Poly (Ethylene Glycol)-<b><i>Block</i></b>-Brush Poly (L-Lysine) Copolymer as an Efficient Nanocarrier for Human Hepatocyte Growth Factor with Enhanced Bioavailability and Anti-Ischemia Reperfusion Injury Efficacy

Ischemia-reperfusion injury (IRI) is a clinically important cause of acute kidney injury leading to chronic kidney disease. Furthermore, IRI in renal transplantation still remains a risk factor for delayed graft function. Previous studies on IRI have had some limitations, and few of the studied therapies have been clinically applicable. Therefore, a new method for treating renal IRI is needed. We examined the effects of human mesothelial cell (MC) sheets and hepatocyte growth factor (HGF)-transgenic MC (tg MC) sheets transplanted under the renal capsule in an IRI rat model and compared these two treatments with the intravenous administration of HGF protein and no treatment through serum, histological, and mRNA analyses over 28 days. MC sheets and HGF-tg MC sheets produced HGF protein and significantly improved acute renal dysfunction, acute tubular necrosis, and survival rate. The improvement in necrosis was likely due to the cell sheets promoting the migration and proliferation of renal tubular cells, as observed in vitro. Expression of α-smooth muscle actin at day 14 and renal fibrosis at day 28 after IRI were significantly suppressed in MC sheet and HGF-tg MC sheet treatment groups compared with the other groups, and these effects tended to be reinforced by the HGF-tg MC sheets. These results suggest that the cell sheets locally and continuously affect renal paracrine factors, such as HGF, and support recovery from acute tubular necrosis and improvement of renal fibrosis in chronic disease.

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Late intervention with the small molecule BB3 mitigates postischemic kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00455.2015 ◽

2016 ◽

Vol 311 (2) ◽

pp. F352-F361 ◽

Cited By ~ 8

Author(s):

Prakash Narayan ◽

Bin Duan ◽

Kai Jiang ◽

Jingsong Li ◽

Latha Paka ◽

...

Keyword(s):

Growth Factor ◽

Hepatocyte Growth Factor ◽

Small Molecule ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Graft Function ◽

Kidney Injury ◽

Growth Factor Signaling ◽

Kidney Recipients ◽

Hepatocyte Growth

Ischemia-reperfusion-mediated acute kidney injury can necessitate renal replacement therapy and is a major cause of morbidity and mortality. We have identified BB3, a small molecule, which when first administered at 24 h after renal ischemia in rats, improved survival, augmented urine output, and reduced the increase in serum creatinine and blood urea nitrogen. Compared with control kidneys, the kidneys of BB3-treated animals exhibited reduced levels of kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and reduced tubular apoptosis and acute tubular necrosis but enhanced tubular regeneration. Consistent with its hepatocyte growth factor-like mode of action, BB3 treatment promoted phosphorylation of renal cMet and Akt and upregulated renal expression of the survival protein Bcl-2. These data suggest that the kidney is amenable to pharmacotherapy even 24 h after ischemia-reperfusion and that activation of the hepatocyte growth factor signaling pathway with the small molecule BB3 confers interventional benefits late into ischemia-reperfusion injury. These data formed, in part, the basis for the use of BB3 in a clinical trial in kidney recipients presenting with delayed graft function.

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