Pathophysiology of Unilateral Ischemia-Reperfusion Injury: Importance of Renal Counterbalance and Implications for the AKI-CKD Transition
Unilateral ischemia-reperfusion (UIR) injury leads to progressive renal atrophy and tubulointerstitial fibrosis (TIF) and is commonly used to investigate the pathogenesis of the acute kidney injury-chronic kidney disease transition. Although it is well known that contralateral nephrectomy (CNX), even 2 wk post-UIR injury, can improve recovery, the physiological mechanisms and tubular signaling pathways mediating such improved recovery remain poorly defined. Here, we examined the renal hemodynamic and tubular signaling pathways associated with UIR injury and its reversal by CNX. Male Sprague-Dawley rats underwent left UIR or sham UIR and 2 wk later CNX or sham CNX. Blood pressure, left renal blood flow (RBF), and total glomerular filtration rate were assessed in conscious rats for 3 days before and over 2 wk after CNX or sham CNX. In the presence of a contralateral uninjured kidney, left RBF was lower (P < 0.05) from 2 to 4 wk following UIR (3.6 + 0.3 mL/min) versus sham UIR (9.6 + 0.3 mL/min). Without CNX, extensive renal atrophy, TIF, and tubule dedifferentiation, but minimal pimonidazole and hypoxia-inducible factor-1α positivity in tubules, were present at 4 wk post-UIR injury. Conversely, CNX led (P < 0.05) to sustained increases in left RBF (6.2 ∓ 0.6 mL/min) that preceded the increases in glomerular filtration rate. The CNX-induced improvement in renal function was associated with renal hypertrophy, more redifferentiated tubules, less TIF, and robust pimonidazole and hypoxia-inducible factor-1α staining in UIR injured kidneys. Thus, contrary to expectations, indexes of hypoxia are not observed with the extensive TIF at 4 wk post-UIR injury in the absence of CNX but are rather associated with the improved recovery of renal function and structure following CNX.
Polichnowski, Aaron J.; Griffin, Karen A.; Licea-Vargas, Hector; Lan, Rongpei; Picken, Maria M.; Long, Jainrui; Williamson, Geoffrey A.; Rosenberger, Christian; Mathia, Susanne; Venkatachalam, Manjeri A.; and Bidani, Anil K.. 2020. Pathophysiology of Unilateral Ischemia-Reperfusion Injury: Importance of Renal Counterbalance and Implications for the AKI-CKD Transition. American Journal of Physiology - Renal Physiology. Vol.318(5). F1086-F1099. https://doi.org/10.1152/ajprenal.00590.2019 PMID: 32174143 ISSN: 0363-6127