Increased susceptibility to structural acute kidney injury in a mouse model of presymptomatic cardiomyopathy

Abstract

The early events that signal renal dysfunction in presymptomatic heart failure are unclear. We tested the hypothesis that functional and mechanistic changes occur in the kidney that precede the development of symptomatic heart failure. We employed a transgenic mouse model with cardiomyocyte-specific overexpression of mutant α-B-crystallin that develops slowly progressive cardiomyopathy. Presymptomatic transgenic mice displayed an increase in serum creatinine (1.17 ± 0.34 vs. wild type 0.65 ± 0.16 mg/dl, < 0.05) and in urinary neutrophil gelatinase-associated lipocalin (NGAL; 278.92 ± 176.24 vs. wild type 49.11 ± 22.79 ng/ml, < 0.05) but no renal fibrosis. Presymptomatic transgenic mouse kidneys exhibited a twofold upregulation of the gene, marked overexpression of renin protein in the tubules, and a worsened response to ischemia-reperfusion injury based on serum creatinine (2.77 ± 0.66 in transgenic mice vs. 2.01 ± 0.58 mg/dl in wild type, < 0.05), urine NGAL (9,198.79 ± 3,799.52 in transgenic mice vs. 3,252.94 ± 2,420.36 ng/ml in wild type, < 0.05), tubule dilation score (3.4 ± 0.5 in transgenic mice vs. 2.6 ± 0.5 in wild type, < 0.05), tubule cast score (3.2 ± 0.4 in transgenic mice vs. 2.5 ± 0.5 in wild type, < 0.05), and TdT-mediated dUTP nick-end labeling (TUNEL)-positive nuclei (10.1 ± 2.1 in the transgenic group vs. 5.7 ± 1.6 per 100 cells counted in wild type, < 0.01). Our findings indicate functional renal impairment, urinary biomarker elevations, and induction of renin gene and protein expression in the kidney that occur in early presymptomatic heart failure, which increase the susceptibility to subsequent acute kidney injury.

Acute Decompensated Heart Failure and the Kidney: Physiological, Histological and Transcriptomic Responses to Development and Recovery

“…Our data provide the first mechanistic insights into the molecular changes associated with AKI during the development of, and recovery from, ADHF. These data add to work by Pleasant et al, 49 who used RNA sequencing to investigate renal gene expression in murine pre‐symptomatic HF. In kidney tissue collected at 24 weeks, Pleasant et al identified 6 genes that differed by >1.5‐fold between transgenic mice that develop cardiomyopathy and later progress to HF (after 24 weeks) and matched wild‐type controls.…”

The Genetic Dissection of Ace2 Expression Variation in the Heart of Murine Genetic Reference Population

“…In mice, some strains (e.g., C57BL/6) have only Ren1 , whereas others (e.g., DBA/2, J129) have two, Ren1 and Ren2 , genes ( 43 ). An increase in Ren1 , in particular, causes a striking overexpression of renin in kidney tubules in vivo , partially explaining the association between Ace2 and BP in BXDs ( 44 ). For the inflammation pathway, TNFα is a master cytokine that mediates inflammation and innate immune responses ( 45 ).…”

Heart-kidney interactions: mechanistic insights from animal models

“…In a transgenic mouse model of presymptomatic cardiomyopathy, FVB/N mice, with cardiac-specific overexpression of mutant ␣-B-crystallin, developed cardiomyocyte mitochondrial dysfunction, resulting in symptomatic heart failure with an enlarged and a dilated heart after 6 mo of age (84). Before any symptom of heart failure, transgenic mice had a mild increase in serum creatinine and demonstrated tubular damage, as assessed by a urinary biomarker of neutrophil gelatinaseassociated lipocalin in the absence of overt CKD and renal fibrosis.…”