Comparative analysis of hypertensive nephrosclerosis in animal models of hypertension and its relevance to human pathology. Glomerulopathy

Abstract

Current research on hypertension utilizes more than fifty animal models that rely mainly on stable increases in systolic blood pressure. In experimental hypertension, grading or scoring of glomerulopathy in the majority of studies is based on a wide range of opinion-based histological changes that do not necessarily comply with lesional descriptors for glomerular injury that are well-established in clinical pathology. Here, we provide a critical appraisal of experimental hypertensive glomerulopathy with the same approach used to assess hypertensive glomerulopathy in humans. Four hypertensive models with varying pathogenesis were analyzed–chronic angiotensin II infused mice, mice expressing active human renin in the liver (TTRhRen), spontaneously hypertensive rats (SHR), and Goldblatt two-kidney one-clip rats (2K1C). Analysis of glomerulopathy utilized the same criteria applied in humans–hyalinosis, focal segmental glomerulosclerosis (FSGS), ischemic, hypertrophic and solidified glomeruli, or global glomerulosclerosis (GGS). Data from animal models were compared to human reference values. Kidneys in TTRhRen mice, SHR and the nonclipped kidneys in 2K1C rats had no sign of hyalinosis, FSGS or GGS. Glomerulopathy in these groups was limited to variations in mesangial and capillary compartment volumes, with mild increases in collagen deposition. Histopathology in angiotensin II infused mice corresponded to mesangioproliferative glomerulonephritis, but not hypertensive glomerulosclerosis. The number of nephrons was significantly reduced in TTRhRen mice and SHR, but did not correlate with severity of glomerulopathy. The most substantial human-like glomerulosclerotic lesions, including FSGS, ischemic obsolescent glomeruli and GGS, were found in the clipped kidneys of 2K1C rats. The comparison of affected kidneys to healthy control in animals produces lesion values that are numerically impressive but correspond to mild damage if compared to humans. Animal studies should be standardized by employing the criteria and classifications established in human pathology to make experimental and human data fully comparable for comprehensive analysis and model improvements.

A New Approach for the Development of Multiple Cardiovascular Risk Factors in Two Rat Models of Hypertension

“…Spontaneous hypertensive rats are the most widely used animal model of essential hypertension. This model induces cardiac and renal impairment, without a direct relationship with chronic kidney disease [ 15 ]. The SHR strain of rats originated in Kyoto, Japan, by crossing Wistar rats that exhibited spontaneous elevations of BP.…”

Comparative Analysis of Hypertensive Tubulopathy in Animal Models of Hypertension and Its Relevance to Human Pathology

“…To detect fibrosis, mouse monoclonal anti–α-smooth muscle actin (α-SMA) antibody (1:500; Santa Cruz Biotechnology, Dallas, TX, USA) was used. Primary antibodies were visualized simultaneously with the mixture of fluorescent secondary antibodies A488 and Cy 3 (Jackson ImmunoResearch, West Grove, PA, USA). Microscopic investigations were performed in a blinded manner on coded sections.…”

“…Glomerulopathy was precisely analyzed in our recent study. 3 In the areas with developing CPN, glomeruli were intact and not involved in surrounding lesions (Supplementary Figure 3).…”

“…18 The different criteria cause disagreement and incomparable data in histopathology analysis. Similar to disparity in the glomerulopathy assessment, 3 there is a strong tendency to combine all pathological variables into one “integrated” score (Supplementary Table 3). 19,20,21 Second, in human pathology, for inflammatory infiltrates, it is mandatory to identify cell types and determine their localization relative to the cortex or medulla, glomeruli, or proximal and distal tubules.…”

“…The incidence of end-stage kidney disease related to hypertensive nephrosclerosis has significantly increased in Europe and the United States in the past 20 years and now constitutes 15% and 28% of all new cases, respectively. 1,2 As we discussed in the previous study, 3 the limited number of renal biopsies from hypertensive patients makes animal research extremely important in understanding this polygenic multifactorial disease. 2,4,5 Therefore, more than 50 animal models have been created to study the pathogenesis of hypertension, 6,7,8 and each of the studied models recapitulates a specific pathway in the development of hypertension.…”