Affiliation:
1. III. Department of Medicine University Hospital Hamburg‐Eppendorf Hamburg Germany
2. Hamburg Center for Kidney Health (HCKH) University Medical Center Hamburg‐Eppendorf Hamburg Germany
3. Institute for Pathology, Section Nephropathology University Medical Center Hamburg‐Eppendorf Hamburg Germany
4. Institute of Orthopedic Research and Biomechanics University Medical Center Ulm Ulm Germany
Abstract
Background and PurposeComplement activation may drive hypertension through its effects on immunity and tissue integrity.Experimental ApproachWe examined expression of C3, the central protein of the complement cascade, in hypertension.Key ResultsIncreased C3 expression was found in kidney biopsies and micro‐dissected glomeruli of patients with hypertensive nephropathy. Renal single cell RNA sequence data from normotensive and hypertensive patients confirmed expression of C3 in different cellular compartments of the kidney. In angiotensin II (Ang II) induced hypertension renal C3 expression was up‐regulated. C3−/− mice revealed a significant lower albuminuria in the early phase of hypertension. However, no difference was found for blood pressure, renal injury (histology, glomerular filtration rate, inflammation) and cardiac injury (fibrosis, weight, gene expression) between C3−/− and wildtype mice after Ang II infusion. Also, in deoxycorticosterone acetate (DOCA) salt hypertension, a significantly lower albuminuria was found in the first weeks of hypertension in C3 deficient mice but no significant difference in renal and cardiac injury. Down‐regulation of C3 by C3 targeting GalNAc (n‐acetylgalactosamine) small interfering RNA (siRNA) conjugate decreased C3 in the liver by 96% and lowered albuminuria in the early phase but showed no effect on blood pressure and end‐organ damage. Inhibition of complement C5 by siRNA showed no effect on albuminuria.Conclusion and ImplicationsIncreased C3 expression is found in the kidneys of hypertensive mice and men. Genetic and therapeutic knockdown of C3 improved albuminuria in the early phase of hypertension but did not ameliorate arterial blood pressure nor renal and cardiac injury.
Funder
Deutsche Forschungsgemeinschaft
Cited by
2 articles.
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