Acute renal failure is thought to be largely reversible if the patient survives the initial insult. Patients following recovery from ARF may be susceptable to progressive renal disease, although this is not commonly observed. In contrast, ischemic injury in a transplanted kidney can result in delayed graft function (DGF) which is a clearly a risk factor for long-term graft demise. To understand more clearly the nature of the relationship between acute renal injuries and progressive nephropathies, we have studied rats following recovery from either unilateral or bilateral ischemia/reperfusion injury and showed that there is a permanent alteration in the structure of renal per/tubular capillaries. We hypothesize that a reduction in renal per/tubular capillaries alters renal function and predisposes the development of chronic renal disease. This application is directed toward elucidating the physiological and pathophysiological implications of acute injuries and to decipher possible mechanims by which renal per/tubular capillaries are lost following acute insults.
In specific aim #1, we will explore further the ramification of acute injury on long-term renal function. In this aim, we will investigate alterations in renal pO2 using BOLD MRI. In addition, we will determine if nephrotoxic (e.g., cyclosporine) injury can affect per/tubular capillaries in a fashion similar to that observed with I/R injury. We will also determine if post-ischemic recovered animals have are affected in their renal Na handling abilities and develop salt-sensitive hypertension. We will also determine whether potential intervential therapies (ACE/, VEGF) affect I/R induced changes in renal capillary density, renal hypoxia and/or the progression of chronic renal disease. Finally, we will analyze gene expression patterns in recovered kidneys to gain insight into the potential mechanisms of chronic renal failure following acute injury.
In Specific Aim #2, we will perform experiments geared toward understanding the mechanims of blood vessel loss following injury. In this aim, we will characterize the expression of several angiogenic and antiangiogenic molecules in response to I/R injury. The second aspect of this aim is geared toward deciphering the role and regulation of angiostatin using different strains of knockout mice or newly acquired metalloprotease inhibitors.
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