Refining the Mouse Subtotal Nephrectomy in Male 129S2/SV Mice for Consistent Modeling of Progressive Kidney Disease With Renal Inflammation and Cardiac Dysfunction

Abstract

Chronic kidney disease (CKD) is prevalent worldwide and is associated with significant co-morbidities including cardiovascular disease (CVD). Traditionally, the subtotal nephrectomy (remnant kidney) experimental model has been performed in rats to model progressive renal disease. The model experimentally mimics CKD by reducing nephron number, resulting in renal insufficiency. Presently, there is a lack of translation of pre-clinical findings into successful clinical results. The pre-clinical nephrology field would benefit from reproducible progressive renal disease models in mice in order to avail of more widely available transgenics and experimental tools to dissect mechanisms of disease. Here we evaluate if a simplified single step subtotal nephrectomy (STNx) model performed in the 129S2/SV mouse can recapitulate the renal and cardiac changes observed in patients with CKD in a reproducible and robust way. The single step STNx surgery was well-tolerated and resulted in clinically relevant outcomes including hypertension, increased urinary albumin:creatinine ratio, and significantly increased serum creatinine, phosphate and urea. STNx mice developed significant left ventricular hypertrophy without reduced ejection fraction or cardiac fibrosis. Analysis of intra-renal inflammation revealed persistent recruitment of Ly6Chi monocytes transitioning to pro-fibrotic inflammatory macrophages in STNx kidneys. Unlike 129S2/SV mice, C57BL/6 mice exhibited renal fibrosis without proteinuria, renal dysfunction, or cardiac pathology. Therefore, the 129S2/SV genetic background is susceptible to induction of progressive proteinuric renal disease and cardiac hypertrophy using our refined, single-step flank STNx method. This reproducible model could be used to study the systemic pathophysiological changes induced by CKD in the kidney and the heart, intra-renal inflammation and for testing new therapies for CKD.

A systematic review and meta-analysis of murine models of uremic cardiomyopathy

“…Furthermore, mild diastolic cardiac dysfunction was detected whereas systolic function or left ventricular dimensions were only rarely affected. [16][17][18][19][20][21] Six to 11 weeks after SNX, [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] increased blood pressure, cardiac hypertrophy, and systolic dysfunction were reported in only 40% to 50% of studies while cardiac fibrosis was identified in 2 of 3 studies. Although diastolic dysfunction was observed in 85% of studies, left ventricular diameter was only rarely affected.…”

Shunaoxin pills improve the antihypertensive effect of nifedipine and alleviate its renal lipotoxicity in spontaneous hypertension rats

“…According to the histological examination, nifedipine displayed apparent infiltration of inflammatory cells and fibrosis in the renal tubular interstitium compared with SHR. Compared with nifedipine group, nifedipine + SNX decreased inflammatory cell infiltration and fibrosis, which were regarded as the histological markers for renal injure 28 . Furthermore, the levels of Cr and BUN in SHR group were prominently increased compared with WKY in plasma.…”

Subtotal Nephrectomy as a Model of Chronic Kidney Disease: A Systematic Review

“…Incisions can be in the form of a laparotomy, 11,12 dorsal, 13,14 and an incision in the flank region. 6,9,10,[15][16][17] The majority of surgical procedures are carried out in 2 steps, although there are studies that are carried out in 1 step. 15 When performed in 2 steps, the period between the two surgical procedures also varies between 1-2 weeks.…”

“…6,9,10,[15][16][17] The majority of surgical procedures are carried out in 2 steps, although there are studies that are carried out in 1 step. 15 When performed in 2 steps, the period between the two surgical procedures also varies between 1-2 weeks. However, some are only 1 day away.…”

“…Decreased in renal function in the 5/6 nephrectomy model can be seen through an increase in serum creatinine, phosphate, and urea in the blood. 15 The accumulation of metabolic waste products in the blood over a long period will lead to uremia. The high levels of protein and albumin detected in the urine also indicate a defect in the glomerular filtration function.…”