Tipping the balance from angiogenesis to fibrosis in CKD

Abstract

Chronic progressive renal fibrosis leads to end-stage renal failure many patients with chronic kidney disease (CKD). Loss of the rich peritubular capillary network is a prominent feature, and seems independent of the specific underlying disease. The mechanisms that contribute to peritubular capillary regression include the loss of glomerular perfusion, as flow-dependent shear forces are required to provide the survival signal for endothelial cells. Also, reduced endothelial cell survival signals from sclerotic glomeruli and atrophic or injured tubule epithelial cells contribute to peritubular capillary regression. In response to direct tubular epithelial cell injury, and the inflammatory reaction that ensues, capillary pericytes dissociate from their blood vessels, also reducing endothelial cell survival. In addition, direct inflammatory injury of capillary endothelial cells, for instance in chronic allograft nephropathy, also contributes to capillary dropout. Chronic tissue hypoxia, which ensues from the rarefaction of the peritubular capillary network, can generate both an angiogenic and a fibrogenic response. However, in CKD, the balance is strongly tipped toward fibrogenesis. Understanding the underlying mechanisms for failed angiogenesis in CKD and harnessing endothelial-specific survival and pro-angiogenic mechanisms for therapy should be our goal if we are to reduce the disease burden from CKD.

Renal Aging: Causes and Consequences

“…In experimental CKD, the expected angiogenic response to hypoxia fails, instead resulting in fibrosis. 111 Increased renal hypoxia has also been shown throughout aged rat kidneys, most prominently in the cortical zones, as detected by use of the hypoxia-sensitive marker pimonidazole. 112 Aged rat kidneys show decreased VEGF globally and increased antiangiogenic thrombospondin-1, resulting in capillary loss with increased glomerular sclerosis.…”

View from the heart: cardiac fibroblasts in development, scarring and regeneration

“…Fibrosis is a common cause of organ failure in many disease settings, including idiopathic pulmonary fibrosis (Spagnolo et al, 2015), liver cirrhosis (Schuppan, 2015), kidney disease (Ballermann and Obeidat, 2014) and systemic sclerosis (Ebmeier and Horsley, 2015), among others. It is predicted that nearly 45% of all deaths in the developed world are related to chronic fibrosis (Wynn, 2008).…”

Galectin‐3 contributes to vascular fibrosis in monocrotaline‐induced pulmonary arterial hypertension rat model

“…Vascular fibrosis is a hallmark feature of aging, hypertension, and chronic kidney disease . Vascular remodeling involves alterations in cell phenotypes, cell hypertrophy, and accumulation of extracellular matrix (ECM) in pulmonary hypertension .…”