Brain Overexpression of Uncoupling Protein-2 (UCP2) Delays Renal Damage and Stroke Occurrence in Stroke-Prone Spontaneously Hypertensive Rats

Abstract

The downregulation of uncoupling protein-2 (UCP2) is associated with increased brain and kidney injury in stroke-prone spontaneously hypertensive rats (SHRSP) fed with a Japanese style hypersodic diet (JD). Systemic overexpression of UCP2 reduces organ damage in JD-fed SHRSP. We examined the effect of brain-specific UCP2 overexpression on blood pressure (BP), stroke occurrence and kidney damage in JD-fed SHRSP. Rats received a single i.c.v. injection of a lentiviral vector encoding UCP2 (LV-UCP2), or an empty vector. The brain delivery of LV-UCP2 significantly delayed the occurrence of stroke and kidney damage. The large reduction of proteinuria observed after LV-UCP2 injection was unexpected, because BP levels were unchanged. At the time of stroke, rats treated with LV-UCP2 still showed a large UCP2 upregulation in the striatum, associated with increases in OPA1 and FIS1 protein levels, and reductions in PGC1-α, SOD2, TNFα mRNA levels and NRF2 protein levels. This suggested UCP2 overexpression enhanced mitochondrial fusion and fission and reduced oxidative damage and inflammation in the striatum of JD-fed SHRSP rats. Our data suggest the existence of central mechanisms that may protect against hypertension-induced organ damage independently of BP, and strengthen the suitability of strategies aimed at enhancing UCP2 expression for the treatment of hypertensive damage.

Gardenia jasminoides Attenuates Allergic Rhinitis-Induced Inflammation by Inhibiting Periostin Production

“…We also showed that GJW and GJE increase the expression of UCP2, which is a component of another mitochondrial ROS-associated signaling pathway [42][43][44]. Located in the inner mitochondrial membrane, UCP2 functions to protect against oxidative stress by regulating the production of superoxide anions [42,[44][45][46]. Our findings illustrated that GJW and GJE reduce mitochondrial ROS via the upregulation of UCP2, not by regulating antioxidant enzymes per se.…”

Mitochondrial Quality Control: A Pathophysiological Mechanism and Therapeutic Target for Stroke

“…Research on HEK293 and HeLa cells has found that the inhibition of Drp1-induced fission impaired the selectivity of mitophagy, thus enhancing its rate of elimination of even healthy mitochondria via the unchecked PINK1/Parkin pathway (Burman et al, 2017). After selective overexpression of uncoupling protein-2 (UCP2) in the corpus striatum of stroke-prone spontaneously hypertensive (SHRSP) rats, Busceti et al (2020) found the upregulation of OPA1 and Fis1, which respectively amplified mitochondrial fusion and fission in the striatum tissue. Although the causality was not explicit, this experiment implied that UCP2 exerted neuroprotection by driving mitochondrial fusion and fission.…”

Stress Reactivity, Susceptibility to Hypertension, and Differential Expression of Genes in Hypertensive Compared to Normotensive Patients

“…In this work, we analyzed all the publicly available independent experimental RNA-Seq datasets-on transcriptomes from the tissues of hypertensive versus normotensive patients [26][27][28][29][30][31][32][33][34][35][36][37][38][39], hypertensive versus normotensive animals [7,[40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57], and domestic versus wild animals [72,[176][177][178][179][180][181][182][183][184][185][186][187][188][189][190][191][192][193].…”