Increased Klk9 Urinary Excretion Is Associated to Hypertension-Induced Cardiovascular Damage and Renal Alterations

Abstract

Early detection of hypertensive end-organ damage and secondary diseases are key determinants of cardiovascular prognosis in patients suffering from arterial hypertension. Presently, there are no biomarkers for the detection of hypertensive target organ damage, most outstandingly including blood vessels, the heart, and the kidneys.We aimed to validate the usefulness of the urinary excretion of the serine protease kallikrein-related peptidase 9 (KLK9) as a biomarker of hypertension-induced target organ damage.Urinary, plasma, and renal tissue levels of KLK9 were measured by the Western blot in different rat models of hypertension, including angiotensin-II infusion, DOCA-salt, L-NAME administration, and spontaneous hypertension. Urinary levels were associated to cardiovascular and renal injury, assessed by histopathology. The origin of urinary KLK9 was investigated through in situ renal perfusion experiments.The urinary excretion of KLK9 is increased in different experimental models of hypertension in rats. The ACE inhibitor trandolapril significantly reduced arterial pressure and the urinary level of KLK9. Hypertension did not increase kidney, heart, liver, lung, or plasma KLK9 levels. Hypertension-induced increased urinary excretion of KLK9 results from specific alterations in its tubular reabsorption, even in the absence of overt nephropathy. KLK9 urinary excretion strongly correlates with cardiac hypertrophy and aortic wall thickening.KLK9 appears in the urine in the presence of hypertension as a result of subtle renal handling alterations. Urinary KLK9 might be potentially used as an indicator of hypertensive cardiac and vascular damage.

The Urinary Level of Injury Biomarkers Is Not Univocally Reflective of the Extent of Toxic Renal Tubular Injury in Rats

“…These include the maleate model and the megalin knock-out model. Acute administration of sodium maleate uncouples proximal transmembrane transport and inhibits proximal reabsorption [ 34 , 35 , 36 ], leading to increased urinary excretion of a variety of protein biomarkers in the ultrafiltrate, with no effect on renal structures [ 26 , 34 , 37 , 38 , 39 , 40 ]. A very similar scenario is generated by knocking out megalin [ 41 ], an essential member of the proximal multiligand binding receptor endocytic complex responsible for protein reclamation [ 42 ].…”

A new enzyme-linked immunosorbent assay (ELISA) for human free and bound kallikrein 9

“…KLK9 gene expression has also been related to non-malignant diseases. Recent studies associate KLK9 expression patterns with cardiac hypertrophy and hypertension-induced target organ damage [10], psoriatic lesions [11] and complications in asthma patients [12]. In general, KLK9-related studies are still very few.…”

“…Further analysis of cancer cell lines revealed that KLK9 is constitutively expressed in breast, ovarian and lung cancer [9]. Recent studies associate KLK9 expression patterns with non-malignant diseases, such as cardiac hypertrophy and hypertension-induced target organ damage [10] psoriatic lesions [11] and complications in asthma patients [12]. …”