Vitamin D receptor-modulated Hsp70/AT1 expression may protect the kidneys of SHRs at the structural and functional levels

Abstract

Previous hypertension studies have shown that low levels of vitamin D are linked to elevated renin-angiotensin system. The heat shock protein 70 regulates signaling pathways for cellular oxidative stress responses. Hsp70 has been shown to protect against angiotensin II-induced hypertension and exert a cytoprotective effect. Here, we wanted to evaluate whether the vitamin D receptor (VDR) associated with Hsp70/ AT 1 expression may be involved in the mechanism by which paricalcitol provides renal protection in spontaneously hypertensive rats (SHRs). One-month-old female SHRs were treated for 4 months with vehicle, paricalcitol, enalapril, or a combination of both paricalcitol and enalapril. The following were determined: blood pressure; biochemical parameters; fibrosis; apoptosis; mitochondrial morphology; and VDR, AT 1 receptor, and Hsp70 expression in the renal cortex. Blood pressure was markedly reduced by enalapril or the combination but not by paricalcitol alone. However, VDR activation, enalapril or combination, prevented fibrosis, the number of TUNEL-positive apoptotic cells, mitochondrial damage, and NADPH oxidase activity in SHRs. Additionally, high AT 1 receptor expression, like low Hsp70 expression (immunohistochemical/immunofluorescence studies), was reversed in the renal cortices of paricalcitol-and/or enalapriltreated animals (SHRs), and these changes were most marked in the combination therapy group. Finally, all of the recovery parameters were consistent with an improvement in VDR expression. Data suggest that Hsp70/AT 1 modulated by VDR is involved in the mechanism by which paricalcitol provides renal protection in SHRs. We propose that low AT 1 expression through VDR induction could be a consequence of the heat shock response Hsp70-mediated cell protection.

Antiarrhythmic effect linked to melatonin cardiorenal protection involves AT1 reduction and Hsp70‐VDR increase

“…Of interest for our finding, melatonin increases Hsp70 and protects the livers of toluene‐exposed rats from oxidative stress‐induced cytotoxicity . Hsp70 regulates antioxidant responses to cellular oxidative stress, and our laboratory showed that Hsp70 reduces the activity and expression of NADPH oxidase . In agreement with our previous findings, we now demonstrate an increase in Hsp70 in melatonin‐treated rats.…”

Mediators and mechanisms of heat shock protein 70 based cytoprotection in obstructive nephropathy

“…These results thus show a novel strategy to prevent UUO-induced kidney damage by using chitosan/siRNA nanoparticles to knockdown COX-2 specifically in macrophages (Yang et al 2015). Moreover, mitochondrial abnormality has been shown in many kidney disease models Diez et al 2015;Manucha 2014;García et al 2014García et al , 2014. However, its role in the pathogenesis of CKD is still uncertain.…”

“…NADPH oxidase activity was reverted in mitochondrial fractions from vitamin D inducer-treated animals (García et al 2012a, b). Furthermore, VDR-modulated Hsp70/AT 1 expression may protect the kidneys of spontaneously hypertensive rats (SHR) at the structural and functional levels (García et al 2014). Previously, vitamin D treatment increased Hsp70 expression which was localized to renal tubular cells in the outer medulla (Kim et al 2005).…”

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

“…In SHR, the same renal protective effects were brought about by 4 mo paricalcitol, enalapril, or combined paricalcitol-enalapril treatments. Importantly, both paricalcitol and enalapril improved VDR expression (146).…”