NLRP3-MEDIATED RENAL LIPID ACCUMULATION OCCURS DURING EARLY DEVELOPMENT OF DIET-INDUCED CHRONIC KIDNEY DISEASE

Abstract

Metabolic syndrome (MetSyn) is an important risk factor for the development of chronic kidney disease (CKD). Metsyn-driven CKD is characterized by a state of chronic low-grade inflammation and the innate immune receptor Nlrp3 mediates inflammation. Therefore, we investigated the role of Nlrp3 on the development of Metsyn-driven CKD. Nlrp3 -/- (Nlrp3ko) and wild-type C57BL/6J (wt) mice (n=8 per group) were subjected to either a control diet or a Western diet (WD) containing increased fat and cholesterol levels. Diets continued for 16 weeks after which mice were sacrificed. A Western diet induced Metsyn in both wt and Nlrp3ko mice to a similar extent. Although renal function was preserved, the development of CKD was established in wt WD mice as reflected by the presence of micro-albuminuria, inflammation and fibrosis. No development of CKD could be seen in Nlrp3ko mice fed a WD. Development of Metsyn-driven CKD was observed together with an increase in vacuolated proximal tubuli, renal cholesterol and phospholipid levels in wt WD mice. Phospholipids were visualized using a Nile Red staining and co-localized with vacuolated tubuli. Oil Red O Staining showed increased numbers of granulus containing neutral lipids in proximal tubuli of wildtype Western diet-fed mice. Unexpectedly, no renal lipid accumulation occurred in Nlrp3ko mice fed a Western Diet. A Western diet induced cholesterol accumulation in wildtype mice despite decreased uptake, increased excretion and decreased synthesis based on gene expression analysis. We propose a novel role for the immune receptor Nlrp3 in mediating renal cholesterol and phospholipid accumulation during the early development of Metsyn-driven CKD. Further research is conducted to investigate the therapeutic potential of Nlrp3 in early renal CKD development.