Up-regulation of PKR pathway contributes to L-NAME induced hypertension and renal damage

Abstract

Hypertension induced kidney damage is often associated with fibrosis and tubular apoptosis. Doublestranded protein kinase (PKR) is a well recognized inducer of inflammation and apoptosis. However, role of PKR in hypertension coupled renal damage is still not explored. Therefore here we sought to investigate the role of PKR in the pathogenesis of L-NAME induced hypertension and renal damage in Wistar rats and the underneath molecular mechanism. Methods: L-NAME (40 mg/kg, p.o) and imoxin (0.5 mg/kg, i.p) was given to Wistar rats for 4 weeks. Increased eNOS expression, serum creatinine, BUN and changes in mean arterial pressure confirmed for hypertensive renal damage. Western blot and immunohistochemistry was carried out for PKR and markers for fibrosis and apoptosis. Morphological alterations were assessed by H&E staining. Sirius red and Masson's Trichrome staining was performed for collagen and fibrosis. TUNEL assay was done for tubular cell death and apoptosis. Results: Increased expression of PKR and its downstream markers were reported in L-NAME rats, attenuation was observed with imoxin treatment. L-NAME treated rats showed a significant increase in MAP, serum calcium, creatinine and BUN along with the significant morphological changes, attenuation was reported with the imoxin treatment. Conclusion: PKR is a core contributor in the pathogenesis of L-NAME induced renal damage and tubular apoptosis. Therapeutically targeting of PKR could be an attractive approach to treat the renal complications associated with hypertension.

Antihypertensive effect of the stem bark aqueous extract of Garcinia lucida Vesque (Clusiaceae) in L-NAME-treated rats: Contribution of endothelium-dependent and -independent vasorelaxation

“…The L-NAME model has been associated with structural changes at the cardiac, aortic, and kidney levels [ 35 , 36 ]. Left ventricular hypertrophy has been reported by some authors [ 31 , 35 ], whereas others found no change in left ventricular mass [ 37 , 38 ].…”

Pharmacological evaluation of Euphorbia hirta, Fagonia indica and Capparis decidua in hypertension through in-vivo and in vitro-assays

“…Arsenic induces hypertension in animal via endothelial impairment and inactivates the endothelial nitric oxide synthase, consequently attenuating the bio -generation and availability of nitric oxide [45]. This endothelial cells dysfunction is likely to make straight effects on the vascular cells.…”

“…On the account of the established traditional usage of E. hirta , F. indica and C. decidua in cardiovascular disorders like as hypertension [ 9 , 19 , 28 ], the oral administration of E. hirta, F. indica and C. decidua extract (500 mg/kg) reduced systolic blood pressure (SBP) significantly in arsenic-induced hypertensive rats with following order of potency; EH.Cr ˃ CD.Cr ˃ FI.Cr. Arsenic induces hypertension in animal via endothelial impairment and inactivates the endothelial nitric oxide synthase, consequently attenuating the bio -generation and availability of nitric oxide [ 45 ]. This endothelial cells dysfunction is likely to make straight effects on the vascular cells.…”

Diosmetin Ameliorates Vascular Dysfunction and Remodeling by Modulation of Nrf2/HO-1 and p-JNK/p-NF-κB Expression in Hypertensive Rats

“…This is supported by evidence that ROS can activate the mitogen-activated protein kinase (MAPK) component and NF-κB pathways to mediate cell growth, proliferation, and inflammation [ 20 ]. Kalra and co-workers reported that the administration of L-NAME increases the expression of phosphor c-Jun N-terminal kinases (p-JNK), while NF-κB protein expression leads to tissue inflammation [ 21 ].…”