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Klotho protein supplementation reduces blood pressure and renal hypertrophy in db/db mice, a model of type 2 diabetes.

Klotho interacts with various membrane proteins, such as receptors for transforming growth factor (TGF)-β and insulin-like growth factor (IGF), to alter their function. Renal expression of klotho is diminished in diabetes. The present study examined whether exogenous klotho protein supplementation ameliorates kidney injury and renin-angiotensin system (RAS) in db/db mice.

We investigated the effects of klotho supplementation on diabetic kidney injury and RAS. Recombinant human klotho protein (10 μg/kg/d) was administered to db/db mice daily.

Klotho protein supplementation reduced kidney weight, systolic blood pressure (SBP), albuminuria, glomerular filtration rate, and 8-epi-prostaglandin F2α excretion without affecting body weight. Although klotho supplementation did not alter glycated albumin, it reduced renal angiotensin II levels associated with reduced renal expression of angiotensinogen. Klotho supplementation improved renal expression of superoxide dismutase (SOD), and endogenous renal expression of klotho. Klotho supplementation reduced the levels of hypoxia-inducible factor, phosphorylated Akt, and phosphorylated mTOR and decreased the renal expression of TGF-β, tumour necrosis factor (TNF), and fibronectin.

These data indicate that klotho supplementation reduces blood pressure and albuminuria along with ameliorating renal RAS activation in db/db mice. Furthermore, these results suggest that klotho inhibits IGF signalling, induces SOD expression to reduce oxidative stress, and suppresses Akt-mTOR signalling to inhibit abnormal kidney growth. Collectively, the results suggest that klotho inhibits TGF-β and TNF signalling, resulting in a decline in renal fibrosis.

© 2018 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

epithelial-mesenchymal transition; insulin-like growth factor; mTOR; superoxide dismutase; transforming growth factor; tumour necrosis factor



Bioelectronic Approaches to Control Neuroimmune Interactions in Acute Kidney Injury

Recent studies have shown renal protective effects of bioelectric approaches, including ultrasound treatment, electrical vagus nerve stimulation, and optogenetic brainstem C1 neuron stimulation. The renal protection acquired by all three modalities was lost in splenectomized mice and/or α7 subunit of the nicotinic acetylcholine receptor–deficient mice. C1 neuron-mediated renal protection was blocked by β2-adrenergic receptor antagonist. These findings indicate that all three methods commonly, at least partially, activate the cholinergic anti-inflammatory pathway, a well-studied neuroimmune pathway. In this article, we summarize the current understanding of neuroimmune axis-mediated kidney protection in preclinical models of acute kidney injury by these three modalities. Examination of the differences among these three modalities might lead to a further elucidation of the neuroimmune axis involved in renal protection and is of interest for developing new therapeutic approaches.

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Klotho Deficiency Causes Hypertension and Renal Damage and Its Mechanism
Zhou Xiaoli1 , Lei Han1 , Sun Zhongjie2  1 The First Affiliated Hospital of Chongqing Medical University,2 University of Oklahoma Health Sciences Center
Objectives: Klotho (KL) is a recently discovered aging-suppressing gene. Insertional mutation of KL gene resulted in a premature aging syndrome. Overexpression of KL gene extended the lifespan by 20% and rescued other aging disorders. Hypertension and kidney damage are common aging-related diseases. The purpose of this study is to assess if KL deficiency affects blood pressure (BP) and renal damage as well as the underlying mechanism.
Methods: One group of heterozygous mutant KL (KL (+/-) ) mice and one group of wild type (WT) mice were used to measure BP continuously when they were from the age of 8 months to 13 months. Each strain of mice was further divided into 2 subgroups when the mice were at the age of 15 months, which received eplerenone treatment (6 mg/kg/day, IP) or an equal dose vehicle, respectively. BP was measured and urine was collected during treatment. At the end of the treatment for 3 weeks, the animals were sacrificed and blood was collected. Plasma aldosterone level was detected with an aldosterone ELISA kit. Kidney sections were used for periodic acid Schiff staining, Masson’s trichrome staining and immunohistochemical staining (CD4, CD8, and CD68). Adrenal sections were used for immunohistochemical staining (klotho, CYP11B2). Plasma urea and creatinine level were detected with quantichromTM assay kits. Urinary albumin concentration was measured with a microalbuminuria ELISA kit. Western blotting was done to detect the expression of MR, SGK1, NCC, and ATP synthase b, TNF-a, MCP-1, IL-6 and osteopontin in kidney. Results: The results demonstrated that the systolic BP was significantly and persistently elevated accompanied by aldosterone level increase and CYP11B2 (key enzyme of aldosterone synthesis) upregulation in KL (+/-) mice. Chronic treatment with eplerenone (aldosterone receptor blocker) decreased hypertension to the control level and prevented the upregulation of SGK1, NCC and ATP synthase b level in kidneys of KL (+/-) mice, suggesting that KL deficiency causes hypertension due to plasma aldosterone increase and the subsequent renal sodium retention through SGK1-NCC signaling. Moreover, significant renal structure damage (glomerulus collapse, tubule fibrosis) and function decline (plasma creatinine, urea and urine albumin increase) were observed in KL (+/-) mice. Further analysis indicated that several proinflammatory cytokines (TNFa, MCP-1, IL-6 and osteopontin) were upregulated and leucocyte (T cell and macrophage) infiltration were increased in kidneys of KL (+/-) mice. Eplerenone rescued KL deficiency-induced kidney damage and abolished the activated inflammatory process.
Conclusions: KL is essential to the maintenance of normal BP. KL deficiency caused hypertension and kidney damage via upregulating aldosterone level and consequently increasing inflammation and SGK1-NCC signaling in kidneys.
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Electrically stimulated acupuncture increases renal blood flow through …
by JD Klein – ‎2018 – ‎Related articles

