Renal injury is accelerated by global hypoxia-inducible factor 1 alpha deficiency in a mouse model of STZ-induced diabetes

Gabriela Pavlinkova,Romana Bohuslavova,Katerina Nepomucka,Radka Cerychova

doi:10.1186/s12902-017-0200-8

Abstract

BackgroundHypoxia inducible factor 1 (HIF-1) activates protective pathways to counteract hypoxia and prevent tissue damage in conjunction with renal injury. The aim of this study was to evaluate a role of HIF-1 in diabetes-induced kidney damage.MethodsWe used a streptozotocin-induced diabetes mouse model and compared biochemical, histological and molecular parameters associated with kidney damage in Hif1α deficient (Hif1α+/-) and wild-type mice.ResultsWe showed that Hif1α deficiency accelerated pathological changes in the early stage of DN. Six weeks after diabetes-induction, Hif1α deficient mice showed more prominent changes in biochemical serum parameters associated with glomerular injury, increased expression of podocyte damage markers, and loss of podocytes compared to wild-type mice. These results indicate that Hif1α deficiency specifically affects podocyte survival in the early phase of DN, resulting in diabetic glomerular injury. In contrast, renal fibrosis was not affected by the global reduction of Hif1α, at least not in the early phase of diabetic exposure.ConclusionsTogether our data reveal that HIF-1 has an essential role in the early response to prevent diabetes-induced tissue damage and that impaired HIF-1 signaling results in a faster progression of DN. Although the modulation of HIF-1 activity is a high-priority target for clinical treatments, further study is required to investigate HIF-1 as a potential therapeutic target for the treatment of DN.

Highlights

Hypoxia inducible factor 1 (HIF-1) activates protective pathways to counteract hypoxia and prevent tissue damage in conjunction with renal injury
To provide more insight into the functional role of HIF-1α pathways, we examine the relationship between diabetes-induced kidney injury and the partial deficiency of HIF-1α caused by the global deletion of the Hif1α functional allele with a specific focus on the early phase of diabetes-exposure
Increased serum levels of creatinine and phosphorus, and decreased serum levels of albumin are the first markers of kidney damage due to high glucose concentrations [4]

Summary

Introduction

Hypoxia inducible factor 1 (HIF-1) activates protective pathways to counteract hypoxia and prevent tissue damage in conjunction with renal injury. The aim of this study was to evaluate a role of HIF-1 in diabetes-induced kidney damage. Clinical features of DN are progressive albuminuria, proteinuria, and an eventual reduction in the glomerular filtration rate [1]. The complex progressive histopathological changes associated with DN include mesangial matrix expansion, thickening of basement membranes, glomerular and tubular hypertrophy, podocyte loss, and glomerulosclerosis and tubulointerstitial fibrosis [2]. A master regulator of transcriptional responses to hypoxia is hypoxia inducible factor 1 (HIF-1). HIF-1 has been recently associated with the progression of chronic renal injuries including DN [4,5,6]. HIF-1 directly regulates the expression of more than 1000 human genes

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