Medaka fish, Oryzias latipes, as a model for human obesity-related glomerulopathy

Abstract

Obesity, an ongoing significant public health problem, is a part of complex disease characterized as metabolic syndrome. Medaka and zebrafish are useful aquatic experimental animals widely used in the field of toxicology and environmental health sciences and as a human disease models. In medaka, simple feeding of a high fat diet (HFD) can induce body weight gain, excessive accumulation of visceral adipose tissue, hyperglycemia, hyperlipidemia, and steatohepatitis, which mimics human metabolic syndrome. In the present study, to explore the possibility that the adult medaka fed with HFD (HFD-medaka) can be used as an animal model for human metabolic syndrome-associated glomerular disease, including obesity-related glomerulopathy (ORG), we analyzed structural alterations and protein expression in the mesonephric kidney of HFD-medaka. We found that the histopathology was consistent with glomerulomegaly accompanied by the dilation of glomerular capillaries and proliferative expansion of the mesangium, a condition partially comparable to human ORG. Moreover, expressions of several kinds of kidney disease-related proteins (such as MYH9, SM22α) were significantly elevated. Thus, the HFD-medaka has a high potential as an animal model useful for exploring the mechanism underling human ORG.

Introduction

Medaka, Oryzias latipes, is a freshwater fish native to East Asian countries, primarily Japan, Korea, China, and Taiwan. This small fish is one of the most useful aquatic experimental animals due to its completely sequenced genome, high fecundity, transparency of embryos, and adaptation to a wide range of temperatures [1]. As in zebrafish, researchers can manipulate gene expression in medaka by the use of forward and reverse genetic techniques, and medaka is also widely used in the fields of developmental biology, toxicology, and environmental health sciences [1], [2], [3].

Recently, it was reported that, in adult medaka, simple feeding of a high fat diet (HFD) could induce body weight gain, excess accumulation of visceral adipose tissue, hyperglycemia and hyperlipidemia (both hypertriglyceridemia and hypercholesterolemia) over a relatively short period. In this condition, medaka adult that are fed HFD (HFD-medaka) consistently exhibit a fatty liver and subsequently develop non-alcoholic steatohepatitis (NASH) [4]. Using this system, several useful drugs for NASH were found [4], [5], [6]. In humans, non-alcoholic fat liver disease followed by NASH initially cause chronic liver dysfunction that may later progress to liver cirrhosis and ultimately hepatocellular carcinoma, and thus new guideline of NASH was developed [7].

Obesity and weight control are ongoing important public health problems. Broadly viewed, obesity may be considered part of a complex disease characterized as obesity-initiated metabolic syndrome, which comprises abdominal obesity, hypertriglyceridemia, low HDL cholesterol, hypertension, and hyperglycemia [8], [9]. The HFD-medaka adult exhibits a variety of similar features consistent with those characteristic seen in human metabolic syndrome, and therefore can be utilized as an informative animal model for the disease. Metabolic syndrome is associated with increased prevalence of chronic kidney disease (CKD), and obesity itself is also known to induce obesity-related glomerulopathy (ORG), which is defined by a combination of obesity, glomerular enlargement (glomerulomegaly), and proteinuria with or without nephrotic state [10], [11], [12], [13]. Kambham and colleagues (2001) reported that ORG patients were all associated with glomerulomegaly [14]. Two histological types were identified: glomerulomegaly with or without focal segmental glomerulosclerosis (FSGS), a pathological feature characterized by partial scarring of the glomerular structure.

In the present study, to explore the potential of the HFD-medaka as an animal model for human metabolic syndrome-associated glomerular disease including ORG, we analyzed the histopathology and protein expression in the mesonephric kidney of HFD-medaka. We found these fish demonstrated characteristic histopathology partially compatible to human ORG. Moreover, the expression of several kidney-disease-related proteins were significantly elevated. We thus present the HFD-medaka adult as a new animal model to study human ORG.