Rapid development of severe end-organ damage in C57BL/6 mice by combining DOCA salt and angiotensin II

Abstract

The C57BL/6 mouse strain serves as the genetic background of many transgenic and gene knockout models; however, this strain appears to be resistant to hypertension-induced renal injury. We developed a new model of hypertensive end-organ damage in C57BL/6 mice by combining deoxycorticosterone acetate (DOCA) and salt with angiotensin II infusion. The systolic blood pressure (SBP) was significantly elevated in DOCA salt-angiotensin II mice compared to control mice or mice treated individually with DOCA salt or angiotensin II. Hypertensive glomerular damage, increased expression of profibrotic and inflammatory genes, albuminuria, tubular casts, increased plasma cholesterol, cardiac hypertrophy, and fibrosis were found in mice treated with DOCA salt-angiotensin II. The SBP in the angiotensin II-infused group was further increased by increasing the infusion rate; only mild injury was observed in these mice, suggesting that blood pressure was not a causal factor. Removal of DOCA and the angiotensin pump lowered blood pressure to normal; however, albuminuria along with the glomerular and cardiac damage did not completely resolve. Our study describes a new model of hypertensive end-organ damage and repair in C57BL/6 mice.

Depletion of endogenous kallistatin exacerbates renal and cardiovascular oxidative stress, inflammation, and organ remodeling

“…Studies have shown that TGF-␤ promotes glomerular hypertrophy in diabetic mice (36) and cardiomyocyte hypertrophy in cultured cells (33). Angiotensin II and endothelin-1, which are both expressed in DOCA-salt hypertension (20,23), have also been demonstrated to stimulate glomerular enlargement (21,40) and cardiomyocyte hypertrophy (22,33). Although KS gene delivery has been shown to attenuate renal and cardiac tissue remodeling (16,37), KS depletion by anti-KS antibody worsened both glomerular and cardiomyocyte hypertrophy.…”

Adiponectin Promotes Functional Recovery after Podocyte Ablation

“…9 Likewise, chemical injury models cause direct simultaneous damage to multiple cell types, such as renal tubules. 8 Several diabetic models exhibit some forms of nephropathy but are metabolically more complicated than podocyte-specific injuries. Genetic mouse models deficient in key slit diaphragm proteins, such as nephrin or podocin, for example, develop early severe nephritis with multiple secondary effects and die shortly after birth.…”

“…Rodent remnant models, such as uninephrectomies and 5/6 nephrectomies, and various chemical injury models have multiple effects on different nephron structures. 8,9 Genetic manipulations of podocytes in mice and rats have demonstrated the importance of specific surface and structural proteins on podocyte function or rendered the models' podocytes more susceptible to injury or cytotoxic ablation. 4,[10][11][12] Correlating many of these models to initial human podocyte loss, however, has not always been possible because of design limitations or non-physiologic pathologic progression.…”

AT1 antagonism and renin inhibition in mice: pivotal role of targeting angiotensin II in chronic kidney disease

“…Systolic blood pressure was measured in conscious mice using computerized tail-cuff plethysmography (Process Control Blood Pressure 2900 series; TSE Systems) as described elsewhere (23). Mice were trained to get used to this procedure in advance, and initial measurements were not incorporated.…”

“…ANG II has long been considered the major bioactive contributor to chronic kidney disease (CKD). Chronic ANG II infusion induces albuminuria and renal injury (23). Conversely, angiotensin-converting enzyme (ACE) inhibition and ANG II type 1 receptor (AT 1 ) antagonism are nephroprotective (1,4,29).…”