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Connectivity mapping of a chronic kidney disease progression signature identified lysine deacetylases as novel therapeutic targets

ABSTRACT: Motivation and design: Renal tubulointerstitial injury is an important determinant of chronic kidney disease (CKD) progression, yet treatment is limited to renin angiotensin system blockade. Accordingly, we performed global expression profiling in a 2 × 2 factorial design (N = 8 in each group) on RNA extracted from male Col4a3–/– mice and littermate controls on a 129X1/SvJ background at 4 and 7 weeks of age. Col4a3–/– mice have a mutation in the gene encoding the α3 chain of type IV collagen, associated with proteinuria and progressive loss of kidney function. We analyzed expression with Affymetrix GeneChip Mouse Gene 2.0 ST Arrays and derived a novel CKD progression signature based on aging and disease in Col4a3–/– mice. Using our progression signature, we sought to repurpose existing drugs for the treatment of progressive CKD. Results: Computational drug repurposing with the Connectivity Map identified lysine deacetylase inhibitor, vorinostat, as a novel candidate treatment for this murine model of CKD. Treatment with vorinostat attenuated tubulointerstitial injury, fibrosis, and altered inflammation. Vorinostat administration significantly increased the lifespan of Col4a3–/– mice although effects on urinary albumin excretion, plasma creatinine, and blood urea nitrogen were modest. Conclusions: Our data suggest that expression profiling and computational drug repurposing can be used to identify novel drugs that may reverse gene expression changes in experimental CKD. Lysine deacetylase inhibition may be a novel treatment approach to CKD associated with proteinuria and progressive tubulointerstitial injury.

ORGANISM(S): Mus musculus

PROVIDER: GSE137086 | GEO | 2020/01/31

REPOSITORIES: GEO

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Project description:Evolution of glomerulonephritis (GN) to tubulointerstitial disease is a universal antecedent to the development of chronic kidney disease (CKD). There is also evidence that angiotensin converting enzyme (ACE) inhibition may attenuate the development of CKD in some forms of glomerulonephritis. We tested the role of ACE inhibition in a model of GN in which complement-dependent tubulointerstitial disease develops. GN was induced in C57BL/6 mice with intraperitoneal injections of horse spleen apoferritin (HSA) using lipopolysaccharide (LPS) as an adjuvant. Four groups of six animals were studied: saline-injected control mice treated with captopril or water, and GN mice treated with captopril or water. GN developed in all HSA-treated animals. In those receiving captopril, however, proteinuria (albumin/creatinine ratio) was significantly reduced by captopril treatment. Array screening was used to examined the expression of collagen-related genes and determine if these effects could be mediated by regulation of collagen genes. Six genes were identified for further analysis by quantitative RT-PCR. This model demonstrates that tubulointerstitial disease can be attenuated by ACE inhibition, with clinical, histologic, and gene expression measures. All protocols were approved by the Institutional Animal Care and Use Committee at SUNY Upstate Medical University. We employed four groups of six mice each: saline-injected control mice with and without captopril, and GN with and without captopril. C57BL/6 mice were purchased from The Jackson Laboratories (Bar Harbor, ME). Glomerulonephritis (GN) was induced by intraperitoneal (i.p.) injection of 10 mg of apoferritin from horse spleen (HSA, Sigma, St. Louis, MO) five days per week, with i.p. injection of 100 micrograms lipopolysaccharide (LPS, from Salmonella minnesota; EMD Biosciences, La Jolla, CA), as adjuvant, three times per week. Control animals received equal volumes of 0.15 M NaCl by i.p. injection. Injections were begun when the mice were approximately eight weeks of age and were continued for six weeks. Captopril, at 100 mg/kg/day was given in the drinking water. After 9 weeks, the animals were euthanized and kidneys were removed for RNA purification and analysis.

Project description:Proteinuria is the most important predictor of outcome in glomerulonephritis and experimental data suggest that the tubular cell response to proteinuria is an important determinant of progressive fibrosis in the kidney. However, it is unclear whether proteinuria is a marker of disease severity or has a direct effect on tubular cells in the kidneys of patients with glomerulonephritis. Accordingly we studied an in vitro model of proteinuria, and identified 231 albumin-regulated genes differentially expressed by primary human kidney tubular epithelial cells exposed to albumin. We translated these findings to human disease by studying mRNA levels of these genes in the tubulo-interstitial compartment of kidney biopsies from patients with IgA nephropathy using microarrays. Biopsies from patients with IgAN (n=25) could be distinguished from those of control subjects (n=6) based solely upon the expression of these 231 albumin-regulated genes. The expression of an 11-transcript subset related to the degree of proteinuria, and this 11-mRNA subset was also sufficient to distinguish biopsies of subjects with IgAN from control biopsies. We tested if these findings could be extrapolated to other proteinuric diseases beyond IgAN and found that the all forms of primary glomerulonephritis (n=33) can be distinguished from controls (n=21) based solely on the expression levels of these 11 genes derived from our in vitro proteinuria model. Pathway analysis suggests common regulatory elements shared by these 11 transcripts. In conclusion, we have identified an albumin-regulated 11-gene signature shared between all forms of primary glomerulonephritis. Our findings support the hypothesis that albuminuria may directly promote injury in the tubulo-interstitial compartment of the kidney in patients with glomerulonephritis. We used microarrays to analyze the transcriptome of microdissected renal biopsies from patients with IgA nephropathy (IgAN) RNA from tubulointerstitial compartments was extracted and processed for hybridization on Affymetrix HG-U133A microarrays.

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Connectivity mapping of a chronic kidney disease progression signature identified lysine deacetylases as novel therapeutic targets

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