IDH2 gene deficiency accelerates unilateral ureteral obstructioninduced kidney inflammation through oxidative stress and activation of macrophages

Mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2) produces NADPH, which is known to inhibit mitochondrial oxidative stress. Ureteral obstruction induces kidney inflammation and fibrosis via oxidative stress. Here, we investigated the role and underlying mechanism of IDH2 in unilateral ureteral obstruction (UUO)-induced kidney inflammation using IDH2 gene deleted mice (IDH2–/–). Eight- to 10-week-old female IDH2–/– mice and wild type (IDH2+/+) littermates were subjected to UUO and kidneys were harvested 5 days after UUO. IDH2 was not detected in the kidneys of IDH2–/– mice, while UUO decreased IDH2 in IDH2+/+ mice. UUO increased the expressions of markers of oxidative stress in both IDH2+/+ and IDH2–/– mice, and these changes were greater in IDH2–/– mice compared to IDH2+/+ mice. Bone marrow-derived macrophages of IDH2–/– mice showed a more migrating phenotype with greater ruffle formation and Rac1 distribution than that of IDH2+/+ mice. Correspondently, UUO-induced infiltration of monocytes/macrophages was greater in IDH2–/– mice compared to IDH2+/+ mice. Taken together, these data demonstrate that IDH2 plays a protective role against UUO-induced inflammation through inhibition of oxidative stress and macrophage infiltration.

IDH2 gene deficiency accelerates unilateral ureteral obstructioninduced kidney inflammation through oxidative stress and activation of macrophages

Mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2) produces NADPH, which is known to inhibit mitochondrial oxidative stress. Ureteral obstruction induces kidney inflammation and fibrosis via oxidative stress. Here, we investigated the role and underlying mechanism of IDH2 in unilateral ureteral obstruction (UUO)-induced kidney inflammation using IDH2 gene deleted mice (IDH2–/–). Eight- to 10-week-old female IDH2–/– mice and wild type (IDH2+/+) littermates were subjected to UUO and kidneys were harvested 5 days after UUO. IDH2 was not detected in the kidneys of IDH2–/– mice, while UUO decreased IDH2 in IDH2+/+ mice. UUO increased the expressions of markers of oxidative stress in both IDH2+/+ and IDH2–/– mice, and these changes were greater in IDH2–/– mice compared to IDH2+/+ mice. Bone marrow-derived macrophages of IDH2–/– mice showed a more migrating phenotype with greater ruffle formation and Rac1 distribution than that of IDH2+/+ mice. Correspondently, UUO-induced infiltration of monocytes/macrophages was greater in IDH2–/– mice compared to IDH2+/+ mice. Taken together, these data demonstrate that IDH2 plays a protective role against UUO-induced inflammation through inhibition of oxidative stress and macrophage infiltration.

Renal sympathetic nerve activation via α₂-adrenergic receptors in chronic kidney disease progression

Chronic kidney disease (CKD) is increasing worldwide without an effective therapeutic strategy. Sympathetic nerve activation is implicated in CKD progression, as well as cardiovascular dysfunction. Renal denervation is beneficial for controlling blood pressure (BP) and improving renal function through reduction of sympathetic nerve activity in patients with resistant hypertension and CKD. Sympathetic neurotransmitter norepinephrine (NE) via adrenergic receptor (AR) signaling has been implicated in tissue homeostasis and various disease progressions, including CKD. Increased plasma NE level is a predictor of survival and the incidence of cardiovascular events in patients with end-stage renal disease, as well as future renal injury in subjects with normal BP and renal function. Our recent data demonstrate that NE derived from renal nerves causes renal inflammation and fibrosis progression through alpha-2 adrenergic receptors (α₂-AR) in renal fibrosis models independent of BP. Sympathetic nerve activation-associated molecular mechanisms and signals seem to be critical for the development and progression of CKD, but the exact role of sympathetic nerve activation in CKD progression remains undefined. This review explores the current knowledge of NE-α₂-AR signaling in renal diseases and offers prospective views on developing therapeutic strategies targeting NE-AR signaling in CKD progression.

17beta-estradiol Attenuates Renal Fibrosis in Mice with Obstructive Uropathy

PURPOSE: Men are generally more prone to chronic renal disease and progression to end stage renal disease than women. The purpose of this study is to prove the effect of gender and sex hormone on renal fibrosis in mice with unilateral ureteral obstruction (UUO) and to elucidate the specific underlying mechanisms. METHODS: We compared the expression of alpha-smooth muscle actin (alpha-SMA) in female and male mice with complete UUO (day 7). After this, we estimated the changes of renal fibrosis in the female mice with oophorectomy and in the female mice with oophorectomy and replacement of 17beta-estradiol, respectively. RESULTS: The level of alpha-SMA in the female kidney with UUO was significantly lower than that in the male kidney with UUO. oophorectomy and replacement of 17beta-estradiol did not change the expression of angiotensin II type 1 (AT1) receptor in the female kidney with UUO, whereas the expression of angiotensin II type 2 (AT2) receptor was significantly more elevated in the intact female (IF) and the oophorectomized female with estrogen (OF+E) than that in the oophorectomized female (OF). The expressions of inducible nitric oxide synthase (iNOS) in the IF and OF+E mice were significantly more elevated than that in the OF mice, which was similar to the expression of AT2 receptor. CONCLUSION: The female gender is associated with resistance to renal fibrosis in obstructive uropathy and this gender difference may originate from the existence of 17beta-estradiol, which has an anti-fibrotic effect via upregulation of the AT2 receptor and iNOS.