The role of hypoxia for the development of diabetic nephropathy : Temporal relationship and involvement of endothelin receptor signaling

Abstract

PrefaceThis thesis is the reflection of me, my work and my experiences. It has mostly been frustration but apparently I managed to stay alive the whole way through.For some it might have seemed easy but I am convinced that a big part has been extreme luck. I don't consider it my skill that it has sometimes run smoothly, because mostly it has been Murphy all over the place. Research is very much about luck. The luck to get the "right" animal batch, the luck to have equipment that isn't broken, the luck to have reviewers who like your paper, the luck that no one interferes with your settings, the luck to actually get results, etc etc. I could go one forever… Anyway, here it is. My work. To be understood or not. AbstractDiabetic nephropathy is one of the most common causes of end stage renal disease and develops in approximately one third of all diabetes patients. Disease progression is characterized by deteriorating glomerular filtration rate and escalating urinary albumin/protein excretion; both are used as clinical markers for disease progression. Recently, it has been proposed that intrarenal hypoxia is a unifying mechanism for chronic kidney disease, including diabetic nephropathy. Several mechanistic pathways have been linked to the development of intrarenal hypoxia and diabetic nephropathy including increased angiotensin II signaling, oxidative stress and hyperglycemia per se. Furthermore, pathological endothelin signaling has recently immerged as a possible contributing factor for chronic kidney disease and diabetic nephropathy. The overall aims of this thesis were therefore to determine the temporal relationship between development of intrarenal hypoxia and kidney disease as well as elucidate the potential link between endothelin signaling, intrarenal hypoxia and kidney disease in experimental insulinopenic diabetes. It is well established that different mouse strains have different susceptibility for kidney and cardiovascular disease. The first step was therefore to compare four commonly used mouse strains with regards to development of kidney disease after onset of insulinopenic diabetes. From the results of this study, we concluded that the NMRI mouse strain has a disease progression closest to the human disease and this strain was chosen in the subsequent studies in mice. The next step was to adapt and optimize a suitable method for repetitive measurements of intrarenal oxygen tension during the course of disease development. Electron paramagnetic resonance (EPR) oximetry had previously been used in tumor biology and was now adapted and optimized for measurements of kidney oxygenation in our diabetic mouse model. EPR oximetry in normoglycemic control mice recorded cortical oxygen tension values similar to previous reports using invasive techniques. Surprisingly, intrarenal hypoxia developed already within the first 72h after induction of hyperglycemia and persisted throughout the two-week study period. Importantly, this was well before albuminuria developed. The final part of this thesis was to invest...

Deficiency of hypoxia inducible factor‑1α promoted progression of diabetic nephropathy with hypertension

“…HIF-1α expression could be induced by hypoxia and was correlated with early progression of some diseases (6). One of the leading causes of DN in diabetes is renal hypoxia (23). Elevated HIF-1α expression in kidney of mice with hypertensive nephropathy and renal fibrosis had been proved to promote the progression of diseases (5,11).…”