Hypoxia in Diabetic Kidneys

Abstract

Diabetic nephropathy (DN) is now a leading cause of end-stage renal disease. In addition, DN accounts for the increased mortality in type 1 and type 2 diabetes, and then patients without DN achieve long-term survival compatible with general population. Hypoxia represents an early event in the development and progression of DN, and hypoxia-inducible factor- (HIF-) 1 mediates the metabolic responses to renal hypoxia. Diabetes induces the “fraternal twins” of hypoxia, that is, pseudohypoxia and hypoxia. The kidneys are susceptible to hyperoxia because they accept 20% of the cardiac output. Therefore, the kidneys have specific vasculature to avoid hyperoxia, that is, AV oxygen shunting. The NAD-dependent histone deacetylases (HDACs) sirtuins are seven mammalian proteins, SIRTs 1–7, which are known to modulate longevity and metabolism. Recent studies demonstrated that some isoforms of sirtuins inhibit the activation of HIF by deacetylation or noncatalyzing effects. The kidneys, which have a vascular system that protects them against hyperoxia, unfortunately experience extraordinary hypernutrition today. Then, an unexpected overload of glucose augments the oxygen consumption, which ironically results in hypoxia. This review highlights the primary role of HIF in diabetic kidneys for the metabolic adaptation to diabetes-induced hypoxia.

Involvement of the metabolic sensor GPR81 in cardiovascular control

“…Locally in the kidney, vasoconstriction in response to physiological or pathophysiological GPR81 agonism seems incompatible with blood flow autoregulation and tissue survival. Thus, an accumulation of lactate might worsen ischemic damage, especially if glomerular filtration rate, the major determinant of kidney metabolic rate and oxygen demand (47), remains unchanged. In line with this, chronic hypoxia in the tubulointerstitium of the kidney is thought to be a driver of impaired glomerular function and fibrosis leading to the development of end-stage renal disease (48).…”

The role of hypoxia and Morg1 in renal injury

“…Taken together, the therapeutic short activation of HIF may be protective for kidneys by switching from oxidative phosphorylation to glycolysis, accompanied by decreased oxygen consumption, suppressed ROS production and minimum ATP production . In contrast, it is possible that chronic activation of HIF may not have therapeutic potential for treatment of for example DN, because HIF would consistently mediate hypoxia‐caused cell injury via the HIF‐downstream molecules . Friederich‐Persson et al .…”

Should we use gait speed in COPD, FEV1in frailty and dyspnoea in both?

“…As a result, the function of many organs or systems, including the kidneys, central nervous system, cardiovascular system, skeletal muscles and even the immune system, are affected by chronic hypoxic insult [38]. This might explain some of the links between impaired lung function and extrathoracic organ disorders [39]. Hypoxia has pervasive effects on the function of adipocytes and appears to be a key factor in adipose tissue dysfunction in obesity [40].…”