Dataset Information

Proteomics of obstructed kidneys from patients with obstructive nephropathy and unilateral ureteral obstruction mice

ABSTRACT: Here, we performed proteomics of kidneys obtained from patients with obstructive nephropathy and healthy controls (n=11/8), or from unilateral ureteral obstruction (UUO) mice and sham mice (n=6/6). Proteomic measurement of all human kidney samples resulted in a total of 6089 proteins with an average of 5780 proteins per sample. Compared to control kidneys, 614 proteins were up-regulated and 855 proteins were down-regulated (p value < 0.05, q value < 0.05, and fold change > 2 or < 0.5) in human obstructed kidneys. The up-regulated proteins were significantly enriched in collagen formation and immune response. Moreover, the human and mouse kidney proteomics reveled an aberrant NAD+ metabolism and NAD+-related metabolic pathways, including mitochondrial dysfunction, oxidative phosphorylation, and tryptophan metabolism. The expression patterns of several key enzymes catalyzing NAD+ biosynthesis and consumption were dramatically altered in obstructive nephropathy. Moreover, the major NAD+ consumer CD38 was strongly induced in obstructed kidneys which contributed to the decline of renal NAD+ levels. Functional studies demonstrated that CD38 deletion or inhibition significantly recovered renal NAD+ levels and reduced obstruction-induced renal fibrosis.

ORGANISM(S): Homo Sapiens Mus Musculus

SUBMITTER: Fuquan Yang

PROVIDER: PXD039314 | iProX | Sun Jan 08 00:00:00 GMT 2023

REPOSITORIES: iProX

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Publications

Comprehensive Proteomics Analysis Identifies CD38-Mediated NAD<sup>+</sup> Decline Orchestrating Renal Fibrosis in Pediatric Patients With Obstructive Nephropathy.

Tao Yuandong Y Wang Jifeng J Lyu Xuexue X Li Na N Lai Dong D Liu Yuanyuan Y Zhang Xingyue X Li Pin P Cao Shouqing S Zhou Xiaoguang X Zhao Yang Y Ma Lifei L Tao Tian T Feng Zhichun Z Li Xiubin X Yang Fuquan F Zhou Huixia H

Molecular & cellular proteomics : MCP 20230217 3

Obstructive nephropathy is one of the leading causes of kidney injury and renal fibrosis in pediatric patients. Although considerable advances have been made in understanding the pathophysiology of obstructive nephropathy, most of them were based on animal experiments and a comprehensive understanding of obstructive nephropathy in pediatric patients at the molecular level remains limited. Here, we performed a comparative proteomics analysis of obstructed kidneys from pediatric patients with uret ...[more]

PMID: 36804530

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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. Animal studies: All animal studies were approved by the IACUC committee of Mount Sinai School of Medicine. HIV-1 transgenic mice, Tg26, and their littermates were generated and genotyped as described. Only male heterozygous Tg26 in the FVB/N background were used in the study, because homozygous HIV-transgenic mice are not viable for more than few weeks postnatally. UUO and folic acid-induced nephropathy models were created as described . Mice were grouped as wild type, Tg26 with mild kidney injury, Tg26, with serious kidney injury. The kidneys were collected from these mice for histology, western blot, real-time PCR analysis, and microarray studies. Kidney disease was confirmed by measurement of proteinuria, renal function, and histologic analysis. Microarray studies: Affymetrix gene expression microarrays were performed at the Mount Sinai Institution Microarray Core Facility. The Affymetrix GeneChip® Mouse Genome 430 2.0 Array was used to profile gene expression in the kidney cortex of Tg26 and WT mice 37. One-way analysis of variance test (ANOVA) was applied to the dataset to identify the genes that were differentially expressed between the two groups. P-values were corrected using Benjamini–Hochberg false discovery rate (FDR) with a threshold of 0.05.

Dataset Information

Proteomics of obstructed kidneys from patients with obstructive nephropathy and unilateral ureteral obstruction mice

Publications

Comprehensive Proteomics Analysis Identifies CD38-Mediated NAD<sup>+</sup> Decline Orchestrating Renal Fibrosis in Pediatric Patients With Obstructive Nephropathy.

Similar Datasets

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