Complement component C3 as a new target to lower albuminuria in hypertensive kidney disease

TY - JOUR

T1 - Complement component C3 as a new target to lower albuminuria in hypertensive kidney disease

AU - Bode, Marlies

AU - Diemer, Jan Niklas

AU - Luu, The Vinh

AU - Ehnert, Nikolas

AU - Teigeler, Teresa

AU - Wiech, Thorsten

AU - Lindenmeyer, Maja T

AU - Herrnstadt, Georg R

AU - Bülow, Jasmin

AU - Huber, Tobias B

AU - Tomas, Nicola M

AU - Wenzel, Ulrich O

N1 - © 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

PY - 2023/9

Y1 - 2023/9

N2 - BACKGROUND AND PURPOSE: Complement activation may drive hypertension through its effects on immunity and tissue integrity.EXPERIMENTAL APPROACH: We examined expression of C3, the central protein of the complement cascade, in hypertension.KEY RESULTS: Increased 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 IMPLICATIONS: Increased 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.

AB - BACKGROUND AND PURPOSE: Complement activation may drive hypertension through its effects on immunity and tissue integrity.EXPERIMENTAL APPROACH: We examined expression of C3, the central protein of the complement cascade, in hypertension.KEY RESULTS: Increased 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 IMPLICATIONS: Increased 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.

U2 - 10.1111/bph.16097

DO - 10.1111/bph.16097

M3 - SCORING: Journal article

C2 - 37076314

VL - 180

SP - 2412

EP - 2435

JO - BRIT J PHARMACOL

JF - BRIT J PHARMACOL

SN - 0007-1188

IS - 18

ER -