| Abstract: |
Incident chronic kidney disease (CKD) varies in populations with hypertension of similar severity. Proteinuria promotes CKD progression in part due to activation of plasminogen to plasmin in the podocytes, resulting in oxidative stress-mediated injury. Additional mechanisms include deficiency of renal alpha-klotho, that inhibits Wnt/beta-catenin, an up regulator of intra-renal renin angiotensin system (RAS) genes. Alpha-klotho deficiency therefore results in upregulation of the intra-renal RAS via Wnt/beta-catenin. In hypertensive, Dahl salt sensitive (DS) and spontaneously hypertensive rats (SHR), we investigated renal and vascular injury, miR-155, AT1R, alpha-klotho, and TNF-α. Hypertensive high salt DS (DS-HS), but not SHR developed proteinuria, plasminuria, and glomerulosclerosis. Compared to DS low salt (DS-LS), in hypertensive DS-HS alpha-klotho decreased 5-fold in serum and 2.6-fold in kidney, whereas serum mir-155 decreased 3.3-fold and AT1R increased 52% in kidney and 77% in aorta. AT1R, alpha-klotho, and miR-155 remained unchanged in prehypertensive and hypertensive SHR. TNF-α increased by 3-fold in serum and urine of DS-HS rats. These studies unveiled in salt sensitive DS-HS, but not in SHR, a genetically conditioned dysfunction of the intermolecular network integrated by alpha-klotho, RAS, miR-155, and TNF-α that is at the helm of their end-organ susceptibility while plasminuria may participate as a second hit. © 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society. |
| Keywords: |
unclassified drug; genetics; hypertension; nonhuman; animal; metabolism; animals; reverse transcription polymerase chain reaction; microrna; animal experiment; body weight; in vitro study; immunoreactivity; blood; kidney; tumor necrosis factor-alpha; kidney injury; disease progression; densitometry; rat; western blotting; renal insufficiency, chronic; rats; micrornas; disease exacerbation; proteinuria; chronic kidney failure; rna extraction; polyacrylamide gel electrophoresis; tumor necrosis factor; plasmin; beta glucuronidase; urinary excretion; plasminogen; renin-angiotensin system; glucuronidase; podocyte; periodic acid schiff stain; spontaneously hypertensive rat; microrna 155; angiotensin 1 receptor; receptor, angiotensin, type 1; chemoluminescence; klotho protein; mir-155; male; article; experimental test; injury scale; dahl rat; rats, inbred dahl; dahl salt sensitive rat; renin angiotensin aldosterone system; alpha-klotho; salt sensitivity; klotho proteins; rats, inbred shr; alpha klotho; mirn155 microrna, rat; decapitation; genetically conditioned interaction; glomerular injury score; intra renal renin angiotensin system; left ventricular hypertrophy; ventricular hypertrophy
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