Myocardial infarction does not further impair renal damage in 5/6 nephrectomized rats

Windt, Willemijn A.K.M.; Henning, Robert H.; Kluppel, Alex C. A.; Xu, Ying; Zeeuw, Dick de; Dokkum, Richard P. E. van

doi:10.1093/ndt/gfn233

Cited by 34 publications

(53 citation statements)

References 31 publications

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“…Renal mass reduction clearly induced cardiac alterations in vehicle-treated 5/6Nx rats, including LV hypertrophy and elevated LVSP and LVEDP, as previously described (Amann et al, 1998;Kennedy et al, 2003;Windt et al, 2008a). Although PKI-166 did not lower heart weight, indicating that it did not prevent LV hypertrophy, the drug completely normalized the 5/6Nx-induced increase in LVEDP.…”

Section: Chronic Egfr Inhibition Prevents Hypertensionsupporting

confidence: 74%

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Epidermal Growth Factor Receptor Inhibitor PKI-166 Governs Cardiovascular Protection without Beneficial Effects on the Kidney in Hypertensive 5/6 Nephrectomized Rats

Ulu

Mulder

Vavrinec

et al. 2013

J Pharmacol Exp Ther

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Transactivation of epidermal growth factor receptor (EGFR) signaling by G protein-coupled receptors has been implicated in several cardiovascular (CV) conditions, including hypertension, heart failure, and cardiac and vascular hypertrophy. However, the therapeutic potential of EGFR inhibition in these conditions is currently unknown. The main objective of the present study was to investigate cardiac, vascular, and renal effects of EGFR inhibition by 4- in the hypertensive chronic kidney disease model. Rats underwent 5/6 nephrectomy (5/ 6Nx) and were treated with PKI-166, lisinopril or vehicle from week 6 after disease induction until week 12. Sham animals received either PKI-166 or vehicle. Treatment with PKI-166 did not affect the development of the characteristic renal features in 5/6Nx, including proteinuria, diminished creatinine clearance, and increased glomerulosclerosis, whereas these were attenuated by lisinopril. Despite absence of effects on progressive renal damage, PKI-166 attenuated the progression of hypertension and maintained cardiac function (left ventricle end-diastolic pressure) to a similar extent as lisinopril. Also, PKI-166 attenuated the increase in phosphorylated EGFR in the heart as induced by 5/6Nx. Moreover, PKI-166 and lisinopril restored the impaired contraction of isolated thoracic aortic rings to phenylephrine and angiotensin II and impaired myogenic constriction of small mesenteric arteries in 5/6Nx rats. Blockade of the EGFR displays a CV benefit independent of limiting the progression of renal injury. Our findings extend the evidence on EGFR signaling as a target in CV disorders.

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Section: Chronic Egfr Inhibition Prevents Hypertensionsupporting

confidence: 74%

“…PKI-166 was provided by Dr. Giorgio Caravatti (Novartis Pharma AG, Basel, Switzerland). The dose of lisinopril was selected based on our previous study (Windt et al, 2008a) in which lisinopril at a dose of 5 mg/kg/day decreased blood pressure in exactly the same model of chronic kidney disease.…”

mentioning

confidence: 99%

Epidermal Growth Factor Receptor Inhibitor PKI-166 Governs Cardiovascular Protection without Beneficial Effects on the Kidney in Hypertensive 5/6 Nephrectomized Rats

Ulu

Mulder

Vavrinec

et al. 2013

J Pharmacol Exp Ther

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“…31,32 Other clinical and experimental studies provide evidence that coronary microvascular rarefaction in diastolic and hypertrophic heart failure promotes tissue hypoxia, cell death, and fibrosis, all contributing to the progression from compensated hypertrophy to contractile dysfunction. 33,34 In adults, vascular proliferation is part of the compensatory and repair response to local hypoxia and tissue damage in which endothelial cells proliferate and migrate into the ischemic injury site during macrophage influx and phagocytosis of necrotic tissue.…”

Section: Microvascular Fibrotic Changes In Zsf1 Ob Ratsmentioning

confidence: 99%

Distinct Endothelial Cell Responses in the Heart and Kidney Microvasculature Characterize the Progression of Heart Failure With Preserved Ejection Fraction in the Obese ZSF1 Rat With Cardiorenal Metabolic Syndrome

Dijk

Oosterhuis

et al. 2016

Circ: Heart Failure

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Background— The combination of cardiac and renal disease driven by metabolic risk factors, referred to as cardiorenal metabolic syndrome (CRMS), is increasingly recognized as a critical pathological entity. The contribution of (micro)vascular injury to CRMS is considered to be substantial. However, mechanistic studies are hampered by lack of in vivo models that mimic the natural onset of the disease. Here, we evaluated the coronary and renal microvasculature during CRMS development in obese diabetic Zucker fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1) rats. Methods and Results— Echocardiographic, urine, and blood evaluations were conducted in 3 groups (Wistar-Kyoto, lean ZSF1, and obese ZSF1) at 20 and 25 weeks of age. Immunohistological evaluation of renal and cardiac tissues was conducted at both time points. At 20 and 25 weeks, obese ZSF1 rats showed higher body weight, significant left ventricular hypertrophy, and impaired diastolic function compared with all other groups. Indices of systolic function did not differ between groups. Obese ZSF1 rats developed hyperproliferative vascular foci in the subendocardium, which lacked microvascular organization and were predilection sites of inflammation and fibrosis. In the kidney, obese ZSF1 animals showed regression of the peritubular and glomerular microvasculature, accompanied by tubulointerstitial damage, glomerulosclerosis, and proteinuria. Conclusions— The obese ZSF1 rat strain is a suitable in vivo model for CRMS, sharing characteristics with the human syndrome during the earliest onset of disease. In these rats, CRMS induces microvascular fibrotic responses in heart and kidneys, associated with functional impairment of both organs.

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“…Only two animal studies investigated the effect of 'dual damage' to heart and kidneys, with MI following shortly after a renal insult in rats, with conflicting results. 65,67 Different models of nephrectomy exist in mice, but these are not as robust as those in rats, with variable changes in renal function and cardiac abnormalities. [68][69][70][71][72] The renal hemodynamic response to heart failure (HF) induced by pacing in dogs has also been investigated, [73][74][75] but whether there is histological damage is unknown.…”

Section: Previous Research On the Cardiorenal Interactionsmentioning

confidence: 99%

Origins of Cardiorenal Syndrome and the Cardiorenal Connection

Bongartz¹,

Joles²

2012

Chronic Kidney Disease

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Myocardial infarction does not further impair renal damage in 5/6 nephrectomized rats

Cited by 34 publications

References 31 publications

Epidermal Growth Factor Receptor Inhibitor PKI-166 Governs Cardiovascular Protection without Beneficial Effects on the Kidney in Hypertensive 5/6 Nephrectomized Rats

Epidermal Growth Factor Receptor Inhibitor PKI-166 Governs Cardiovascular Protection without Beneficial Effects on the Kidney in Hypertensive 5/6 Nephrectomized Rats

Distinct Endothelial Cell Responses in the Heart and Kidney Microvasculature Characterize the Progression of Heart Failure With Preserved Ejection Fraction in the Obese ZSF1 Rat With Cardiorenal Metabolic Syndrome

Origins of Cardiorenal Syndrome and the Cardiorenal Connection

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