Aug 22, 2018 – Electrically stimulated acupuncture increases renal blood flow through exosome- carried miR-181. Klein JD(1), Wang XH(1). Author information:

Electrically-stimulated acupuncture improves muscle function and increases renal blood flow through exosomes-carried miR-181

    Published Online:Abstract Number:


    our previous study found that acupuncture with low frequency electrical stimulation (Acu/LFES) can prevent muscle atrophy by increasing muscle protein anabolism in mouse models of chronic kidney disease, diabetes and denervation. Previous other studies have found that Acu/LFES improves renal blood flow and GFR in nephropathy patients and animals. We hypothesized that Acu/LFES benefits both skeletal muscle and kidney possibly through exosome carried microRNA.


    Normal C57BL6 mice were awake without any anesthesia and appeared to be comfortable throughout the Acu/LFES. Acupuncture points selected were according to the WHO Standard Acupuncture guidelines. The mice were treated with Acu/LFES (anode: Yang Ling Quan, GB34 and cathode: Zu San Li, ST36) daily for 15 days. Renal plasma flow was measured by p-Aminohippuric acid infusion. Glomerular filtration rate was determined using inulin infusion and measured with a FIT-GFR kit. Exosomes were isolated by serial centrifugations. A miR deep sequencing assay and qPCR were used to identify microRNA expression in exosomes.


    Skeletal muscle grip function and muscle regeneration markers were increased after Acu/LFES treatment. Acu/LFES increased muscle cross-sectional area in normal mice vs. sham Acu-LFES mice. The abundance of Pax7, MyoD, myogenin and embryo myosin heavy chain was significantly increased by Acu-LFES in soleus, extensor digitorum longus (EDL) and gastrocnemius muscle. The number of central nuclei was increased in Acu-LFES treated muscle fibers. Interestingly, PAH clearance was increased by 45% in the mice after 15 minutes of muscle Acu/LFES versus mice with sham Acu/LFES (sham 6.1 ± 1.3 vs. Acu/LFES 8.9 ± 2.7 ml/min/g BW, P = 0.009, n=8/group). Inulin clearance was increased 39.8% (sham 65.9 ± 16.3 vs. Acu/LFES108.9 ± 19.7 ul/min/BW, P = 0.014). We found that Acu/LFES increases serum exosome abundance. When exosome secretion was blocked using GW4869, the Acu/LFES-induced increase in renal blood flow and GFR were limited. To identify how exosomes regulate renal blood flow, we performed microRNA deep sequencing of exosomes isolated from mouse serum and found that 34 microRNAs were altered by Acu/LFES. Notably, miR-181d-5p, a microRNA that is involved in regulating translation of renin, was significantly increased in the serum exosomes of Acu/LFES treated mice. Using a luciferase reporter assay, we demonstrated that miR-181 directly inhibits angiotensinogen, which provides potential evidence of Acu/LFES regulation of renal blood flow.


    Acu/LFES not only improves muscle function, but also increases miR-181 in serum exosomes and increases renal blood flow, suggesting that miR181 may regulate renal blood flow possibly by influencing the renin-angiotensin system. This study provides new insights about the mechanism(s) of muscle-organ cross talk through exosome-delivered microRNA.
    Support or Funding Information
    NIH R01 AR060268 and AHA 17IBDG33780000
    Support or Funding Information
    NIH R01 AR060268 and AHA 17IBDG33780000
    This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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