Unbiased Human Kidney Tissue Proteomics Identifies Matrix Metalloproteinase 7 as a Kidney Disease Biomarker

Abstract

Significance Statement Although gene expression changes have been characterized in human diabetic kidney disease (DKD), unbiased tissue proteomics information for this condition is lacking. The authors conducted an unbiased aptamer-based proteomic analysis of samples from patients with DKD and healthy controls, identifying proteins with levels that associate with kidney function (eGFR) or fibrosis, after adjusting for key covariates. Overall, tissue gene expression only modestly correlated with tissue protein levels. Kidney protein and RNA levels of matrix metalloproteinase 7 (MMP7) strongly correlated with fibrosis and with eGFR. Single-cell RNA sequencing indicated that kidney tubule cells are an important source of MMP7. Furthermore, plasma MMP7 levels predicted future kidney function decline. These findings identify kidney tissue MMP7 as a biomarker of fibrosis and blood MMP7 as a biomarker for future kidney function decline. Background Diabetic kidney disease (DKD) is responsible for close to half of all ESKD cases. Although unbiased gene expression changes have been extensively characterized in human kidney tissue samples, unbiased protein-level information is not available. Methods We collected human kidney samples from 23 individuals with DKD and ten healthy controls, gathered associated clinical and demographics information, and implemented histologic analysis. We performed unbiased proteomics using the SomaScan platform and quantified the level of 1305 proteins and analyzed gene expression levels by bulk RNA and single-cell RNA sequencing (scRNA-seq). We validated protein levels in a separate cohort of kidney tissue samples as well as in 11,030 blood samples. Results Globally, human kidney transcript and protein levels showed only modest correlation. Our analysis identified 14 proteins with kidney tissue levels that correlated with eGFR and found that the levels of 152 proteins correlated with interstitial fibrosis. Of the identified proteins, matrix metalloprotease 7 (MMP7) showed the strongest association with both fibrosis and eGFR. The correlation between tissue MMP7 protein expression and kidney function was validated in external datasets. The levels of MMP7 RNA correlated with fibrosis in the primary and validation datasets. Findings from scRNA-seq pointed to proximal tubules, connecting tubules, and principal cells as likely cellular sources of increased tissue MMP7 expression. Furthermore, plasma MMP7 levels correlated not only with kidney function but also associated with prospective kidney function decline. Conclusions Our findings, which underscore the value of human kidney tissue proteomics analysis, identify kidney tissue MMP7 as a diagnostic marker of kidney fibrosis and blood MMP7 as a biomarker for future kidney function decline.

Multiomics Analyses Identify AKR1A1 as a Biomarker for Diabetic Kidney Disease

“…The Mendeley data set contained 33 human kidney cortical samples: 23 samples from patients with DKD and 10 from healthy participants ( https://data.mendeley.com/datasets/83k89shdx5/ ). Detailed demographics of the study sample have been described previously ( 4 ). Differential protein expression results show that AKR1A1 levels were significantly lower in patients with DKD compared with healthy control participants (FDR = 0.029; log 2 FC = −0.61; see Supplementary Table 1 ).…”

“…Recently, Hirohama et al. ( 4 ) identified, via unbiased human kidney tissue proteomics, matrix metalloproteinase 7 (MMP7) as a diagnostic marker of kidney fibrosis and blood MMP7 as a biomarker for future kidney function decline in patients with DKD.…”

Matrix Metalloproteinase-7 in Urinary Extracellular Vesicles Identifies Rapid Disease Progression in Autosomal Dominant Polycystic Kidney Disease

“…[40][41][42][43] A recent kidney tissue proteomics study identified MMP-7 as a kidney disease biomarker that correlated with fibrosis and predicted faster eGFR decline. 44 The role of MMP-7 in kidney disease appears to be multifactorial. MMP-7 knockout mice show reduced collagen deposition, reduced interstitial fibrosis, but increased albuminuria.…”

NR5A2 promotes epithelial-to-mesenchymal transition in renal fibrosis by targeting MMP25 transcription

“…Matrix metalloproteinases (MMPs), pivotal in processes such as development, inflammation, tissue repair, and angiogenesis, contribute to renal TIF through mechanisms involving EMT and TGF-β signaling pathways 6,7 . Specifically, MMP-7 and MMP-9 facilitate extracellular matrix remodeling [8][9][10] . Sato et al first identified membrane type matrix metalloproteinases(MT-MMP), and believed that they have a dual effect of activate other MMPs and degrade the extracellular matrix 11,12 .…”