Novel Roles and Mechanisms of Proximal Tubule Mitochondrial Angiotensin II and Sirtuin 3 in Hypertension

Tulane University Of Louisiana, New Orleans LA

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Abstract

Hypertension is a major risk factor for stroke, cardiovascular and kidney injury with nearly 50% of the US adults develop hypertension and take antihypertensive drugs daily. However, the mechanisms underlying the development of hypertension and kidney injury remain incompletely understood. During the last funding period, we demonstrated two functional mitochondrial angiotensin II (Ang II)/Agtr1a/O2- and Ang II/Agtr2/NO/cGMP signaling pathways in the proximal tubules that play key counteracting roles in regulating mitochondrial function, inducing mitochondrial dysfunction, and Ang II- induced hypertension. The proximal tubules are a key player in Ang II-induced hypertension and ischemia and reperfusion (I/R)-induced kidney injury (AKI), because the proximal tubules reabsorb >65% of the filtered NaCl from the glomeruli and are extremely sensitive to mitochondrial dysfunction in hypertension and I/R-induced AKI. Sirtuin 3 (SIRT3), a NAD- dependent deacetylase, is a major mitochondrial protein in the matrix that is encoded by the SIRT3 gene. The key functions of SIRT3 in the mitochondria include important anti-oxidative, anti-inflammation, and blood pressure-lowering effects by decreasing reactive oxygen species/O2- production via activation of long chain fatty acyl-CoA dehydrogenase (LCAD), succinate dehydrogenase (SDH), and NADH dehydrogenase. Ang II induces mitochondrial dysfunction by inhibiting SIRT3 expression and increasing O2- production which contributes to hypertension and AKI. Moreover, SIRT3 has been implicated in sex dimorphism in Ang II-induced hypertension and I/R-induced AKI, with premenopausal females expressing higher levels of SIRT3 and more protective against the development of hypertension and AKI. However, whether SIRT3 in the mitochondria of the proximal tubules plays an important sex-specific role in Ang II-induced hypertension and I/R-induced AKI has not been studied previously. In preliminary studies, we have demonstrated for the 1st time that deletion of SIRT3 selectively in the mitochondria of the proximal tubules augments, whereas overexpression of a mitochondria-targeting SIRT3 in the proximal tubules attenuates, Ang II-induced hypertension and I/R-induced AKI in a novel proximal tubule- specific PT-Sirt3-/- mouse model. In this revised R01 renewal proposal, we will mechanistically test this new hypothesis using novel proximal tubule-specific, mitochondria-targeting loss and gain of function in proximal tubule cell and mutant mouse models. Specific Aim 1 will determine whether deletion of SIRT3 in the mitochondria of the proximal tubules will aggravate Ang II-induced and 2-kidney, 1-clip (2K1C) Goldblatt hypertension, whereas overexpression of SIRT3 in the mitochondria of the proximal tubules will attenuate Ang II-induced and 2K1C Goldblatt hypertension. Specific Aim 2 will determine whether deletion of SIRT3 selectively in the mitochondria of the proximal tubules will aggravate I/R-induced AKI, whereas overexpression of SIRT3 selectively in the mitochondria of the proximal tubules will attenuate I/R-induced AKI. Finally, Specific Aim 3 will mechanistically elucidate the molecular and signaling mechanisms underlying the detrimental effects of deletion and beneficial effects of overexpression of SIRT3 selectively in the mitochondria of mouse proximal tubule cells. This project will help uncover new mechanisms of Ang II-induced hypertension and AKI and develop novel proximal tubule-specific, mitochondria-targeting therapeutic drugs to treat poorly controlled hypertension and AKI.