Renoprotective effects of hepatocyte growth factor in the stenotic kidney

Abstract

Stewart N, Chade AR. Renoprotective effects of hepatocyte growth factor in the stenotic kidney. Am J Physiol Renal Physiol 304: F625-F633, 2013. First published December 26, 2012 doi:10.1152/ajprenal.00504.2012 damage and loss contribute to the progression of renal injury in renal artery stenosis (RAS). Hepatocyte growth factor (HGF) is a powerful angiogenic and antifibrotic cytokine that we showed to be decreased in the stenotic kidney. We hypothesized that renal HGF therapy will improve renal function mainly by protecting the renal microcirculation. Unilateral RAS was induced in 15 pigs. Six weeks later, single-kidney RBF and GFR were quantified in vivo using multidetector computed tomography (CT). Then, intrarenal rh-HGF or vehicle was randomly administered into the stenotic kidney (RAS, n ϭ 8; RASϩHGF, n ϭ 7). Pigs were observed for 4 additional weeks before CT studies were repeated. Renal MV density was quantified by 3D micro-CT ex vivo and histology, and expression of angiogenic and inflammatory factors, apoptosis, and fibrosis was determined. HGF therapy improved RBF and GFR compared with vehicle-treated pigs. This was accompanied by improved renal expression of angiogenic cytokines (VEGF, p-Akt) and tissue-healing promoters (SDF-1, CXCR4, MMP-9), reduced MV remodeling, apoptosis, and fibrosis, and attenuated renal inflammation. However, HGF therapy did not improve renal MV density, which was similarly reduced in RAS and RASϩHGF compared with controls. Using a clinically relevant animal model of RAS, we showed novel therapeutic effects of a targeted renal intervention. Our results show distinct actions on the existing renal microcirculation and promising renoprotective effects of HGF therapy in RAS. Furthermore, these effects imply plasticity of the stenotic kidney to recuperate its function and underscore the importance of MV integrity in the progression of renal injury in RAS. kidney; HGF; renal artery stenosis; microcirculation; remodeling; imaging MICROVASCULAR (MV) dysfunction, damage, and/or rarefaction are often observed in target organs during the progression of hypertension, diabetes, and cardiovascular disease. In turn, evidence supports a central pathophysiological role for MV dysfunction and damage in promoting cardiovascular diseaseinduced organ injury (29), underscoring a cause-effect relationship between MV disease and the pathophysiology of organ damage. In the kidney, glomerular and peritubular MV damage and loss have been linked to renal functional impairment and progression of renal damage in chronic renal disease (irrespective of the etiology) (17) and renal graft function (41). Indeed, renal MV disease is an important contributor to the progression of renal injury (23,40) and an important determinant of whether treatments are effective (7).Almost 15% of patients with renal artery stenosis (RAS) develop intractable hypertension or progressive loss of kidney function (15). RAS is the main cause of chronic renovascular disease (RVD), a disorder capable of inducing severe, progressive, a...

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