title: Original Research: Potential of urinary nephrin as a biomarker reflecting podocyte dysfunction in various kidney disease models.
abstract: Urinary nephrin is a potential non-invasive biomarker of disease. To date, however, most studies of urinary nephrin have been conducted in animal models of diabetic nephropathy, and correlations between urinary nephrin-to-creatinine ratio and other parameters have yet to be evaluated in animal models or patients of kidney disease with podocyte dysfunction. We hypothesized that urinary nephrin-to-creatinine ratio can be up-regulated and is negatively correlated with renal nephrin mRNA levels in animal models of kidney disease, and that increased urinary nephrin-to-creatinine ratio levels are attenuated following administration of glucocorticoids. In the present study, renal nephrin mRNA, urinary nephrin-to-creatinine ratio, urinary protein-to-creatinine ratio, and creatinine clearance ratio were measured in animal models of adriamycin nephropathy, puromycin aminonucleoside nephropathy, anti-glomerular basement membrane glomerulonephritis, and 5/6 nephrectomy. The effects of prednisolone on urinary nephrin-to-creatinine ratio and other parameters in puromycin aminonucleoside (single injection) nephropathy rats were also investigated. In all models tested, urinary nephrin-to-creatinine ratio and urinary protein-to-creatinine ratio increased, while renal nephrin mRNA and creatinine clearance ratio decreased. Urinary nephrin-to-creatinine ratio exhibited a significant negative correlation with renal nephrin mRNA in almost all models, as well as a significant positive correlation with urinary protein-to-creatinine ratio and a significant negative correlation with creatinine clearance ratio. Urinary protein-to-creatinine ratio exhibited a significant negative correlation with renal nephrin mRNA. Following the administration of prednisolone to puromycin aminonucleoside (single injection) nephropathy rats, urinary nephrin-to-creatinine ratio was significantly suppressed and exhibited a significant positive correlation with urinary protein-to-creatinine ratio. In addition, the decrease in number of glomerular Wilms tumor antigen-1-positive cells was attenuated, and urinary nephrin-to-creatinine ratio exhibited a significant negative correlation in these cells. In conclusion, these results suggest that urinary nephrin-to-creatinine ratio level is a useful and reliable biomarker for predicting the amelioration of podocyte dysfunction by candidate drugs in various kidney disease models with podocyte dysfunction. This suggestion will also be validated in a clinical setting in future studies.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tasukuba-shi, Ibaraki 3058585, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Wada
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tasukuba-shi, Ibaraki 3058585, Japan masaki.abe@astellas.com.
authors.forename: Masaki
authors.initials: M
authors.lastname: Abe
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tasukuba-shi, Ibaraki 3058585, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Moritani
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tasukuba-shi, Ibaraki 3058585, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Mitori
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tasukuba-shi, Ibaraki 3058585, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kondo
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tasukuba-shi, Ibaraki 3058585, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Tanaka-Amino
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tasukuba-shi, Ibaraki 3058585, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Eguchi
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tasukuba-shi, Ibaraki 3058585, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Imasato
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tasukuba-shi, Ibaraki 3058585, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Inoki
authors.affiliation: Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Moroyama 3500495, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kajiyama
authors.affiliation: Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Moroyama 3500495, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Mimura
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tasukuba-shi, Ibaraki 3058585, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tomura
mesh_terms: D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000503:physiopathology / Q000652:urine; D015415:Biomarkers / Q000652:urine; D003404:Creatinine / Q000652:urine; D003928:Diabetic Nephropathies / Q000503:physiopathology / Q000652:urine; D004317:Doxorubicin / Q000494:pharmacology; D007674:Kidney Diseases / Q000139:chemically induced / Q000503:physiopathology* / Q000652:urine; D008297:Male; D008565:Membrane Proteins / Q000652:urine*; D051379:Mice; D008807:Mice, Inbred BALB C; D050199:Podocytes / Q000502:physiology*; D011692:Puromycin Aminonucleoside / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D015415:Biomarkers; D008565:Membrane Proteins; C113267:nephrin; D011692:Puromycin Aminonucleoside; D004317:Doxorubicin; D003404:Creatinine
keywords: Podocyte; animal; biomarkers; disease; models; renal