Upregulation of Piezo2 in the mesangial, renin, and perivascular mesenchymal cells of the kidney of Dahl salt-sensitive hypertensive rats and its reversal by esaxerenone.

The recent discovery of mechanosensitive ion channels has promoted mechanobiological research in the field of hypertension and nephrology. We previously reported Piezo2 expression in mouse mesangial and juxtaglomerular renin-producing cells, and its modulation by dehydration. This study aimed to investigate how Piezo2 expression is altered in hypertensive nephropathy. The effects of the nonsteroidal mineralocorticoid receptor blocker, esaxerenone, were also analyzed. Four-week-old Dahl salt-sensitive rats were randomly assigned to three groups: rats fed a 0.3% NaCl diet (DSN), rats fed a high 8% NaCl diet (DSH), and rats fed a high salt diet supplemented with esaxerenone (DSH + E). After six weeks, DSH rats developed hypertension, albuminuria, glomerular and vascular injuries, and perivascular fibrosis. Esaxerenone effectively decreased blood pressure and ameliorated renal damage. In DSN rats, Piezo2 was expressed in Pdgfrb-positive mesangial and Ren1-positive cells. Piezo2 expression in these cells was enhanced in DSH rats. Moreover, Piezo2-positive cells accumulated in the adventitial layer of intrarenal small arteries and arterioles in DSH rats. These cells were positive for Pdgfrb, Col1a1, and Col3a1, but negative for Acta2 (αSMA), indicating that they were perivascular mesenchymal cells different from myofibroblasts. Piezo2 upregulation was reversed by esaxerenone treatment. Furthermore, Piezo2 inhibition by siRNA in the cultured mesangial cells resulted in upregulation of Tgfb1 expression. Cyclic stretch also upregulated Tgfb1 in both transfections of control siRNA and Piezo2 siRNA. Our findings suggest that Piezo2 may have a contributory role in modulating the pathogenesis of hypertensive nephrosclerosis and have also highlighted the therapeutic effects of esaxerenone on salt-induced hypertensive nephropathy. Mechanochannel Piezo2 is known to be expressed in the mouse mesangial cells and juxtaglomerular renin-producing cells, and this was confirmed in normotensive Dahl-S rats. In salt-induced hypertensive Dahl-S rats, Piezo2 upregulation was observed in the mesangial cells, renin cells, and notably, perivascular mesenchymal cells, suggesting its involvement in kidney fibrosis.

Treatment Results of Endovascular Aneurysm Repair Using the Parallel Stent-Graft Double D Technique for Distal Saccular Abdominal Aortic Aneurysms and Common Iliac Aneurysms.

BACKGROUND: Endovascular aneurysm repair (EVAR) using a bifurcated stent graft may involve technical challenges when aortic disease (aneurysm or dissection) consists of a length <70 mm between the inferior renal artery and aortic bifurcation or narrow aortic bifurcation that is common in asymmetric distal abdominal aortic aneurysms (AAAs) or iliac artery aneurysms (IAAs). We use EVAR with the double D technique (DDT-EVAR) for such cases, which involves straight type of stent grafts with same diameter in left and right that are deployed parallel to an aortic cuff that has been previously placed. In addition, DDT-EVAR can preserve the inferior mesenteric artery (IMA) for IAA. METHODS: DDT-EVAR was performed for 21 of 910 (2%) cases from April 2007 to April 2019 at our institution. The median patient age was 74 years (range, 52-85). Nineteen patients (90%) were men. Six patients (all saccular; 1 rupture) had AAAs, 12 had IAAs, and 3 had chronic type B aortic dissociation (TBAD) for re-entry closure. AAA and IAA had diameters of 45 mm (range, 34-71) and 34 mm (range, 25-58), respectively. An aortic cuff was used for 19 (90%) cases. Endurant II (Medtronic, Santa Rosa, CA) was used for 12 cases. The Excluder (W.L. Gore & Associates, Inc, Flagstaff, AZ) was used for 7 cases. Endurant II was used for 20 cases, and the VBX (W.L. Gore & Associates, Inc) was used for 1 case as stent-graft limbs. RESULTS: The procedural success rate was 100%. The median operative time was 146 min (range, 88-324). IMA planned for preservation was successful for all 12 cases. Type I and type III endoleaks were not observed. With TBAD, flow to the false lumen decreased or disappeared, and no complications during the hospital stay were associated with the procedure. For 2 patients whose procedure involved Endurant II stent-graft limb, limb occlusions were observed postoperatively, and reintervention was required. No other patients required additional treatment at a median follow-up of 18 months (range, 4-50). CONCLUSIONS: DDT-EVAR is a safe and straightforward technique for the treatment of distal AAA, common iliac artery aneurysm, and TBAD. It may help preserve the IMA and internal iliac artery, even when it is impossible to preserve them with a bifurcated stent graft.

Skin fragility in obese diabetic mice: possible involvement of elevated oxidative stress and upregulation of matrix metalloproteinases.

The purpose of this study was to test the hypothesis that obese diabetic mice exhibit marked skin fragility, which is caused by increased oxidative stress and increased matrix metalloproteinase (MMP) gene expression in the subcutaneous adipose tissue. Scanning electron microscopy of skin samples from Tsumura-Suzuki obese diabetic (TSOD) mice revealed thinner collagen bundles, and decreased density and convolution of the collagen fibres. Furthermore, skin tensile strength measurements confirmed that the dorsal skin of TSOD mice was more fragile to tensile force than that of non-obese mice. The mRNA expressions of heme oxygenase 1 (Hmox1), a marker of oxidative stress, Mmp2 and Mmp14 were increased in the adipose tissue of TSOD mice. Antioxidant experiments were subsequently performed to determine whether the changes in collagen fibres and skin fragility were caused by oxidative stress. Strikingly, oral administration of the antioxidant dl-α-tocopherol acetate (vitamin E) decreased Hmox1, Mmp2 and Mmp14 mRNA expressions, and improved the skin tensile strength and structure of collagen fibres in TSOD mice. These findings suggest that the skin fragility in TSOD mice is associated with dermal collagen damage and weakened tensile strength, and that oxidative stress and MMP overexpression in the subcutaneous adipose tissue may, at least in part, affect dermal fragility via a paracrine pathway. These observations may contribute to novel clinical interventions, such as dietary supplementation with antioxidants or application of skin cream containing antioxidants, which may overcome skin fragility in obese patients with diabetes.

Repeated treatment protocols for melasma and acquired dermal melanocytosis.

BACKGROUND AND OBJECTIVE: Melasma and acquired dermal melanocytosis (ADM; acquired bilateral nevus of Ota-like macules) are both seen most commonly symmetrically on the face of women with darker skin and are also known as difficult conditions to treat. METHODS: Our topical bleaching protocol with 0.1 to 0.4% tretinoin gel and 5% hydroquinone was performed repeatedly (1-3 times) for melasma (n=163), and a combination treatment with topical bleaching and Q-switched ruby (QSR) laser was performed repeatedly (1-3 times) for ADM (n=62). RESULTS: There is a significant correlation between clinical results (clearance of pigmentation) and the number of sessions in both melasma (p=.019) and ADM (p<.0001). CONCLUSION: The repeated treatment protocol for melasma and ADM showed successful clinical results compared with conventional ones, and they may be applied to other pigment conditions. It may be better that epidermal and dermal pigmentations are treated separately, especially in dark-skinned people who are more likely to suffer postinflammatory hyperpigmentation after inflammation-inducing therapies.