Moderate loss of renal mass exacerbates renal damage in a genetic mouse model of high-renin hypertension.

Chronic renal failure is a growing global health concern. While experimental and clinical data suggest that the loss of functional renal mass itself is a key driver of the progression to renal failure, mice typically exhibit resistance to this pathogenic mechanism. Since human chronic renal failure usually develops slowly over years and hypertension and an activated renin-angiotensin system are common comorbidities, we hypothesized that coexistence of both changes over a prolonged period may increase susceptibility to a reduction in renal mass in mice. To investigate this, we examined the effects of unilateral nephrectomy in SV-129 renin transgenic mice, which exhibit chronically elevated blood pressure levels due to a genetically clamped high renin. The reduction of renal mass led to stronger albuminuria and histopathological alterations, including glomerulosclerosis and protein casts compared to wildtype animals. All pathological changes were exacerbated by high salt intake, a known driver of kidney injury. In contrast, myocardial and aortic fibrosis were not aggravated in transgenic compared to control animals. These results show that loss of renal mass, particularly when combined with a high salt intake, acts as a pathogenic stimulus for chronic renal damage in mice in the context of high-renin hypertension. Renin transgenic mice may represent a valuable model for studying chronic renal failure associated with high-renin hypertension.