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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. Could treatment with a urotensin II receptor antagonist slow progression of renal disease?What is the main finding and its importance?In the rat, expression of urotensin II and its receptor increased, extending into cortical structures as CKD progressed towards end‐stage renal failure. Subchronic 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. Elevated serum and urine urotensin II (UII) concentrations have been reported in patients with end‐stage 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 characterize urotensin system expression as renal disease progresses to end‐stage failure in a ⅚ subtotal nephrectomy (SNx) rat model. Male Sprague–Dawley rats underwent SNx or sham surgery and were killed at 8 weeks postsurgery [early (E)] or immediately before end‐stage renal failure [30 ± 3 weeks postsurgery; late (L)]. Systolic blood pressure, urinary albumin:creatinine ratio and glomerulosclerosis index were all increased in SNx‐E rats compared with sham‐E by 8 weeks postsurgery. 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. Subchronic 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 2 week delay in the increase in both systolic blood pressure and urinary albumin:creatinine ratio observed in vehicle‐treated SNx but did not prevent the progression of renal dysfunction. The urotensin system is upregulated as renal function deteriorates in the rat; UT antagonism can slow but not prevent disease progression, suggesting that UII plays a role in CKD. [ABSTRACT FROM AUTHOR]

To address the pathophysiological mechanisms underlying chronic kidney disease with comorbid cardiac dysfunction, we investigated renal and cardiac, functional and structural damage when myocardial infarction ( MI) was applied in the setting of kidney injury (induced by 5/6 nephrectomy- STNx). STNx or Sham surgery was induced in male Sprague-Dawley rats with MI or Sham surgery performed 4 weeks later. Rats were maintained for a further 8 weeks. Rats ( n = 36) were randomized into four groups: Sham+Sham, Sham+ MI, STNx+Sham and STNx+ MI. Increased renal tubulointerstitial fibrosis ( P < 0.01) and kidney injury molecule-1 expression ( P < 0.01) was observed in STNx+ MI compared to STNx+Sham animals, while there were no further reductions in renal function. Heart weight was increased in STNx+ MI compared to STNx+Sham or Sham+ MI animals ( P < 0.05), despite no difference in blood pressure. STNx+ MI rats demonstrated greater cardiomyocyte cross-sectional area and increased cardiac interstitial fibrosis compared to either STNx+Sham ( P < 0.01) or Sham+ MI ( P < 0.01) animals which was accompanied by an increase in diastolic dysfunction. These changes were associated with increases in ANP, cTGF and collagen I gene expression and phospho-p38 MAPK and phospho-p44/42 MAPK protein expression in the left ventricle. Addition of MI accelerated STNx-induced structural damage but failed to significantly exacerbate renal dysfunction. These findings highlight the bidirectional response in this model known to occur in cardiorenal syndrome ( CRS) and provide a useful model for examining potential therapies for CRS. [ABSTRACT FROM AUTHOR]

Chronic kidney disease is associated with higher risk of cardiovascular complication and this interaction can lead to accelerated dysfunction in both organs. Renalase, a kidney-derived cytokine, not only protects against various renal diseases but also exerts cardio-protective effects. Here, we investigated the role of renalase in the progression of cardiorenal syndrome ( CRS) after subtotal nephrectomy. Sprague-Dawley rats were randomly subjected to sham operation or subtotal (5/6) nephrectomy ( STNx). Two weeks after surgery, sham rats were intravenously injected with Hanks' balanced salt solution (sham), and STNx rats were randomly intravenously injected with adenovirus-β-gal ( STNx+Ad-β-gal) or adenovirus-renalase ( STNx+Ad-renalase) respectively. After 4 weeks of therapy, Ad-renalase administration significantly restored plasma, kidney and heart renalase expression levels in STNx rats. We noticed that STNx rats receiving Ad-renalase exhibited reduced proteinuria, glomerular hypertrophy and interstitial fibrosis after renal ablation compared with STNx rats receiving Ad-β-gal; these changes were associated with significant decreased expression of genes for fibrosis markers, proinflammatory cytokines and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase components. At the same time, systemic delivery of renalase attenuated hypertension, cardiomyocytes hypertrophy and cardiac interstitial fibrosis; prevented cardiac remodelling through inhibition of pro-fibrotic genes expression and phosphorylation of extracellular signal-regulated kinase (ERK)-1/2. In summary, these results indicate that renalase protects against renal injury and cardiac remodelling after subtotal nephrectomy via inhibiting inflammation, oxidative stress and phosphorylation of ERK-1/2. Renalase shows potential as a therapeutic target for the prevention and treatment of CRS in patients with chronic kidney disease. [ABSTRACT FROM AUTHOR]

Background Chronic kidney disease ( CKD), and its associated cardiovascular events, is one of the major causes of morbidity and recurrent hospitalization in Asian Pacific region. The subtotal nephrectomy ( STNx) model has remained the state-of-the-art prototype which closely mimics human CKD and cardiac-renal syndrome. Aim and Methods In this article, we comprehensively outline the procedure and methodology required to develop the rat model 5/6 nephrectomy and the associated procedures involved in assessing cardiac and renal functional outcomes. Results and Conclusion In addition, the expected functional outcomes from our own experience, and those of others, have been described. The STNx model in the rat is an established model of CKD and displays all the functional and structural hallmarks observed in the human condition. Lesser known are the cardiac effects of this model which make it ideal for studying cardiorenal syndrome. [ABSTRACT FROM AUTHOR]

SUMMARY: Cell proliferation, matrix accumulation and cell infiltration are characteristic features of progressive glomerulosclerosis and tubulointerstitial fibrosis. Platelet-derived growth factor (PDGF), a cytokine which has proliferative, prosclerotic and chemokine properties, has been shown to be upregulated in the rat remnant kidney model. Inhibition of the renin–angiotensin system by angiotensin-converting enzyme (ACE) inhibitors has a beneficial effect on renal function and morphology, but the effect of ACE inhibition on PDGF gene expression and PDGF-mediated cellular proliferation in subtotal nephrectomy has not been studied in detail. Twelve rats were subtotally nephrectomized (STNx) and received either the ACE inhibitor perindopril or a placebo for 12 weeks. Five sham-operated rats served as controls. Subtotal nephrectomy was associated with hypertension, proteinuria, elevated plasma creatinine and increased kidney weight. After 12 weeks, PDGF B-chain mRNA was significantly upregulated in the glomeruli and tubulointerstitium of subtotally nephrectomized rats. ACE inhibition attenuated PDGF mRNA expression in association with a reduction in tubular and glomerular proliferation, as assessed by staining for proliferating cell nuclear antigen. In the context of the known in vitro and in vivo effects of PDGF, it is postulated that the renoprotective action of ACE inhibitors may be partially related to PDGF-mediated antiproliferative mechanisms. [ABSTRACT FROM AUTHOR]