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

La Tawnya Pleasant, Qing Ma, Mahima Devarajan, Priyanka Parameswaran, Keri Drake, Brian Siroky, Kritton Shay-Winkler, Jeffrey Robbins, Prasad Devarajan

Research output: Contribution to journalArticle

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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, P < 0.05) and in urinary neutrophil gelatinase-associated lipocalin (NGAL; 278.92 ± 176.24 vs. wild type 49.11 ± 22.79 ng/ ml, P < 0.05) but no renal fibrosis. Presymptomatic transgenic mouse kidneys exhibited a twofold upregulation of the Ren1 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, P < 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, P < 0.05), tubule dilation score (3.4 ± 0.5 in transgenic mice vs. 2.6 ± 0.5 in wild type, P < 0.05), tubule cast score (3.2 ± 0.4 in transgenic mice vs. 2.5 ± 0.5 in wild type, P < 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, P < 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.

Original languageEnglish (US)
Pages (from-to)F699-F705
JournalAmerican Journal of Physiology - Renal Physiology
Volume313
Issue number3
DOIs
StatePublished - Sep 1 2017

Fingerprint

Cardiomyopathies
Acute Kidney Injury
Transgenic Mice
Kidney
Heart Failure
Renin
Creatinine
Crystallins
Reperfusion Injury
Serum
Cardiac Myocytes
Dilatation
Proteins
Fibrosis
Up-Regulation
Biomarkers
Urine
Gene Expression
Genes

Keywords

  • Acute kidney injury
  • Cardiorenal syndrome
  • Ischemia-reperfusion injury
  • Neutrophil gelatinase-associated lipocalin
  • Renin

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Increased susceptibility to structural acute kidney injury in a mouse model of presymptomatic cardiomyopathy. / Pleasant, La Tawnya; Ma, Qing; Devarajan, Mahima; Parameswaran, Priyanka; Drake, Keri; Siroky, Brian; Shay-Winkler, Kritton; Robbins, Jeffrey; Devarajan, Prasad.

In: American Journal of Physiology - Renal Physiology, Vol. 313, No. 3, 01.09.2017, p. F699-F705.

Research output: Contribution to journalArticle

Pleasant, LT, Ma, Q, Devarajan, M, Parameswaran, P, Drake, K, Siroky, B, Shay-Winkler, K, Robbins, J & Devarajan, P 2017, 'Increased susceptibility to structural acute kidney injury in a mouse model of presymptomatic cardiomyopathy', American Journal of Physiology - Renal Physiology, vol. 313, no. 3, pp. F699-F705. https://doi.org/10.1152/ajprenal.00505.2016
Pleasant, La Tawnya ; Ma, Qing ; Devarajan, Mahima ; Parameswaran, Priyanka ; Drake, Keri ; Siroky, Brian ; Shay-Winkler, Kritton ; Robbins, Jeffrey ; Devarajan, Prasad. / Increased susceptibility to structural acute kidney injury in a mouse model of presymptomatic cardiomyopathy. In: American Journal of Physiology - Renal Physiology. 2017 ; Vol. 313, No. 3. pp. F699-F705.
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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, P < 0.05) and in urinary neutrophil gelatinase-associated lipocalin (NGAL; 278.92 ± 176.24 vs. wild type 49.11 ± 22.79 ng/ ml, P < 0.05) but no renal fibrosis. Presymptomatic transgenic mouse kidneys exhibited a twofold upregulation of the Ren1 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, P < 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, P < 0.05), tubule dilation score (3.4 ± 0.5 in transgenic mice vs. 2.6 ± 0.5 in wild type, P < 0.05), tubule cast score (3.2 ± 0.4 in transgenic mice vs. 2.5 ± 0.5 in wild type, P < 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, P < 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.",
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