Submitted on August 3, 2008
Revised on November 12, 2008
Accepted on November 21, 2008
Endothelial injury due to eNOS deficiency accelerates the progression of chronic renal disease in the mouse
Takahiro Nakayama1, Waichi Sato2, Tomoki Kosugi1, Li Zhang1, Martha Campbell-Thompson, Ashio Yoshimura3, Byron P Croker, Richard J Johnson1, and Takahiko Nakagawa4*
1 University of Florida
2 Nagoya Universtiy Graduate School of Medicine
3 Showa University Fujigaoka Hospital
4 University of Colorado Denver
* To whom correspondence should be addressed. E-mail: TAKAHIKO.NAKAGAWA{at}UCHSC.EDU.
The vascular endothelium expresses endothelial nitric oxide synthase (eNOS) which generates nitric oxide (NO) to help maintain vascular integrity due to its anti-inflammatory, antiproliferative and antithrombogenic effects. Pharmacologic blockade of NO production has been shown to exacerbate renal injury in chronic renal disease and induces endothelial cell loss. However, pharmacological inhibition of NO nonspecifically blocks other types of NOS, and therefore does not define the specific role of eNOS in kidney disease. We hypothesized that a lack of endothelial eNOS can induce a loss of glomerular capillary and peritubular capillary endothelium and to exacerbate renal disease in progressive renal disease. We tested out hypothesis using the mouse remnant kidney (RK). Systolic blood pressure was significantly higher, and renal function was worse in RK-eNOSKO mice compared to those in RK-C57BL6 mice. eNOS deficiency resulted in more severe glomerulosclerosis, mesangiolysis and tubular damage. Glomerular and tubular macrophage infiltration and collagen deposition were also greater in RK-eNOSKO mice. Renal injuries in the RK-eNOS KO mice were accompanied by a greater loss of endothelial cells that was shown to be due to both a decrease in endothelial cell proliferation and an increase in apoptosis. A lack of eNOS accelerates both glomerular and tubulointerstitial injury with a loss of glomerular capillaries and peritubular capillaries. Impaired endothelial function is likely a direct risk factor for renal disease
