Abstract
The aim of this study was to investigate if urinary glutamyl aminopeptidase (GluAp), alanyl aminopeptidase (AlaAp), Klotho and hydroxyproline can be considered as potential biomarkers of renal injury and fibrosis in an experimental model of obesity. Male Zucker lean (ZL) and obese (ZO) rats were studied from 2 to 8 months old. Kidneys from ZO rats at the end of the study (8 months old) developed mild focal and segmental glomerulosclerosis as well as moderate tubulointerstitial injury. Urinary excretion of Klotho was higher in ZO rats at 2, 5, and 8 months of study, plasma Klotho levels were reduced and protein abundance of Klotho in renal tissue was similar in ZL and ZO rats. GluAp and AlaAp urinary activities were also increased in ZO rats throughout the time-course study. ZO rats showed an augmentation of hydroxyproline content in renal tissue and a significant increase of tubulointerstitial fibrosis. Correlation studies demonstrated that GluAp, AlaAp, and Klotho are early diagnostic markers of renal lesions in Zucker obese rats. Proteinuria and hydroxyproline can be considered delayed diagnostic markers because their contribution to diagnosis starts later. Another relevant result is that GluAp, AlaAp, and Klotho are related not only with diagnosis but also with prognosis of renal lesions in Zucker obese rats. Moreover, strong predictive correlations of aminopeptidasic activities with the percentage of renal fibrosis or with renal hydroxyproline content at the end of the experiment were observed, indicating that an early increased excretion of these markers is related with a higher later extent of fibrosis in Zucker obese rats. In conclusion, GluAp, AlaAp, and Klotho are early diagnostic markers that are also related with the extent of renal fibrosis in Zucker obese rats. Therefore, they have a potential use not only in diagnosis, but also in prognosis of obesity-associated renal lesions.
Highlights
The Zucker obese rat is an experimental model that mimicked diabetes type II in human (de Artinano and Castro, 2009)
Tubulointerstitial injury was defined as inflammatory cell infiltrates, tubular dilation and/or atrophy, tubular casts or interstitial fibrosis, and tubular atrophy, tubular casts, and chronic inflammatory infiltrate were statistically significant increased in ZO rats (Table 2 and Figure 1)
This study shows that urinary aminopeptidases and urinary Klotho correlates with the morphological changes observed in the renal injury of the ZO rats analyzed at the end of the experimental period
Summary
The Zucker obese rat is an experimental model that mimicked diabetes type II in human (de Artinano and Castro, 2009) This model results from an autosomal recessive mutation of the fa-gene, en coding the leptin receptor; and courses with obesity, insulin resistance, dyslipidemia, mild glucose intolerance and renal injury, whereas the Zucker lean rat is lacking of leptin receptor mutation and of metabolic and renal abnormalities. Enzymes released from damaged tubular cells and excreted into urine are the most promising biomarkers for an early detection of kidney injury. They have an obvious diagnostic benefit because their measurements may provide detailed information about the nature, size and site of the damage to tubular cells and their possible necrosis or dysfunction (Lisowska-Myjak, 2010). Alanyl aminopeptidase (AlaAp, EC3.4.11.2), and glutamyl aminopeptidase (GluAp, EC 3.4.11.7) are present in the renal tubular cells (Kenny and Maroux, 1982; Song et al, 1994; Albiston et al, 2011) and exert its aminopeptidasic activity in the renal angiotensin II metabolism, factor that is activated in renal injury of diabetic rodents and humans (Gagliardini et al, 2013)
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