Novel signaling pathways in ischemic and hypertensive renal injury

Abstract

Acute kidney injury (AKI) is a common complication in hospitalized patients affecting approximately 10–15% of them and almost 50% of those patients in the intensive care unit. Whereas chronic kidney disease (CKD) - according to the 2010 Global Burden of Disease study - is ranked 18th in the list of causes of the total number of deaths and affects an estimated 800 million people worldwide. Hypertension is the second leading cause of end-stage renal disease and a significant risk factor for developing CKD. Since AKI and both hypertension-associated CKD have limited treatment options (mainly supportive or reduced to treating complications and consequences of renal function loss) there is an urgent need to find therapeutic targets. We developed novel mouse models and applied existing ones to discover and investigate novel signaling pathways and mediators in the kidney that could influence the outcome of ischemic AKI and inflammatory signaling pathways as novel mediators of hypertension-induced chronic renal damage. The presented experimental works shed light on the importance of renal tubular specific activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) as an important initiator of inflammatory processes in the course of AKI. On the other hand, lacking the canonical transient receptor potential 6 (TRPC6) ion channel, which has been recently identified as a cause of a familiar form of focal segmental glomerulosclerosis, or reduced levels of the gasotransmitter hydrogen sulfide, which has been shown to be protective in diverse kidney damage models, did not influence the immediate outcome of AKI. Investigating hypertension-induced renal damage we identified the protein Bcl10 as part of a complex bridging the angiotensin II receptor and NF-kB which mediates cell infiltration and renal fibrosis, on the other hand, indispensable for podocyte health in this model. Finally, we shed light on the role of T helper (Th)1 and Th17 immune cells in the development of angiotensin II-induced target-organ damage.