Experimental mild renal insufficiency mediates early cardiac apoptosis, fibrosis, and diastolic dysfunction

A kidney-heart connection

Fernando L. Martin, Paul McKie, Alessandro Cataliotti, S Jeson Sangaralingham, Josef Korinek, Brenda K. Huntley, Elise A. Oehler, Gerald E. Harders, Tomoko Ichiki, Sarah Mangiafico, Karl A Nath, Margaret May Redfield, Horng Haur Chen, John C Jr. Burnett

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Impaired renal function with loss of nephron number in chronic renal disease (CKD) is associated with increased cardiovascular morbidity and mortality. However, the structural and functional cardiac response to early and mild reduction in renal mass is poorly defined. We hypothesized that mild renal impairment produced by unilateral nephrectomy (UNX) would result in early cardiac fibrosis and impaired diastolic function, which would progress to a more global left ventricular (LV) dysfunction. Cardiorenal function and structure were assessed in rats at 4 and 16 wk following UNX or sham operation (Sham); (n = 10 per group). At 4 wk, blood pressure (BP), aldosterone, glomerular filtration rate (GFR), proteinuria, and plasma B-type natriuretic peptide (BNP) were not altered by UNX, representing a model of mild early CKD. However, UNX was associated with significantly greater LV myocardial fibrosis compared with Sham. Importantly, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining revealed increased apoptosis in the LV myocardium. Further, diastolic dysfunction, assessed by strain echocardiography, but with preserved LVEF, was observed. Changes in genes related to the TGF-β and apoptosis pathways in the LV myocardium were also observed. At 16 wk post-UNX, we observed persistent LV fibrosis and impairment in LV diastolic function. In addition, LV mass significantly increased, as did LVEDd, while there was a reduction in LVEF. Aldosterone, BNP, and proteinuria were increased, while GFR was decreased. The myocardial, structural, and functional alterations were associated with persistent changes in the TGF-β pathway and even more widespread changes in the LV apoptotic pathway. These studies demonstrate that mild renal insufficiency in the rat results in early cardiac fibrosis and impaired diastolic function, which progresses to more global LV remodeling and dysfunction. Thus, these studies importantly advance the concept of a kidney-heart connection in the control of myocardial structure and function.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume302
Issue number2
DOIs
StatePublished - Jan 2012

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Renal Insufficiency
Fibrosis
Apoptosis
Kidney
Brain Natriuretic Peptide
Left Ventricular Dysfunction
Aldosterone
Glomerular Filtration Rate
Proteinuria
Myocardium
Ventricular Remodeling
DNA Nucleotidylexotransferase
Nephrons
Nephrectomy
Chronic Renal Insufficiency
Left Ventricular Function
Echocardiography
Staining and Labeling
Blood Pressure
Morbidity

Keywords

  • Heart failure
  • Kidney
  • Natriuretic peptides
  • Nephrectomy
  • Remodeling

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Experimental mild renal insufficiency mediates early cardiac apoptosis, fibrosis, and diastolic dysfunction : A kidney-heart connection. / Martin, Fernando L.; McKie, Paul; Cataliotti, Alessandro; Sangaralingham, S Jeson; Korinek, Josef; Huntley, Brenda K.; Oehler, Elise A.; Harders, Gerald E.; Ichiki, Tomoko; Mangiafico, Sarah; Nath, Karl A; Redfield, Margaret May; Chen, Horng Haur; Burnett, John C Jr.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 302, No. 2, 01.2012.

Research output: Contribution to journalArticle

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AU - Sangaralingham, S Jeson

AU - Korinek, Josef

AU - Huntley, Brenda K.

AU - Oehler, Elise A.

AU - Harders, Gerald E.

AU - Ichiki, Tomoko

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