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Role of ENaC in Spinal Cord Injury

Funder: Craig H Neilsen Foundation

Funding period
USD 300 K
Funding amount
Spinal cord injury (SCI) has an annual incidence up to 50 cases per million population. Urinary complications include polyuria (increased urine output), combined with loss of bladder control, negatively impacts quality of life; it increases the probability of urinary incontinence and frequency of manual bladder emptying. So far, there is no efficient treatment to control polyuria. Previous studies suggest that decreased levels of the hormone arginine vasopressin (AVP) contribute to the pathogenesis of the polyuria. Recently, it has been shown that in parallel with the reduced AVP levels, the urinary levels of atrial natriuretic peptide (ANP) are elevated in a rat SCI model. Interestingly, while ANP is produced in the atria, with endocrine actions, it is also expressed in the kidney by the cells of proximal convoluted tubule (PCT). Thus, ANP may regulate the kidney function via both endocrine and paracrine mechanisms. Urodilatin is an ANP homologue synthesized exclusively in the kidney. As a renal natriuretic peptide released from distal convoluted tubule (DCT), urodilatin acts via local paracrine mechanism and has clinical implications. Overall, there are currently huge gaps in understanding SCI-induced changes in these hormones, their relation to polyuria, and the underlying changes in renal signal transduction pathways. Both reduced AVP and elevated ANP are known to reduce the activity of epithelial sodium channel (ENaC) in the cortical collecting duct (CCD). It is also well known that reduced AVP, also known as antidiuretic hormone, results in reduced aquaporins in the tubular cell membranes, especially aquaporine-2 (AQP-2) in the CCD. Both reduced activity of ENaC and reduced membrane localization of AQP-2 should lead to natriuresis/diuresis (natriuresis: excretion of sodium in the urine; diuresis: increased or excessive production of urine) to cause polyuria. Therefore, we hypothesize that ENaC and AQP-2 might be the major target of reduced AVP and elevated ANP found in SCI patients to mediate SCI-induced polyuria. Our preliminary data show that SCI at the tenth thoracic vertebral level (T10): (1) attenuates sympathetic drive to afferent arteriole (AA) (enhanced sympathetic drive autonomic dysreflexia usually occurs at T6 or above), (ii) induces DCT hypertrophy, and (iii) reduces the protein levels and function of ENaC in the CCD. Therefore, the investigation of the signal transduction pathways from SCI to reduced ENaC function should provide important information for the treatment of polyuria to improve the quality of life of SCI patients.The specific aims of this proposal are to determine whether SCI reduces sodium and water reabsorption through ENaC and AQP-2 by elevating ANP in the kidney and whether urodilatin also participates in SCI-induced reduction of ENaC activity and AQP-2 memebrane localization. T10 contusion SCI and sham mice will be used to test these hypotheses. (CHN: SCIRTS chn:wdg)
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    1103 Clinical Sciences


    1109 Neurosciences

  • RCDC

    Injury (total) Accidents/Adverse Effects

  • RCDC

    Injury - Trauma - (Head and Spine)

  • RCDC

    Spinal Cord Injury

  • RCDC

    Kidney Disease

  • RCDC



    Renal and Urogenital


    2.1 Biological and endogenous factors

  • Health Research Areas


  • Broad Research Areas

    Basic Science