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Pathogenic role of innate immunity in a model of chronic NO inhibition associated with salt overload.

Nitric oxide inhibition with Nw-nitroarginine-methylester (L-NAME) along with salt overload leads to hypertension, albuminuria, glomerulosclerosis, glomerular ischemia and interstitial fibrosis, characterizing a chronic kidney disease (CKD) model. Previous findings of this laboratory and elsewhere suggest that activation of at least two pathways of innate immunity, TLR4/NF-κB and NLRP3 inflammasome/IL-1β, occurs in several experimental models of CKD, and that progression of renal injury can be slowed with inhibition of these pathways. In the present study, we investigated whether activation of innate immunity, through either the TLR4/NF-κB or NLRP3/IL-1β pathway, is involved in the pathogenesis of renal injury in chronic NO inhibition with salt overload model. Adult male Munich-Wistar rats receiving L-NAME in drinking water and salt overload (Group HS+N) were treated with Allopurinol (ALLO), as an NLRP3 inhibitor (Group HS+N+ALLO), or Pyrrolidine Dithiocarbamate (PDTC) a NF-κB inhibitor (Group HS+N+PDTC). After 4 wks, HS+N rats developed hypertension, albuminuria and renal injury, along with renal inflammation, oxidative stress and activation of both the NLRP3/IL-1β and TLR4/NF-κB pathways. ALLO lowered renal uric acid and inhibited the NLRP3 pathway. These effects were associated with amelioration of hypertension, albuminuria and interstitial inflammation/fibrosis, but not glomerular injury. PDTC inhibited the renal NF-κB system and lowered the number of interstitial cells staining positively for NLRP3. PDTC also reduced the renal xanthine oxidase activity and uric acid. Overall, PDTC promoted a more efficient anti-inflammatory and nephroprotective effect than ALLO. The NLRP3/IL-1β and TLR4/NF-κB pathways act in parallel to promote renal injury/inflammation and must be simultaneously inhibited for best nephroprotection.