Timeline of Changes in Biomarkers Associated with Spinal Cord Injury–Induced Polyuria

Abstract

Deficits in upper and lower urinary tract function, which include detrusor overactivity, urinary incontinence, detrusor-sphincter dyssynergia, and polyuria, are among the leading issues that arise after spinal cord injury (SCI) affecting quality of life. Given that overproduction of urine (polyuria) has been shown to be associated with an imbalance in key regulators of body fluid homeostasis, the current study examined the timing of changes in levels of various relevant hormones, peptides, receptors, and channels post-contusion injury in adult male Wistar rats. The results show significant up- or downregulation at various time points, beginning at 7 days post-injury, in levels of urinary atrial natriuretic peptide, serum arginine vasopressin (AVP), kidney natriuretic peptide receptor-A, kidney vasopressin-2 receptor, kidney aquaporin-2 channels, and kidney epithelial sodium channels (β- and γ-, but not α-, subunits). The number of AVP-labeled neurons in the hypothalamus (supraoptic and -chiasmatic, but not paraventricular, nuclei) was also significantly altered at one or more time points. These data show significant fluctuations in key biomarkers involved in body fluid homeostasis during the post-SCI secondary injury phase, suggesting that therapeutic interventions (e.g., desmopressin, a synthetic analogue of AVP) should be considered early post-SCI.

Effect of T3 Spinal Contusion Injury on Upper Urinary Tract Function

“… 14 Notably, daily urine volumes in T3 SCI animals were equivalent to T9 SCI animals of past studies. 9 , 14 Further, similar to previous findings with a T9 SCI, there were no significant changes in drink volumes at any of the time points. 7 , 9 Stability in drink volume from pre-SCI through chronic SCI, taken together with an increase in urine production per passage, is indicative of the extent to which systemic body water/solute balance is severely disrupted after SCI.…”

“…Given that the spinal sympathetic supply to the kidney is mostly intact below a T3 level of injury, the development and maintenance of SCI-induced polyuria was likely attributable to damage of descending supraspinal circuitries, which likely disrupts fluid and metabolite homeostasis, precipitating plasticity within the kidney itself, such as previously observed with fluctuations in the relative expression of receptors and channels 9 , 14 , 15 as well as central regions, including those containing AVP-producing neurons within the hypothalamus. 14 Notably, daily urine volumes in T3 SCI animals were equivalent to T9 SCI animals of past studies. 9 , 14 Further, similar to previous findings with a T9 SCI, there were no significant changes in drink volumes at any of the time points.…”

“…At least four different sections of nuclei per animal were averaged together for analyses, per our published protocols. 14 …”

“…13 The SCN, which is a main regulator of circadian control, including sleep/wake cycles, was recently shown, in a T9-level contusion rat model, to contain significantly fewer AVP-labeled cells beginning as early as 14 days post-injury (dpi). 14 …”

“…However, significant up- or downregulation at various time points, beginning at 7 days post-injury, have been shown for kidney natriuretic peptide receptor-A (NPRA), atrial natriuretic peptide (ANP), kidney vasopressin-2 receptor (V2R), kidney aquaporin-2 (AQP2) channels, and kidney epithelial sodium channels (ENaC; β and γ but not α subunits), suggesting that both central and peripheral mechanisms are involved in the development and maintenance of polyuria. 9 , 14 , 15 Together, these biomarkers are key for both water/sodium and cardiovascular homeostasis. Specifically, ANP causes an increase of sodium/water excretion opposite to that of AVP.…”