The endothelial TM-PC system regulates tubular senescence and regeneration via p21 in diabetic nephropathy

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The endothelial TM-PC system regulates tubular senescence and regeneration via p21 in diabetic nephropathyDiabetic nephropathy (dNP) is the leading cause of end stage renal disease in industrialized countries. Tubulointerstitial fibrosis predicts the decline of renal function better then glomerulosclerosis. The pathomechanisms of tubular injury remain, however, largely unknown, hampering the development of new therapeutic approaches. The latter reflects in part the lack of suitable animal models. We developed a mouse model, diabetic mice with reduced levels of the endothelial cell dependent serine protease activated protein C (aPC, a cytoprotective and anticoagulant protease), which develop marked tubulointerstitial fibrosis if diabetic, enabling us to study mechanisms regulating diabetic tubulointerstitial fibrosis. Preliminary work identified increased expression of p21 and increased tubular senescence in these mice. In vitro studies demonstrate that aPC regulates p21 expression and tubular senescence. Tubular p21 expression is epigenetic regulated, thus potentially contributing to the metabolic memory. Importantly, restoring aPC-dependent signalling can reverse these changes, demonstrating that this pathomechanisms is therapeutically amendable. Based on these results we hypothesize that endothelial dysfunction and loss aPC causes sustained p21 expression and tubular senescence, thus impairing the re-generative tubular capacity in dNP. We hypothesize that this will aggravate chronic tubular injury, but also impair tubular repair after an acute renal injury in pre-existing dNP (acute on chronic kidney injury). The aPC-dependent regulation of tubular senescence and hence tubular regeneration would provide a new framework linking endothelial dysfunction and tubular injury and would provide a unifying mechanism underlying the chronic tubular injury as well as the impaired tubular regeneration after acute kidney injury in dNP. To evaluate the proposed mechanism we intend to address the following aims: Aim 1: Delineate the mechanistic interaction of aPC and p21 in controlling tubular cell proliferation and repair in dNP.Aim 2: Define the mechanistic relevance of hyperglycaemia induced and sustained tubular p21 expression for impaired outcome following acute renal injury.Aim 3: Identify the mechanism through which aPC restricts p21 expression.