SUN-172 SELECTIVE INHIBITION OF PKR AMELIORATES HYPERTENSIVE NEPHROPATHY AND AORTIC REMODELLING IN L-NAME TREATED WISTAR RATS

Abstract

Arterial hypertension shares a global prevalence and is associated with hypertensive nephropathy and severe damage to the vasculature in the general population. Hypertensive Nephrosclerosis is often associated with fibrosis, inflammation and tubular cell death due to apoptosis accompanied by structural alterations in the vasculature. Double-stranded RNA dependent protein kinase (PKR) is a known inducer of inflammation and apoptosis. However, no research has been done so far to elucidate the role of PKR in hypertensive nephropathy and vascular complications. Thus, the aim of the present study was to investigate the role of PKR in nephropathy/vascular complications and the underlying molecular mechanism. Experimental hypertension was induced by administration of L-NAME (40 mg/kg b.w, p.o) along with selective PKR inhibitor imoxin (0.5mg/kg, i.p.) to Wistar rats for four weeks. Changes in physiological parameters were assessed by recording non-invasive blood pressure (BP), heart rate (HR) and body weight (BW) on days 0, 7, 14, 21, and 28 for all the rats. Serum creatinine, BUN, intracellular calcium, HDL, LDL, and TGs were measured for biochemical estimations. Expression of PKR and its downstream markers for inflammation, fibrosis, apoptosis and vascular damage (JNK, p-JNK, NLRP3, Ang-II, TGF-β, eNOS, p-CREB, and caspase-3,) in rat kidney and aorta were determined by western blot and immunohistochemistry (IHC). Dilation in renal corpuscles, tubules, glomerulosclerosis and collapsed glomeruli in kidney sections along with changes in the luminal diameter of aortic rings were studied by histological examination. Renal fibrosis was determined by Sirius red and Masson’s Trichrome staining. TUNEL assay was done for tubular cell death and apoptosis. L-NAME treated rats showed a significant increase in BP, biochemical parameters together with a decrease in HR and BW compared to control, attenuation was observed with imoxin administration, however, lipid profile remained unaltered. Results of western blot and IHC indicate a significant increase in expression of PKR and its downstream markers in kidney and aorta when compared to control, attenuation was observed in imoxin co-treated group. PKR is a major contributor involved in hypertensive nephropathy and aortic remodeling in L-NAME Treated Wistar Rats. The observed alterations in the kidney and vasculature could be mediated in part by activation of the JNK/TGF-β/eNOS pathway in a PKR dependent manner. Additionally, we also propose that these PKR mediated perturbations are blocked by selective inhibition of PKR by imoxin.