Biography

Biography: Xiong Z Ruan

Abstract

When the ‘lipid nephrotoxicity hypothesis’ was proposed in 1982 by Moorhead, increasing evidence from our and
other laboratories has supported the hypothesis that lipid abnormalities contribute to both atherosclerosis and
glomerulosclerosis. The lipid profile of patients with CKD is typified by high circulating levels of VLDL triglycerides/free fatty
acids (FAs), and by low plasma levels of HDL cholesterol. The plasma LDL level is not usually increased in patients with CKD
and might even be reduced. Surprisingly, low plasma levels of LDL-cholesterol are associated with an increased cardiovascular
risk of death in these patients a case of ‘reverse epidemiology’. We have demonstrated, both in vitro and in vivo that inflammatory
stress increases intracellular cholesterol influx into vascular smooth muscle cells, mesangial cells and macrophages by inducing
scavenger receptor expression. This increased influx disrupts LDL receptor feedback regulation and causes unrestrained LDL
receptor-mediated LDL uptake. Inflammation also inhibits ATP-binding-cassette-transporter-1-mediated cholesterol efflux
from these cells. Hence inflammatory stress accompanied by CKD modifies cholesterol homeostasis by diverting cholesterol
from blood to tissues. This cholesterol redistribution causes cholesterol to accumulate in kidney and vessel wall, and also
lowers circulating cholesterol levels. This is why cardiovascular risk is increased up to 33-fold in patients with renal failure,
but plasma cholesterol levels are not high. In addition, inflammatory stress causes a degree of statin resistance by overriding
the suppression of HMGCoA reductase activity by statins. Albumin carries >99% of plasma FAs. In CKD (especially diabetic
kidney disease) the circulating levels of FAs are markedly increased leading to an increase in the FA load per albumin molecule,
with a molar FA: albumin ratio of approximately 6 compared to ≤1 in health. Serum FAs bound to albumin in glomerular
filtrate are reabsorbed by the proximal tubular cells and mediate tubular damage by poorly understood mechanisms. We have
demonstrated that palmitic acid (FA) increased CD36 gene expression and protein modifications in HK-2 cells (glycosylations
and palmitoylations) which either mediate FA uptake or form complexes with TLR4, activating an inflammatory response.
High fat diet increased CD36 expression in the kidneys of mice and enhanced tubulointerstitital lipid accumulation and
tubulointerstitial fibrosis all of which would be prevented by knocking-out CD36, suggesting that CD36 acts as a ‘bridge’
linking high levels of FAs, fatty kidney, inflammatory response and CD36 de-palmitoylation would be a potential molecular
target for anti-fibrotic therapy. In conclusion, high levels of FAs induce metabolic inflammatory stress which causes cholesterol
redistribution from circulation to kidney and vessels and lowers serum cholesterol levels. This suggests that there is no safe
serum cholesterol level in the presence inflammatory stress. Statin resistance suggests that higher concentrations of statin may
be required to achieve the same biological and clinical effects in CKD.