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Renal Structure‐Function Relationship in the Obese ZSF1 Rat Model of Diabetic Nephropathy
Author(s) -
Kuo Jay,
Lee Chung Wein,
Qian Hu Sheng,
Fryer Ryan
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.959.5
Subject(s) - glomerulosclerosis , medicine , renal function , proteinuria , diabetic nephropathy , urology , endocrinology , nephropathy , focal segmental glomerulosclerosis , lesion , kidney disease , kidney , diabetes mellitus , pathology
Although the obese ZSF1 rat is a preclinical model of type 2 diabetic nephropathy (DN) with marked renal dysfunction and structural derangement, the course of disease progression has not been evaluated in an age‐dependent manner. This study characterizes temporal changes in renal function relative to changes in proteinuria and glomerular and tubulointerstitial structure to further understand renal disease progression in this model. Male obese ZSF1 rats were aged to 20, 25, 30, 35, or 40 weeks of age. At those times, proteinuria (UPCR) and GFR (anesthetized, FITC‐inulin, kidney weight (KW) normalized) were measured. The left kidney was processed for histopathological analyses of glomerular lesions (% glomerulosclerosis) and tubulointerstitial damage (foci number, interstitial collagen, a‐SMA, KIM‐1, ED‐1+). GFR was steady from 20 to 30 weeks of age (avg 0.71±0.06 mL/min/g KW). At 35 and 40 weeks, GFR declined markedly to 0.29±0.11 and 0.23±0.05 mL/min/g KW, respectively. Glomerulosclerosis increased steadily from 12±1% at 20 weeks to 71±2% by 40 weeks as did UPCR, glomerular lesion severity score, interstitial lesions, a‐SMA, and ED‐1. Interstitial collagen increased modestly from 20 weeks (1.3±0.2%) to 30 weeks (3.7±0.3%) and markedly increased at 35 and 40 weeks, to 8.3±0.6% and 13.3±0.9%, respectively. KIM‐1 increased to 30 weeks (7.5±0.6%) then declined at 40 weeks. In aging obese ZSF1 rats, increased UPCR and glomerulosclerosis occurred prior to the decline in GFR and further increased as GFR fell. The decreased GFR also corresponded with a marked increase in tubulointerstitial fibrosis and injury. These results, consistent with observations in human DN, also support the obese ZSF1 rat as a relevant preclinical model of DN.