Angiotensin II and nitric oxide in renal autoregulation and endothelial function

Guan, Zhengrong. (2004). Angiotensin II and nitric oxide in renal autoregulation and endothelial function PhD Thesis, School of Medicine, The University of Queensland.

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Author Guan, Zhengrong.
Thesis Title Angiotensin II and nitric oxide in renal autoregulation and endothelial function
School, Centre or Institute School of Medicine
Institution The University of Queensland
Publication date 2004
Thesis type PhD Thesis
Supervisor Prof Zoltan H. Endre
A/Prof Glenda Gobe
Total pages 303
Collection year 2004
Language eng
Subjects L
321012 Nephrology and Urology
730115 Urogenital system and disorders
Formatted abstract

Blood flow to the kidney is kept constant by the process of autoregulation. Although many details of renal autoregulation remain controversial, investigations in animals and humans have established that renal autoregulation is critical to maintenance of extracellular fluid volume and systemic blood pressure. Impaired renal autoregulation has been observed in many pathological conditions, including hypertension, chronic and acute renal failure (ARF). 


The endothelium is now recognised as a large and complex endocrine organ, with many important physiological functions controlled through the generation of a number of vasoactive factors. Renal endothelial function directly influences autoregulation through nitric oxide (NO)-dependent and NO-independent mechanisms. Although changes to the L-arginine-NO pathway have been observed in hypertension and in ischaemia-reperfiision injury, endothelial dysfunction has been poorly characterised in the kidney. 


This study was designed to develop a simple in vitro experimental model for studying the role of endothelium in the intact kidney based on the isolated perfused rat kidney (IPRK). Once developed, the model was first used to examine the interaction between angiotensin II (Ang II) and NO in control of renal autoregulation under physiological conditions and then in animal models where endothelial dysfunction was likely to be present, namely in salt-sensitive hypertension utilising the deoxycorticosterone acetate (DOCA)-salt rat model and in ischaemic ARF. 


In Chapter 1, this review of the literature presents a brief review on renal function, autoregulation and of possible mediators and modulators of renal autoregulation and  endothelial function. General methods including the basic IPRK model are described in Chapter 2. Chapter 3 describes the development of the IPRK as a model for investigation of renal autoregulation and methods for quantifying endothelial function in the intact kidney. These studies showed that the IPRK autoregulated well when Ang II was present. The endothelium-dependent vasodilator, methacholine (MCh), antagonised Ang II-facilitated autoregulation. The methods and results were reproducible and the model could be used to study the roles of endothelium-derived vasoactive factors in renal autoregulation. 


The interaction between NO and Ang II in renal autoregulation is explored in Chapter 4. The results from this chapter suggested that excess NO impaired autoregulation under baseline conditions in this model and that endogenous and exogenous NO, vasodilator prostaglandins and endothelium-derived hyperpolarizing factor (EDHF) activity all antagonised Ang II-facilitated autoregulation. Facilitation of autoregulation by Ang II was blocked by inhibition of tubuloglomerular feedback (TGF) by frusemide, the AT1 antagonist Losartan, and the superoxide scavenger Tempol. These results suggested that the actions of Ang II were mediated by an AT1 linked TGF mechanism through depletion of NO, probably by stimulating superoxide generation. 


In Chapter 5, the mechanisms of impaired endothelial function and renal autoregulation in the salt-sensitive hypertensive rat model induced by DOCA-salt treatment are investigated. NO production continued in DOCA-salt kidneys and antagonized autoregulation, but was shielded from Ang Il-mediated reduction. Increasing NO production by chronic L-arginine supplementation reversed the raised autoregulatory threshold and restored Ang II-facilitation of autoregulation, but this was not antagonised by MCh. This study illustrated that impaired renal endothelial function in this model involved reduced activities of both NO and EDHF, while L-arginine supplementation partially reversed NO depletion, reduced EDHF activity appears to be irreversible. 


In Chapter 6, the role of endothelium is explored in kidneys subjected to ARF induced by varying periods of ischaemia followed by 24 hours reperfusion. The maximal vascular responses to both Ang II and MCh were unchanged, but the EC50 of Ang II and MCh were increased in kidneys treated with 60 minutes bilateral ischaemia, demonstrating endothelial dysfunction. Renal autoregulation was impaired by the overproduction of NO due to prolonged ischaemia, but continued to be facilitated by Ang II at a higher dose and was enhanced by NOS inhibition. TGF was still preserved 24 hours after 60 minutes ischaemia. 


These studies demonstrate that the IPRK is a useful model for the in vitro study of endothelial function and renal autoregulation, allowing detailed investigation of the interactions between Ang II and endothelium-derived autacoids. The project provides novel insights into the underlying mechanisms leading to endothelial dysfunction and impaired renal autoregulation in hypertensive and ARF rat kidneys.

Keyword Kidneys -- Diseases
Vascular endothelium -- Physiology
Vascular endothelium -- Pathophysiology
Angiotensins -- Physiological effect
Nitric oxide -- Physiological effect

Document type: Thesis
Collection: UQ Theses (RHD) - UQ staff and students only
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Created: Fri, 24 Aug 2007, 18:33:07 EST