Low molecular weight proteinuria exacerbates experimental ischemic renal injury.
To determine whether tubular reabsorption of low molecular weight proteins (LMWPs) alters ischemic tubular injury, rats were infused with 25 mg of lysozyme (isoelectric point (pI) 11.3), cytochrome C (pI 10.6), ribonuclease (pI 8.7), or myoglobin (pI 7.0), and during this time 25 minutes of bilateral renal artery occlusion (RAO) was induced. RAO control rats received either saline or 25 mg of albumin. Renal injury was assessed 24 hours later by blood urea nitrogen, creatinine, and histology. Lysozyme, ribonuclease, and myoglobin each exacerbated ischemic damage (increased tubular necrosis, cast formation, azotemia), but to comparable degrees (e.g., blood urea nitrogen range 75 +/- 8 to 100 +/- 5 mg/dl versus controls, 29 +/- 2 to 36 +/- 7; p less than 0.01). Rendering lysozyme anionic (pI 4.5) by succinylation did not diminish its acute renal failure-potentiating effect. Cytochrome C which is freely filtered but poorly reabsorbed had a minimal impact on the ischemic process. Infusion of LMWPs did not alter blood pressure, renal blood flow, or induce renal injury in the absence of RAO. During a sublethal ischemic event (10 minutes of RAO) LMWP infusion exacerbated proximal tubular luminal membrane damage before an adverse effect on other critical determinants of cell integrity were apparent (adenine nucleotide pools, oxidant stress). We conclude that endocytic LMWP reabsorption by proximal tubules can exacerbate superimposed ischemic tubular necrosis independent of any direct nephrotoxic protein effect. This action is not influenced by protein isoelectric point and appears to be mediated by a primary intensification of ischemic luminal membrane damage.
D000818:Animals; D001794:Blood Pressure; D005260:Female; D007511:Ischemia / Q000150:complications / Q000503:physiopathology*; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D008970:Molecular Weight; D011507:Proteinuria / Q000150:complications / Q000503:physiopathology*; D051381:Rats; D011919:Rats, Inbred Strains; D012039:Regional Blood Flow; D012077:Renal Artery / Q000502:physiology; D012079:Renal Circulation