Growth hormone (GH)-transgenic insulin-like growth factor 1 (IGF1)-deficient mice allow dissociation of excess GH and IGF1 effects on glomerular and tubular growth.

Andreas Blutke,Marlon R Schneider,Eckhard Wolf,Rüdiger Wanke

doi:10.14814/phy2.12709

Abstract

Growth hormone (GH)‐transgenic mice with permanently elevated systemic levels of GH and insulin‐like growth factor 1 (IGF1) reproducibly develop renal and glomerular hypertrophy and subsequent progressive glomerulosclerosis, finally leading to terminal renal failure. To dissociate IGF1‐dependent and ‐independent effects of GH excess on renal growth and lesion development in vivo, the kidneys of 75 days old IGF1‐deficient (I −/−) and of IGF1‐deficient GH‐transgenic mice (I −/− /G), as well as of GH‐transgenic (G) and nontransgenic wild‐type control mice (I +/+) were examined by quantitative stereological and functional analyses. Both G and I −/− /G mice developed glomerular hypertrophy, hyperplasia of glomerular mesangial and endothelial cells, podocyte hypertrophy and foot process effacement, albuminuria, and glomerulosclerosis. However, I −/− /G mice exhibited less severe glomerular alterations, as compared to G mice. Compared to I +/+ mice, G mice exhibited renal hypertrophy with a significant increase in the number without a change in the size of proximal tubular epithelial (PTE) cells. In contrast, I −/− /G mice did not display significant PTE cell hyperplasia, as compared to I −/− mice. These findings indicate that GH excess stimulates glomerular growth and induces lesions progressing to glomerulosclerosis in the absence of IGF1. In contrast, IGF1 represents an important mediator of GH‐dependent proximal tubular growth in GH‐transgenic mice.

Highlights

During the last decades, a significant role of the growth hormone (GH) and insulin-like growth factor 1 (IGF1) system in kidney development and function, and in the pathogenesis of chronic kidney diseases (CKD) and their sequelae, has become apparent (Wolf et al 2000; Schrijvers et al 2004; Mak et al 2008; Kumar et al 2011; Kamenicky et al 2014; Bach and Hale 2015)
The formal pathogenesis of progressive glomerulosclerosis in Growth hormone (GH)-transgenic mice has been well characterized, the exact mechanisms inducing stimulation of renal and glomerular growth, glomerular and podocyte hypertrophy, mesangial and endothelial hyperplasia, and the well-known subsequent renal lesion patterns seen in GH-transgenic mice are yet not fully understood
GH stimulates the release of predominantly liver-derived IGF1 into the circulation, elevated systemic IGF1 levels are not essential for mediation of GH-induced IGF1-dependent growth-promoting actions (Yakar et al 1999; Le Roith et al 2001), since several, if not the majority, of the growth-stimulating effects of IGF1 are mediated by locally produced IGF1, acting in an autocrine or paracrine fashion (Le Roith et al 2001; Stratikopoulos et al 2008)

Summary

Introduction

A significant role of the growth hormone (GH) and insulin-like growth factor 1 (IGF1) system in kidney development and function, and in the pathogenesis of chronic kidney diseases (CKD) and their sequelae, has become apparent (Wolf et al 2000; Schrijvers et al 2004; Mak et al 2008; Kumar et al 2011; Kamenicky et al 2014; Bach and Hale 2015). In different entities of CKD, including diabetic nephropathy (DN), progressive glomerulosclerosis is the common histopathological feature, and is regarded as the determining mechanism driving the progressive loss of functioning nephrons and subsequent renal scarring, leading to terminal renal failure (Klahr et al 1988; Fogo and Ichikawa 1989, 1991; el Nahas 1989). Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society

Methods

Results

Conclusion