FOR 1368

Hemodynamic Mechanisms of Acute Kidney Injury

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NF-κB and BMP

Project 6: Molecular physiology and epigenetics of NF-κB/BMP interactions in the post-ischemic kidney

Principal Investigators: Schmidt-Ott, Kai, Prof. Dr.Schmidt-Ullrich, Ruth, Dr. and Müller, Dominik, PD, Dr.

Acute kidney injury (AKI) precipitates the development of chronic kidney disease (CKD). Chronic progression of kidney injury results in tubulo-interstitial fibrosis and microvascular rarefaction, which may perpetuate the injury process via microvascular dysfunction and medullary ischemia. In the first funding period, we addressed the role of NF-κB signaling in AKI and a potential interaction of NF-κB with bone morphogenic protein (BMP), which is known to regulate the repair pathway. Our data indicate that postischemic tubular NF-κB signaling promotes early AKI-induced fibrosis. We also provided evidence that tubular NF-κB signaling up-regulates pro-inflammatory mediators and blocks the constitutive canonical BMP signal in renal tubules. Together, our data suggest that NF-κBmediated BMP suppression in postischemic renal tubules may predispose to the development of interstitial fibrosis, microvascular rarefaction and renal dysfunction (i.e. CKD).
In light of our results, we set out to determine the role of NF-κB and BMP signaling in structural and hemodynamic alterations during CKD progression after AKI. Using mice with tubular-specific inhibition of BMP and NF-κB signaling as well as experimental model systems, we will evaluate the impact of these signals on the progression of AKI to postischemic CKD, including postischemic tubular proliferation, apoptosis, autophagy, cell cycle arrest, microvascular rarefaction and dysfunction, and medullary hypoxia (in line with the unifying hypothesis). Moreover, we hypothesize that epigenetic changes caused by NF-κB and BMP signaling pathways affect the progression from AKI to CKD. To gain detailed molecular insights into the role of NF-κB and BMP signaling in postischemic progression to CKD, we will compare global gene expression profiles, global p65 (canonical NF-κB signaling), RelB/p52 (non-canonical NF-κB signaling) and pSMAD1,5,8 (canonical BMP signaling) DNA occupancy, as well as global profiles of activating and repressive histone modifications in injured and uninjured kidneys with and without genetic manipulation of tubular NF-κB and BMP activity. To translate our findings, we will compare our data to human renal specimens representing diseased and healthy kidneys.

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