Aberrant Tubuloglomerular Feedback and HIF-1α Confer Resistance to Ischemia after Subtotal Nephrectomy

Abstract

Nephron loss in a diseased kidney invokes adaptations in the remaining nephrons. Whether and how these adaptations condition the response of the kidney to injury is not known. We examined the susceptibility of the kidney after subtotal (5/6th) nephrectomy (STN) to ischemic injury in rats. GFR in STN kidneys did not significantly change after ischemia reperfusion (IR), whereas GFR fell by 70% after IR in unilateral nephrectomy controls. In micropuncture experiments, single-nephron GFR responses mirrored the whole-kidney responses: in STN, single-nephron GFR decreased by 7% after IR compared with 28% in controls. Furthermore, we found that tubuloglomerular feedback, a mechanism that links proximal tubular injury to a fall in GFR, was inoperative in STN but was normal in controls. Restoration of normal feedback in STN attenuated the functional resistance to IR. In addition to the functional resilience, the morphology of the kidney was better preserved in STN. In STN kidneys, the S3 segment of the proximal tubule, normally injured after ischemia, constitutively expressed hypoxia-inducible factor-1a (HIF-1a), which is cytoprotective in ischemia. Inducing HIF before IR improved GFR in control animals, and inhibiting the HIF target hemeoxygenase-1 before IR reduced GFR in STN animals. Taken together, these data suggest that fewer functioning nephrons in a diseased kidney do not increase the susceptibility to injury, but rather, hemodynamic and molecular adaptations in the remnant nephrons precondition them against ischemic injury.

Severe Renal Mass Reduction Impairs Recovery and Promotes Fibrosis after AKI

“…9 Most prior investigations of the relationships between severe RMR and AKI were limited to the examination of acute injury, usually shorter than 40 minutes in duration, 24 hours after I/R. 14,16 In the only study where the impact of RMR on subsequent AKI was studied over longer periods, subtotal RMR by UNX+ablation/infarction 10 weeks before I/R decreased AKI severity compared with I/R of both intact kidneys, but AKI after I/R in UNX kidneys was more severe. 15 However, there were no differences in repair, which was essentially complete by 10 days in all groups.…”

“…13 AKI-CKD relationships have also been questioned on the grounds that mechanisms for AKI-CKD interactions are ill-defined and controversial. [14][15][16] We addressed these uncertainties by investigating the impact of normotensive renal mass reduction (RMR; 0%, 50%, and 75%) of 2-weeks duration on AKI induced by ischemia-reperfusion (I/R) in rats. We addressed three questions.…”

Renal Autoregulation in Health and Disease

“…Indeed, MD-TGF responses were effectively abolished within 7 days of RRM in most, but not all, rat nephrons (1372,1373). The immediate response of MD-TGF is less clear.…”

Renal Hemodynamics in AKI

“…15 Thus, although restoration of RBF and GFR might be a logical strategy in early prerenal states, hypofiltration mediated by the persistence of the tubuloglomerular feedback system may be protective in the presence of significant renal injury. 16 It must be stressed, however, that the importance of tubuloglomerular feedback in mediating the link between prominent decline in GFR and focal tubular injury has been suggested for ischemiareperfusion and nephrotoxic AKI 17,18 but remains unproven in models of septic AKI and clinical AKI caused by multiple insults. Finally, internephron heterogeneity, the focal distribution of lesions and accessibility limited to a subgroup of superficial nephrons, should be kept in mind when interpreting the results of micropuncture techniques.…”