Urotensin II in the development and progression of chronic kidney disease following 5/6 nephrectomy in the rat

New Findings

What is the central question of this study? Urotensin II is upregulated in patients in the later stages of chronic kidney disease (CKD), particularly in individuals requiring dialysis. However, studies in animals have been limited to the early stages of CKD. What is the main finding and its importance? Expression of urotensin II and its receptor increased, extending into cortical structures as CKD progressed towards end‐stage renal failure in the rat. Sub‐chronic treatment with a urotensin receptor antagonist slowed but did not prevent progression of CKD. This suggests that urotensin II contributes to the decline in renal function in CKD.

Abstract

Elevated serum and urine urotensin II (UII) concentrations have been reported in end‐stage patients with chronic kidney disease (CKD). Similar increases in UII and its receptor, UT, have been reported in animal models of CKD, but only at much earlier stages of renal dysfunction. The aim of this study was to characterise urotensin system expression as renal disease progresses to end‐stage failure in a 5/6 sub‐total nephrectomy (SNx) rat model. Male Sprague‐Dawley rats underwent SNx or sham surgery and were killed at 8 weeks post‐surgery (early – E) or immediately prior to end‐stage renal failure (30 ± 3 weeks post‐surgery, late – L). Systolic blood pressure (SBP), urinary albumin:creatinine ratio (uACR) and glomerulosclerosis index were all increased in SNx‐E rats compared with sham‐E by 8 weeks post‐surgery. These changes were associated with an increase in renal immunoreactive UII‐staining but little change in UT expression. As CKD progressed to end‐stage disease in the SNx‐L group markers of renal function deteriorated further, in association with a marked increase in immunoreactive UII and UT staining. Sub‐chronic administration of a UT antagonist, SB‐611812, at 30 mg kg⁻¹ day⁻¹ for 13 weeks in a separate group of SNx rats resulted in a two week delay in the increase in both SBP and uACR observed in vehicle‐treated SNx, but did not prevent the progression of renal dysfunction. The urotensin system is up‐regulated as renal function deteriorates in the rat; UT antagonism can slow but not prevent disease progression, suggesting that UII plays a role in CKD.

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