in diabetic nephropathy. PLoS One. 2019 May 31;14(5):e0216788. doi: 10.1371/journal.pone.0216788. eCollection 2019.
Ref 3	METTL14-regulated PI3K/Akt signaling pathway via PTEN affects HDAC5-mediated epithelial-mesenchymal transition of renal tubular cells in diabetic kidney disease. Cell Death Dis. 2021 Jan 4;12(1):32. doi: 10.1038/s41419-020-03312-0.
Ref 4	Total Flavones of Abelmoschus manihot Ameliorates Podocyte Pyroptosis and Injury in High Glucose Conditions by Targeting METTL3-Dependent m(6)A Modification-Mediated NLRP3-Inflammasome Activation and PTEN/PI3K/Akt Signaling. Front Pharmacol. 2021 Jul 15;12:667644. doi: 10.3389/fphar.2021.667644. eCollection 2021.
Ref 5	METTL14 aggravates podocyte injury and glomerulopathy progression through N(6)-methyladenosine-dependent downregulating of Sirt1. Cell Death Dis. 2021 Sep 27;12(10):881. doi: 10.1038/s41419-021-04156-y.
Ref 6	FTO-mediated m(6) A modification of SOCS1 mRNA promotes the progression of diabetic kidney disease. Clin Transl Med. 2022 Jun;12(6):e942. doi: 10.1002/ctm2.942.
Ref 7	METTL14 promotes glomerular endothelial cell injury and diabetic nephropathy via m6A modification of Alpha-klotho. Mol Med. 2021 Sep 9;27(1):106. doi: 10.1186/s10020-021-00365-5.
Ref 8	m(6)A-induced lncRNA MALAT1 aggravates renal fibrogenesis in obstructive nephropathy through the miR-145/FAK pathway. Aging (Albany NY). 2020 Mar 23;12(6):5280-5299. doi: 10.18632/aging.102950. Epub 2020 Mar 23.